@article {pmid41205698, year = {2025}, author = {Dunk, MM and Delac, L and Rapp, SR and Driscoll, I and Latorre-Leal, M and Farland, LV and Haring, B and Harris, HR and Jung, SY and Manson, JE and Ochs-Balcom, HM and Shadyab, AH and Weitlauf, JC and Xu, H and Maioli, S}, title = {Exploring biomarkers of neurodegenerative risk: Associations of oxysterols, sex hormones, and reproductive characteristics in older women.}, journal = {Journal of lipid research}, volume = {}, number = {}, pages = {100938}, doi = {10.1016/j.jlr.2025.100938}, pmid = {41205698}, issn = {1539-7262}, abstract = {Women face a higher lifetime risk of developing neurodegenerative diseases such as Alzheimer's disease (AD) and related dementia (ADRD). The menopausal transition, characterized by a decline in estrogen levels, may affect cholesterol metabolism and neurodegenerative processes. Oxysterols, oxidized cholesterol derivatives, play a role in these pathways, with 24(S)-hydroxycholesterol (24HC) reflecting brain cholesterol turnover and 27-hydroxycholesterol (27HC) linked to systemic cholesterol metabolism. We investigated associations of plasma oxysterols with circulating sex hormones and characteristics of reproductive history in 1,974 postmenopausal women with no history of dementia from the Women's Health Initiative, taking into account APOE4 status and cholesterol-lowering medication. We found that higher levels of bioavailable estradiol were associated with higher 24HC and 27HC levels, and higher estrone was associated with higher 24HC (all p-values < 0.05). Associations of estradiol with 24HC and 27HC were stronger among those not using cholesterol medication and APOE4 carriers, with a significant interaction between 27HC and APOE4 in relation to 27HC (p for interaction = 0.04). Having an older age at menopause was associated with lower 24HC among those taking cholesterol medication (p for interaction = 0.03). Our findings suggest that 24HC and 27HC may be proxy biomarkers of neuronal health and estrogen status in postmenopausal women. The stronger associations between estradiol and oxysterols among APOE4 carriers and those not using cholesterol-lowering medication suggest the need to account for hormonal, genetic, and pharmacological factors when evaluating neurodegenerative risk. Longitudinal studies are warranted to further investigate oxysterols as potential early biomarkers of ADRD risk.}, }
@article {pmid41203676, year = {2025}, author = {Duggan, C and de Dieu Tapsoba, J and Warner, J and Dash, A and Wang, CY and McTiernan, A}, title = {Effects of acute exercise on inflammatory and metabolic biomarkers in women: a randomized controlled trial.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {122}, pmid = {41203676}, issn = {2374-4677}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; BRCF-18-107; BCRF-19-107; BCRF-20-107; BRCF-21-107; BRCF-22;107//Breast Cancer Research Foundation,United States/ ; }, abstract = {Mechanisms linking exercise to reduced breast cancer risk are poorly understood. 103 healthy women, 18-75, were randomized to 45-minutes of acute exercise at 60% VO2max (N = 54, intervention), or 45-minutes of rest (N = 49, control). Blood samples were collected at baseline, 45- and 105-minutes, analytes measured by immunoassay, and mean changes from baseline to 45- and 105-minutes modelled using generalized estimating equations, adjusted for confounders. Mean percent changes levels (Δ%) increased in exercisers vs. controls for monocyte chemoattractant protein (MCP)-1 Δ[45 min] + 17.1% (P < 0.0001), Δ[105 min] + 12.0% (P = 0.005); interleukin(IL)-6, Δ[45 min] + 103.5%, Δ[105 min] + 92.3%; and at 45-minutes for glucose Δ[45 min] + 8.8%; insulin Δ[45 min] + 82.4% (all P < 0.0001). Differences between arms for vascular endothelial growth factor (VEGF) Δ[45 min] + 9.8%; c-reactive protein Δ[45 min]-6.6%; irisin Δ[45 min]-5.1%; or plasminogen activator inhibitor (PAI)-1, Δ[45 min]-3.6% were non-statistically significant, with similar results at 105-minutes. Results suggest that acute exercise has specific effects on circulating metabolic and inflammatory biomarkers, implicated in breast cancer etiology, which differ from weight-loss-induced changes. Trial registration: Clincialtrials.gov identifier NCT03779867.}, }
@article {pmid41202991, year = {2025}, author = {Gillespie, EF and Silverwood, S and Lapen, K and Verdini, NP and Bryl, K and Baser, RE and Khan, AJ and Mao, JJ}, title = {A virtual mind-body exercise program during breast radiation: Results from a randomized controlled basket trial.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.10.036}, pmid = {41202991}, issn = {1879-355X}, abstract = {BACKGROUND: National guidelines recommend fitness and mind-body exercise to reduce cancer-related fatigue, but substantial barriers to implementation exist. Virtual programs offer a scalable approach to address this gap. This study aims to evaluate efficacy of a virtual fitness and mind-body exercise program (Integrative Medicine at Home, IM@Home) in reducing fatigue in patients undergoing radiation therapy (RT) for breast cancer.
METHODS: A prospective randomized controlled patient-reported outcome (PRO)-basket clinical trial was conducted. Patients undergoing breast RT who reported moderate or greater fatigue were randomly assigned 1:1 ratio to either IM@Home, which provided live virtual fitness and mind-body exercise classes, or enhanced usual care (EUC). The primary outcome, fatigue, was measured using total Brief Fatigue Inventory (BFI), a composite score including severity and impact on daily functioning, weekly over 12 weeks. Secondary outcomes included Insomnia Severity Index (ISI), Edmonton Symptom Assessment Scale (ESAS), and Hospital Anxiety and Depression Scale (HADS) collected every 4 weeks. Statistical analysis included linear mixed models to compare group differences over time using statistical significance threshold of p < 0.05.
RESULTS: Among 73 enrolled patients, 35 were randomly assigned to IM@Home and 38 to EUC. At week 12, patients in the IM@Home group had significantly less fatigue compared to those in the EUC group (2.06 vs 2.79, p=0.009). Compared to EUC, patients in the IM@Home group showed greater reductions in insomnia (p=0.005), symptom distress (p=0.013), and depression (p=0.04) but not anxiety (p=0.14).
CONCLUSIONS: The IM@Home program significantly reduced fatigue and co-morbid symptoms among women with breast cancer undergoing RT. Future research is needed to confirm these findings, explore mechanisms of the observed benefit, and evaluate scalability as well as barriers and facilitators to implementation.
GOV IDENTIFIER: NCT05053230.}, }
@article {pmid41202812, year = {2025}, author = {Hoi, XP and Stangis, MM and Glass, SE and Kim, JH and Kang, SW and Brennen, WN and Li, Z and Grady, WM and Yegnasubramanian, S and Kuhn, P and Lyssiotis, CA and Sagara, A and Shrubsole, MJ and Kadara, H and Yuan, Y and Coffey, RJ and Lau, KS and De Marzo, AM and Maitra, A and Min, J and Yu, M and Chan, KS and , }, title = {Cellular senescence in precancer lesions and early-stage cancers.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2025.10.006}, pmid = {41202812}, issn = {1878-3686}, abstract = {Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.}, }
@article {pmid41201469, year = {2025}, author = {Damle, SR and Carter, JA and Goodsell, KE and Pineda, JMB and Dickerson, LK and Jiang, X and Mudd, JL and Walsh, T and Kenerson, HL and Cernak, J and Chauhan, SSB and Beirne, E and Jana, S and Koehne, AL and Vij, KR and Ruzinova, MB and Yeung, R and Akilesh, S and Collisson, EA and Fields, RC and Crispe, IN and Pillarisetty, VG}, title = {Intratumoral three-cell-type clusters are a conserved feature of endogenous antitumor immunity.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-25-0062}, pmid = {41201469}, issn = {2326-6074}, abstract = {Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial colocalization of dendritic cells (DCs), helper T cells (Th), and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. Herein, we report the integration of more than one million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma (PDAC). We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules (mregDC), CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.}, }
@article {pmid41201189, year = {2025}, author = {Meyer, J and Tran, A and Ma, TM and Chiang, BH and Egan, T and Chen, JJ and Tao, Y and Cao, N and Kim, KH and Liao, JJ and Koufigar, S and Vuong, W and Weg, ES}, title = {A hybrid IGRT workflow using SGRT and CBCT for prostate SBRT: Feasibility, efficiency, and safety.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {11}, pages = {e70339}, pmid = {41201189}, issn = {1526-9914}, mesh = {Humans ; Male ; *Prostatic Neoplasms/surgery/diagnostic imaging/radiotherapy ; *Cone-Beam Computed Tomography/methods ; *Radiosurgery/methods ; *Radiotherapy Planning, Computer-Assisted/methods ; *Workflow ; Radiotherapy Dosage ; *Radiotherapy, Intensity-Modulated/methods ; Feasibility Studies ; Prospective Studies ; *Radiotherapy, Image-Guided/methods ; Organs at Risk/radiation effects ; Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {BACKGROUND AND PURPOSE: Safe delivery of prostate stereotactic body radiotherapy (SBRT) relies on precise target localization. Without access to real-time intrafraction motion management, careful optimization of IGRT protocols is necessary to safeguard treatment accuracy and patient outcomes.
METHODS: An IGRT workflow is proposed that incorporates surface-monitoring (SGRT) to complement cone-beam CT (CBCT) imaging. The study evaluates 23 consecutive SBRT prostate patients who were treated on a prospective registry study. Each patient received pre- and mid-treatment and a subset received post-treatment CBCTs. The frequency and magnitude of SGRT triggered beam interruptions as well as treatment times were recorded.
RESULTS: The median number of CBCTs acquired per fraction was four and the median treatment time was 23 min (IQR 19-27). SGRT detected intra-fraction surface-based motion beyond a combined 4 mm vector isocenter tolerance in 62% of all fractions treated, with a maximum motion of 15 mm. On average < 2 beam interruptions were triggered by SGRT per treatment fraction. There was no statistically significant correlation between overall treatment time and SGRT-triggered beam interruptions (r = 0.048, p = 0.645). There was a weak but statistically relevant correlation of overall treatment time with the maximum detected motion (r = 0.23, p = 0.026). SGRT detected five fractions where the patients had persistently moved outside the SGRT tolerance, and for three of these (60%), a CBCT verified that the target was out of tolerance.
CONCLUSION: SGRT is a valuable tool that complements CBCT-based IGRT. An SGRT motion vector tolerance of 4 mm provides a pragmatic compromise between detecting patient motion and treatment efficiency. Overall, persistent patient motion during treatment was infrequent in this cohort, however, SGRT was able to detect several cases where the internal target was outside of the tolerance highlighting that patient monitoring with SGRT can contribute to improved quality and safety for prostate SBRT.}, }
@article {pmid41198236, year = {2025}, author = {Mirshahvalad, SA and Iravani, A and Fendler, WP and Maurer, T and Eiber, M and Sharifian, F and Manoochehry, S and Rendl, G and Schweighofer-Zwink, G and Pirich, C and Sathekge, M and Beheshti, M}, title = {Rechallenge and Extended [[177]Lu]Lu-PSMA Therapy in Metastatic Prostate Cancer.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.270889}, pmid = {41198236}, issn = {1535-5667}, abstract = {Continuation of effective and well-tolerated systemic treatment is often performed in care for metastatic castration-resistant prostate cancer. Likewise, continued administration of [[177]Lu]Lu-PSMA radiopharmaceutical therapy beyond the approved number of cycles holds promising potential to enhance therapeutic efficacy. Rechallenge therapy involves readministration of [[177]Lu]Lu-PSMA cycles after a break, whereas extended therapy continues treatment beyond the standard 6 cycles without interruption. Both approaches aim to improve disease control and prolong survival in patients with metastatic castration-resistant prostate cancer. However, practices vary: some clinicians continue treatment in patients with early favorable responses, whereas others recommend pausing therapy after significant prostate-specific antigen declines, even after a few cycles. In this narrative review, we show that safety profiles for continued [[177]Lu]Lu-PSMA radiopharmaceutical therapy are generally favorable, and most adverse events are mild to moderate in severity. Hematotoxicity, particularly anemia and thrombocytopenia, is the most significant concern, with few patients experiencing high-grade adverse events. In addition, cumulative irradiation, particularly during extended therapy, necessitates careful monitoring of hematologic and renal function. Biochemical responses to rechallenge and extended [[177]Lu]Lu-PSMA therapy are promising, with at least 50% reductions in prostate-specific antigen levels observed in a significant proportion of highly selected patients. Moreover, survival outcomes are encouraging, showing the extension of overall and progression-free survival beyond the known data for standard therapy. Despite these advances, challenges remain in optimizing patient selection, managing cumulative toxicities, and harmonizing treatment protocols. In addition, variability in trial designs, influenced by international regulatory differences, limits the current evidence and necessitates consideration of each treatment approach within its regulatory context. Prospective studies are needed to refine therapeutic strategies, implement consistent clinical and imaging response criteria, and identify predictive biomarkers to improve both efficacy and safety.}, }
@article {pmid41196629, year = {2025}, author = {Mehta, RS and Sparapani, RA and Kanakry, CG and McCurdy, SR and Saultz, J and Lazaryan, A and Milano, F and Lee, SJ}, title = {Unrelated Donor Age and Recipient Outcomes After Posttransplant Cyclophosphamide vs Conventional Prophylaxis.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {41196629}, issn = {2374-2445}, abstract = {IMPORTANCE: Advanced age in unrelated donors (URDs) is a well-established risk factor in allogeneic hematopoietic cell transplant (HCT), leading registries to prioritize younger donors. However, this paradigm relevance is uncertain in the era of posttransplant cyclophosphamide (PTCy) for graft-vs-host disease (GVHD) prophylaxis, a strategy increasingly adopted for its effectiveness. Clarifying this association is crucial for optimizing donor selection and potentially expanding the donor pool.
OBJECTIVE: To determine whether the association of older URD age with overall survival differs between patients receiving PTCy-based vs conventional calcineurin inhibitor (CNI)-based GVHD prophylaxis.
This was a multicenter cohort study using registry data from the Center for International Blood and Marrow Transplant Research for January 2017 through June 2021. Eligible participants were adult patients with acute leukemia or myelodysplastic syndrome who underwent an allogeneic HCT from a URD who was fully matched for 8 of 8 human leukocyte antigen loci (MUD) or mismatched for 7 of 8 human leukocyte antigen loci (MMUD). Data were analyzed from January to June 2025.
EXPOSURES: GVHD prophylaxis regimen (PTCy-based vs CNI-based) and donor age (analyzed continuously and categorically).
MAIN OUTCOMES AND MEASURES: Overall survival was the primary outcome, with associations assessed using a multipronged approach including least absolute shrinkage and selection operator (LASSO)-penalized Cox proportional hazards models, inverse probability of treatment weighting (IPTW), and XGBoost machine learning.
RESULTS: The study analysis included 10 025 patients (mean [SD] age, 56.5 [14.4] years; 4379 female [43.7%] and 5646 male [56.3%] individuals) among whom 7272 (72.5%) had received MUD-CNI; 1681 (16.8%%) MUD-PTCy; 613 (6.1%) MMUD-PTCy; and 459 (4.6%) MMUD-CNI. Increasing donor age was associated with worse OS in CNI-based MUD (hazard ratio [HR], 1.004-1.009 per year increase) and MMUD (HR, 1.022-1.034) cohorts. Conversely, this association was not observed in the combined PTCy cohort (HR, 1.001-1.007). These findings were robust across standard and overlap weighted IPTW, LASSO-penalized models, and XGBoost analyses. The attenuated association in the PTCy cohort was primarily driven by a lack of association between donor age and nonrelapse mortality.
CONCLUSIONS AND RELEVANCE: The findings of this cohort study indicate that the association of donor age with URD HCT outcomes appears to be mitigated in the PTCy setting, suggesting that PTCy may counteract some of the adverse effects associated with increased unrelated donor age. This observation challenges existing paradigms and warrants validation in independent cohorts, and if validated, could substantially expand the donor pool.}, }
@article {pmid41195517, year = {2025}, author = {Patel, J and Gopal, A and Cherniawsky, H and Ram, R and Kamble, R and Hamadani, M}, title = {CD19 directed CAR T therapy for intravascular large B-cell lymphoma.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288838}, pmid = {41195517}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41193657, year = {2025}, author = {Li, H and Melnyk, JE and Fu, BXH and Shrestha, R and Zhang, M and Sjöström, M and Feng, S and Anderson, JA and Han, W and Chesner, LN and Shin, HJ and Farsh, T and Suarez, HJ and Nath, S and Chou, J and Das, R and Egusa, EA and Calvert, M and Kishishita, A and Barpanda, A and Zhu, J and Maheshwari, A and Chen, WS and Alshalalfa, M and Winters, A and Hua, JT and Liu, T and Davicioni, E and Wiita, AP and Stohr, BA and Siddiqui, J and Huang, B and Small, EJ and Shokat, KM and Nelson, PS and Quigley, DA and Wasmuth, EV and Gilbert, LA and Feng, FY}, title = {Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {41193657}, issn = {1546-1718}, support = {21YOUN12//Prostate Cancer Foundation (PCF)/ ; Young Investigator Award//Prostate Cancer Foundation (PCF)/ ; YI//Prostate Cancer Foundation (PCF)/ ; PC230420//Prostate Cancer Foundation (PCF)/ ; young investigator//Prostate Cancer Foundation (PCF)/ ; 17CHAL06//Prostate Cancer Foundation (PCF)/ ; CA204602//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P50CA097186 PNW Prostate Cancer SPORE Career Enhancement Program//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 1F32CA236347-01//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA230516-02S1//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 1R01CA221969-01//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 1R01CA244550//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; 1R01CA230516-01//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 1R01CA227025//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P50CA186786//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; DP2 CA239597/CA/NCI NIH HHS/United States ; Prostate Cancer Program 2021 Pilot Research Awards//UC | UC San Francisco | Department of Medicine, University of California, San Francisco (UCSF Department of Medicine)/ ; 2018-00382//Vetenskapsrådet (Swedish Research Council)/ ; HT9425-23-1-0462//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH-20-1-0136//U.S. Department of Defense (United States Department of Defense)/ ; R01GM124334//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM131641//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R00 GM140264/GM/NIGMS NIH HHS/United States ; V2024-016//V Foundation for Cancer Research (V Foundation)/ ; }, abstract = {The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3-a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.}, }
@article {pmid41193051, year = {2025}, author = {, and Morgan, RL and Bathala, TK and Arora, SS and Chandhok, N and Corey, AS and Dandapani, SV and Kim, L and Law, L and Mansoori, B and Morin, CE and Trout, AT and Wolfman, DJ and Wong, TZ}, title = {ACR Appropriateness Criteria® Staging and Follow-Up of Leukemia.}, journal = {Journal of the American College of Radiology : JACR}, volume = {22}, number = {11S}, pages = {S658-S688}, doi = {10.1016/j.jacr.2025.08.034}, pmid = {41193051}, issn = {1558-349X}, mesh = {Humans ; Neoplasm Staging ; United States ; *Leukemia/diagnostic imaging/pathology ; Societies, Medical ; Evidence-Based Medicine ; Follow-Up Studies ; *Practice Guidelines as Topic ; }, abstract = {Imaging associated with staging and follow-up of leukemia can play an important role in accurately assessing disease; however, the type of imaging and usefulness varies significantly by the subtype of leukemia. This document reviews the current literature regarding the impact of imaging for both staging and surveillance of several of the most common leukemic variants. These include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, Richter transformation, and chronic myeloid leukemia. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.}, }
@article {pmid41192776, year = {2025}, author = {Abrams, HR and Starks, H and Bandini, L and Harrington, T and Percival, MM and Walter, RB and Russell, K and Mawad, R and Appelbaum, J and Sorror, ML and Halpern, AB}, title = {National Landscape of Logistical and Non-Medical Requirements for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.10.031}, pmid = {41192776}, issn = {2666-6367}, abstract = {BACKGROUND: New disease indications and supportive care advances have expanded the populations who may benefit from cellular therapies, including autologous or allogeneic hematopoietic cell transplant (HCT) and/or chimeric antigen receptor T-cell therapy (CAR T). However, non-medical requirements for these therapies, such as caregiver and housing availability, may limit access. We sought a detailed national assessment of non-medical requirements for HCT and CAR T-cell therapy to describe and quantify barriers.
OBJECTIVE: Describe the national landscape and implementation of logistical and non-medical requirements for HCT and CAR T-cell therapy.
STUDY DESIGN: We developed a web-based survey of HCT/CAR T-cell therapy requirements and obtained pilot feedback from three centers that regularly perform HCT/CAR T-cell therapy. We distributed the survey via the NCCN Best Practices Committee, which is composed of physician, nursing, and administrative leaders from 34 member institutions. We requested survey completion by an institutional content area expert.
RESULTS: The response rate was 91% (31/34). >80% of centers required a caregiver, local housing, and local transportation, but the number of days required, institutional supports, and acceptable distances varied widely. A subset of centers offered 'all-outpatient' procedures and required more stringent logistical criteria, including autologous HCT by 13/19 centers (68%), allogeneic HCT by 4/8 centers (50%), and CAR T-cell therapy by 10/16 centers (63%). Many centers excluded patients with a history of medication nonadherence, substance use, or psychiatric comorbidity, but most did not employ formal adjudication or definition of patient eligibility. Institutions noted "soft" contraindications or case-by-case review for these patients and those experiencing homelessness, lack of insurance, or without citizenship. Overall, caregiving, housing, cost, and insurance coverage emerged as the top non-medical barriers to HCT and CAR T-cell therapy.
CONCLUSIONS: Significant variability exists in non-medical requirements for HCT and CAR T-cell therapy, with a lack of standard policies across institutions. We recommend that centers formally track reasons for non-eligibility to identify non-medical barriers to HCT and CAR T-cell therapy and develop targeted interventions to reduce the number of patients who are excluded for non-medical reasons.}, }
@article {pmid41191519, year = {2025}, author = {Farhadfar, N and El Jurdi, N and Baker, K and Ghosh, S and Bat-Erdene, M and Chen, H and Sahu, R and Weiss, R and Mi, J and Desatnik, G and Williams, LR and Tkaczyk, ER and Lee, SJ}, title = {Reproducibility and repeatability of the Myoton to quantify sclerotic chronic graft-versus-host disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016648}, pmid = {41191519}, issn = {2473-9537}, abstract = {Validated tools to measure sclerotic cutaneous chronic Graft-versus-Host Disease (scGVHD) is an urgent need. We examined the inter-observer reproducibility within a session and intra-observer repeatability between sessions of the Myoton device for quantifying skin sclerosis in 36 adults with scGVHD. The Myoton was used to measure oscillation frequency and relaxation time of soft tissues at 7 bilateral sites (14 anatomic sites) by two study personnel at two study sessions. Agreement was measured with mean pairwise absolute difference (MPD), and reliability was measured with intraclass correlation coefficient (ICC). For each of the two Myoton parameters, the overall inter-observer MPD was less than 5% of the average overall values and the inter-observer ICC was greater than 0.90 between the two observers, indicating excellent agreement and reliability within a measurement session. The median time between session 1 and session 2 was 47.5 days. The overall normalized intra-observer MPD was less than 7% of the average overall values for each of the two Myoton parameters, reflecting good agreement between sessions. The intra-observer ICC for frequency and relaxation time parameters were 0.85 and 0.84, respectively, indicating good reliability between sessions. Reproducibility and repeatability of a bonus site selected at each study visit was similar to the standard 14 anatomic sites. However, no individual site was nearly as reproducible or repeatable as the overall Myoton measurements averaged across the patient. Our findings emphasize the utility of the Myoton for assessing skin properties in scGVHD with patient-level measurements.}, }
@article {pmid41190251, year = {2025}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Bricker, JB}, title = {Does living near a tobacco retailer impact the efficacy of smoking cessation treatments?: Analysis from a randomized trial.}, journal = {Addictive behaviors reports}, volume = {22}, number = {}, pages = {100635}, pmid = {41190251}, issn = {2352-8532}, abstract = {INTRODUCTION: Whether living near a tobacco retailer impacts the efficacy of smoking cessation treatments remains largely unknown. We used data from a randomized trial comparing two smoking cessation apps among 2415 adults: iCanQuit, based on Acceptance and Commitment Therapy, and QuitGuide, based on standard U.S. Clinical Practice Guidelines. We examined whether tobacco retailer density impacted the efficacy of the treatments on 12-month cessation outcomes.
METHODS: Data on tobacco retailer density per 1,000 people (i.e., "one unit") was linked to each participant's residential ZIP Code. Cessation outcomes included 30-day point prevalence abstinence (PPA) from cigarette smoking, prolonged abstinence, 30-day PPA from nicotine/tobacco products, and relapse. We examined the interaction between density and treatment arm on 12-month 30-day PPA and compared cessation outcomes separately by arm.
RESULTS: The interaction between density and treatment arm on cessation did not reach statistical significance (P = 0.09). For each one-unit increase in density, there was no change in quit rates in the iCanQuit arm (P = 0.62). In the QuitGuide arm, higher density was associated with lower quit rates (OR = 0.54; 95 % CI, 0.27-1.06; P = 0.07), although not-statistically significant. There was a significant interaction between density and treatment arm on prolonged cigarette abstinence (P = 0.03). We found no change in prolonged abstinence in the iCanQuit arm (P = 0.44). In the QuitGuide arm, higher density was associated with lower prolonged abstinence (OR = 0.27; 95 % CI, 0.07-1.02; P = 0.054), although not-statistically significant. Conclusions: Living near tobacco retailers may undermine the effectiveness of standard behavioral treatment but appears to have no impact on the effectiveness of acceptance-based smoking cessation treatments.}, }
@article {pmid41187759, year = {2025}, author = {Qi, G and Lila, E and Ji, Z and Shojaie, A and Battle, A and Sun, W}, title = {Transcriptome-wide association studies at cell-state level using single-cell eQTL data.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {101060}, doi = {10.1016/j.xgen.2025.101060}, pmid = {41187759}, issn = {2666-979X}, abstract = {Transcriptome-wide association studies (TWASs) are widely used to prioritize genes for diseases. Current methods test gene-disease associations at the bulk tissue or cell-type-specific pseudobulk level, which do not account for the heterogeneity within cell types. We present TWiST, a statistical method for TWAS at cell-state resolution using single-cell expression quantitative trait locus (eQTL) data. Our method uses pseudotime to represent cell states and models the effect of gene expression on the trait as a continuous pseudotemporal curve. Therefore, it allows flexible hypothesis testing of global, dynamic, and nonlinear associations. Through simulation studies and real data analysis, we demonstrated that TWiST leads to significantly improved power compared to pseudobulk methods. Application to the OneK1K study identified hundreds of genes with dynamic effects on autoimmune diseases along the trajectory of immune cell differentiation. TWiST presents great promise to understand disease genetics using single-cell studies.}, }
@article {pmid41187375, year = {2025}, author = {Bashi, A and Chen, L and Rouse, K and Elkin, EB and Ferris, JS and Xu, X and Bickell, NA and Blank, S and Rossi, EC and Hazelton, WD and Wright, JD and Havrilesky, LJ and Myers, ER}, title = {Cost-effectiveness of biomarker-based and universal strategies for the treatment of advanced-stage endometrial cancer.}, journal = {Gynecologic oncology}, volume = {203}, number = {}, pages = {130-138}, doi = {10.1016/j.ygyno.2025.09.019}, pmid = {41187375}, issn = {1095-6859}, abstract = {OBJECTIVE: To compare cost-effectiveness of targeted therapeutic strategies for non-Hispanic Black (NHB) and non-Hispanic White (NHB) patients with newly diagnosed, advanced-stage endometrial cancer.
METHODS: A Markov-based cost-utility model using a third-party payer perspective compared concurrent and maintenance treatment strategies incorporating dostarlimab and trastuzumab for newly diagnosed stage III-IV endometrial cancer: chemotherapy alone; 3 universal immunotherapy strategies (universal concurrent and maintenance dostarlimab +/- trastuzumab for HER2/neu-positive serous and/or carcinosarcomas); and 3 targeted immunotherapy strategies (dostarlimab for mismatch repair deficient (dMMR) tumors +/- trastuzumab for HER2/neu positive serous and/or carcinosarcomas). Costs (2024 USD), utilities, and clinical estimates were derived from published literature and the National Cancer Database. The base case analysis was a microsimulation with 10,000 runs, accompanied by a Monte Carlo probabilistic sensitivity analysis with 20,000 trials. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $150,000/quality-adjusted life year (QALY). We performed one-way and two-way sensitivity analyses on key parameters and analyses stratified by race/ethnicity.
RESULTS: All targeted immunotherapy strategies were cost-effective compared to chemotherapy alone in both NHB and NHW, while universal immunotherapy was never cost-effective. Targeted strategies were more cost-effective in NHB than NHW. Targeted dostarlimab for dMMR plus trastuzumab for HER2 serous and carcinosarcomas was the most cost-effective strategy compared to chemotherapy, with an ICER of $119,945/QALY. In sensitivity analysis, assuming longer durations of treatment benefit resulted in lower ICERs.
CONCLUSIONS: Personalized treatment strategies incorporating HER2 and MMR testing should be considered to optimize both cost-effectiveness and equity in care.}, }
@article {pmid41187024, year = {2025}, author = {Pareek, A and Nguyen, E and Rashidi, A}, title = {Successful Treatment of Steroid-refractory Acute Graft-versus-host Disease With Ruxolitinib in a Liver Transplant Recipient.}, journal = {Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1097/TP.0000000000005563}, pmid = {41187024}, issn = {1534-6080}, }
@article {pmid41183215, year = {2025}, author = {Teets, E and Singhvi, A}, title = {Changing minds epigenetically: Germline genes in neurons disrupt animal behavior.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {45}, pages = {e2525456122}, doi = {10.1073/pnas.2525456122}, pmid = {41183215}, issn = {1091-6490}, support = {T32AG066574//HHS | NIH | National Institute on Aging (NIA)/ ; NS114222//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; BRFSG-2023-10//Brain Research Foundation (BRF)/ ; 227823//Esther A. and Joseph Klingenstein Fund (EAJK Fund)/ ; 50005899//Washington Research Foundation (WRF)/ ; }, }
@article {pmid41180139, year = {2025}, author = {Terry, KL and Shafrir, A and Laliberte, A and Vitonis, AF and Garbutt, K and DePari, M and Becker, C and Sasamoto, N and Zondervan, KT and Missmer, SA}, title = {Circulating inflammatory biomarkers and endometriosis lesion characteristics in the WisE consortium.}, journal = {npj women's health}, volume = {3}, number = {1}, pages = {62}, pmid = {41180139}, issn = {2948-1716}, abstract = {Endometriosis is a chronic inflammatory condition requiring surgical or imaging visualization for definitive diagnosis. How endometriotic lesion characteristics relate to circulating inflammatory markers remains unclear. We evaluated 11 inflammatory biomarkers, including interleukin (IL)-1β, -6, -8, -10, -16, tumor necrosis factor (TNF)-α, thymus and activation regulated chemokine (TARC), monocyte chemotactic protein (MCP)-1, -4, and Interferon gamma-induced protein (IP)-10, in 566 participants with endometriosis from the Women's Health Study: From Adolescence to Adulthood (A2A), Endometriosis Oxford Care & Research (CaRe) study (ENDOX) and Endometriosis: Natural History, Diagnosis, and Outcome (ENDO) study to evaluate associations with endometriosis characteristics, including macrophenotype (superficial lesions only, versus endometrioma and/or deep lesions), lesion appearance (color, vascularity), and anatomic location. We observed nominally statistically significant variation in circulating inflammatory markers by lesion color, vascularity, and location but no significant associations between circulating inflammatory markers and rASRM stage or macrophenotype, which could be due to a small number of participants with non-superficial lesions.}, }
@article {pmid41180007, year = {2025}, author = {Moore, HP and Fogel, JM and Marzinke, MA and Halvas, EK and Parikh, UM and Mellors, JW and Penrose, KJ and Seisa, M and Petropoulos, C and Price, AL and Moser, A and Wang, Z and McCauley, M and Valencia-Huamaní, J and Rinehart, AR and Rooney, JF and Soto-Torres, L and Grinsztejn, B and Landovitz, RJ and Eshleman, SH}, title = {Sustained HIV Suppression With Co-formulated Tenofovir Disoproxil Fumarate/Lamivudine/Dolutegravir in a Person With Transmitted Dolutegravir Resistance and Pretreatment Resistance to Lamivudine: a Case Report From HPTN 083.}, journal = {Open forum infectious diseases}, volume = {12}, number = {11}, pages = {ofaf645}, pmid = {41180007}, issn = {2328-8957}, abstract = {Integrase strand transfer inhibitors (INSTIs) are recommended in most first-line HIV treatment regimens. We describe a participant in a clinical trial with transmitted INSTI resistance. The participant had no history of INSTI use and had no evidence of INSTI exposure prior to HIV acquisition. Treatment with tenofovir disoproxil fumarate, lamivudine (3TC), and dolutegravir (DTG) was started 3 weeks after HIV diagnosis. Viral suppression was achieved within a year and was sustained for >3 years on treatment. Retrospective HIV genotyping of a pretreatment sample detected major resistance mutations in 3 drug classes, with predicted high-level resistance to DTG and 3TC. HIV phenotyping confirmed that the transmitted virus had DTG and 3TC resistance but retained susceptibility to DTG at higher drug concentrations. Pharmacologic testing indicated that the DTG concentrations observed in this case were sufficient to overcome the effects of 2 major baseline INSTI resistance mutations (G140S and Q148H).}, }
@article {pmid41180004, year = {2025}, author = {Sadowska-Klasa, A and Xie, H and Zamora, D and Waghmare, A and Hill, JA and Duke, ER and Green, ML and Oshima, MU and Sandmaier, BM and Jerome, KR and Leisenring, WM and Boeckh, M}, title = {Cytomegalovirus Viral Load Continues to Predict Poor Outcomes in Adults and Children Despite Improved Hematopoietic Cell Transplantation Success.}, journal = {Open forum infectious diseases}, volume = {12}, number = {11}, pages = {ofaf612}, pmid = {41180004}, issn = {2328-8957}, abstract = {BACKGROUND: Recent advances of graft-versus-host disease prevention strategies have led to improved overall survival after hematopoietic cell transplantation (HCT). Whether cytomegalovirus (CMV) viral load continues to predict CMV disease, overall mortality, and nonrelapse mortality is poorly defined.
METHODS: CMV-seropositive patients undergoing allogeneic HCT between 2007 and 2017 with weekly CMV DNA polymerase chain reaction surveillance and preemptive therapy were analyzed. Multivariate Cox proportional hazards models were used to estimate the association between CMV viral load by day 100 at different thresholds with CMV disease and overall and nonrelapse mortality up to 1 year post-HCT.
RESULTS: Of 1539 patients who received a transplant in the study period, 1349 survived >100 days after HCT and were included in the analyses. By day 100 post-HCT, CMV reactivation at any level was observed in 76%, with the lowest incidence at all levels in young children. Pediatric patients had significantly less CMV disease compared to the adult population. CMV reactivation was associated with a higher risk of CMV disease (adjusted hazard ratio, 6.8 [95% confidence interval, 3.54-13]); it was also associated with overall and nonrelapse mortality among day 100 survivors, although the association was diminished recently. The strongest correlation was still apparent between viral load and mortality in patients with a viral load >3 log10 and lymphocyte count <300 cells/μL.
CONCLUSIONS: CMV viral load continued to be a strong predictor for CMV disease. With improved transplantation techniques, the association of viral load with overall and nonrelapse mortality is diminished, but the effect was still present in patients with severe immunosuppression.}, }
@article {pmid41178673, year = {2025}, author = {Gong, IY and Rafinejad-Farahani, B and Majeed, H and Soto, MJ and Oza, A and Ehrlich, T and Fernandez Lynch, H and Guerra, CE and Lofters, A and Unger, JM and Conti, RM and Rosenthal, M and Rodin, D}, title = {Reporting and enrollment disparities in hematologic malignancy trials between 2000-2023.}, journal = {Leukemia & lymphoma}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/10428194.2025.2579735}, pmid = {41178673}, issn = {1029-2403}, abstract = {Despite initiatives to enhance diversity in clinical trials (CTs), disparities persist in hematologic malignancy (HM) studies. We reviewed 1,230 US-based phase II-III HM CTs (2000-2023) including 149,434 participants and compared enrollment to SEER benchmarks. Race was reported in 59% of trials and ethnicity in 40%, with significant improvement over time. Trials initiated in 2016 or later were more likely to report race (OR 36.3) and ethnicity (OR 8.0) than those before 2008. Compared with NIH-sponsored studies, institutional (OR 0.34) and industry trials (OR 0.52) had lower odds of reporting demographics. Black and Hispanic individuals were consistently underrepresented, most notably in multiple myeloma (7.0% vs. 20.0% expected) and acute lymphoblastic leukemia (21.5% vs. 36.9% expected). NIH-funded trials enrolled more Black participants than other sponsor types. These findings emphasize the need for enforceable mandates on race and ethnicity reporting, as well as representation targets, to ensure equitable access and generalizability.}, }
@article {pmid41178332, year = {2025}, author = {Newell, EW}, title = {Seeing First: Introducing the Resource Report at Cancer Immunology Research.}, journal = {Cancer immunology research}, volume = {13}, number = {11}, pages = {1696-1697}, doi = {10.1158/2326-6066.CIR-25-1175}, pmid = {41178332}, issn = {2326-6074}, }
@article {pmid41177463, year = {2025}, author = {Jons, CK and Kasse, CM and Mayer, BT and Hyrien, O and Sen, S and Meany, EL and d'Aquino, AI and Ganesh, P and Eckman, N and Dong, C and Yan, J and Nguyen, LT and Doulames, VM and Song, YE and Saouaf, OM and Williams, CM and Williams, SC and Paredes, J and Raghavan, R and Palomares, M and Alpert, M and Yates, NL and Tomaras, GD and Seaman, MS and Farzan, M and Appel, EA}, title = {Hydrogel formulations for sustained-release of broadly neutralizing antibodies.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {114349}, doi = {10.1016/j.jconrel.2025.114349}, pmid = {41177463}, issn = {1873-4995}, abstract = {Sustained serum levels of broadly neutralizing antibodies (bnAbs) are crucial for effective passive immunization against infectious diseases as protection persists only while these bnAbs remain at adequate concentrations within the body. Current obstacles, such as poor pharmacokinetics (PK) and burdensome administration, must be overcome to make bnAbs a viable option for pre- and post-exposure prophylaxis. In this work, we explore how a polymer-nanoparticle (PNP) hydrogel depot technology can be engineered to prolong protein delivery and enable drug exposure on the order of weeks to months. In-vivo studies in mice and rats demonstrate extended protein release compared to bolus administration, and modeling efforts predict the impact of both the elimination half-life of the active pharmaceutical ingredient and hydrogel depot volume on overall pharmacokinetics. Moreover, flow cytometry characterization reveals that immune cell infiltration into the hydrogel depot can result in faster-than-expected release of antibody cargo on account of active transport via cellular uptake. We then demonstrate that co-formulation of antibodies with an anti-inflammatory agent reduces cellular infiltration and resulting active transport, further extending delivery and pharmacokinetics. Finally, multicompartmental modeling predicts the human PK profiles of clinically relevant HIV bnAbs delivered via subcutaneous hydrogel injection. These findings aid in the development of next generation hydrogel materials that stabilize and slowly release bnAbs for long-term pre-exposure immunoprophylaxis.}, }
@article {pmid41176520, year = {2025}, author = {Yu, EY and Suzuki, H and Pieczonka, CM and Gotto, G and Briganti, A and Luz, M and Murphy, D and Malone, R and Hamilton, J and Chan, JE and Sieber, P and Given, RW and Hellmis, E and Kretz, T and Spiegelhalder, P and Gómez-Caamaño, A and Amela, YM and Artignan, X and Uemura, H and Fujita, N and Adorjan, P and Ghadessi, M and Verholen, F and Armstrong, AJ}, title = {DARolutamide ObservationaL (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer: prespecified third interim analysis.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {41176520}, issn = {1476-5608}, abstract = {BACKGROUND: DAROL is an ongoing study of real-world safety and effectiveness of darolutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).
SUBJECTS/METHODS: This prespecified interim analysis included 550 patients with nmCRPC who completed ≥6 months of treatment with darolutamide 600 mg twice daily.
RESULTS: Darolutamide showed consistent safety and effectiveness in DAROL vs ARAMIS. Most treatment-emergent adverse events were grade 1/2. Two-year overall survival and metastasis-free survival rates and prostate-specific antigen responses were similar to ARAMIS.
CONCLUSIONS: These findings indicate that darolutamide offers effectiveness and a favorable safety profile in the broad range of patients seen in clinical practice.}, }
@article {pmid41176373, year = {2025}, author = {Biernacki, MA}, title = {Capturing the Big Picture of HY Antigens and Transplantation Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {851-853}, doi = {10.1016/j.jtct.2025.10.009}, pmid = {41176373}, issn = {2666-6367}, }
@article {pmid41176371, year = {2025}, author = {Carpenter, PA and Warkentin, PI}, title = {Improving Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy: Evolution of ASTCT Practice Guidelines and FACT Inspections.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {843-848}, doi = {10.1016/j.jtct.2025.10.008}, pmid = {41176371}, issn = {2666-6367}, }
@article {pmid41175446, year = {2025}, author = {Levine, KM and Uy, NF and Gooley, TA and Voutsinas, J and Tratt, M and Eaton, KD and Santana-Davila, R and Berger, AH and Baik, CS}, title = {Osimertinib retreatment for patients with advanced EGFR-mutated non-small cell lung cancer.}, journal = {Cancer treatment and research communications}, volume = {45}, number = {}, pages = {101026}, doi = {10.1016/j.ctarc.2025.101026}, pmid = {41175446}, issn = {2468-2942}, abstract = {Resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a key challenge in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). Although retreatment with earlier-generation EGFR tyrosine kinase inhibitors has been studied, data on osimertinib rechallenge are limited. We conducted a single institution retrospective analysis of patients with EGFR-mutated NSCLC who were rechallenged with osimertinib following progression on prior osimertinib and interim systemic therapy, including chemotherapy. Seventeen patients met inclusion criteria, all with adenocarcinoma histology and either EGFR exon 19 deletions or L858R mutations. Median interval between osimertinib treatments was 10.5 months. Osimertinib retreatment resulted in a partial response in 18 % (3/17) and stable disease in 35 % of patients (6/17), for a disease control rate of 53 % (9/17). Median retreatment duration was 4.3 months, and median overall survival following retreatment initiation was 8.9 months. Among patients with central nervous system involvement, several experienced intracranial stability without additional radiation. Duration of initial osimertinib therapy did not strongly predict retreatment benefit. These findings suggest that osimertinib rechallenge may provide clinically meaningful disease control in a subset of patients, especially given its tolerability and oral formulation. Further research is needed to identify biomarkers of sensitivity and to optimize patient selection for osimertinib retreatment following interval chemotherapy.}, }
@article {pmid41173578, year = {2025}, author = {Fairlie, L and Szydlo, DW and Mayo, A and Bunge, K and Mhlanga, F and Piper, J and Dadabhai, S and Gatsi, VM and Horne, E and Ssemambo, PK and Mandiwa, V and Mgodi, NM and Owor, M and Anderson, PL and Marzinke, MA and Nakabiito, C and Scheckter, R and Chappell, C and Hillier, SL and , }, title = {Safety outcomes among infants whose mothers used the dapivirine vaginal ring or oral PrEP during pregnancy (MTN-042/DELIVER): a randomised phase 3b study.}, journal = {The lancet. HIV}, volume = {12}, number = {11}, pages = {e763-e773}, doi = {10.1016/S2352-3018(25)00261-9}, pmid = {41173578}, issn = {2352-3018}, mesh = {Humans ; Female ; Pregnancy ; *HIV Infections/prevention & control ; Adult ; *Anti-HIV Agents/administration & dosage/adverse effects ; *Pre-Exposure Prophylaxis/methods ; Young Adult ; Adolescent ; *Infectious Disease Transmission, Vertical/prevention & control ; Infant, Newborn ; Administration, Oral ; *Contraceptive Devices, Female ; Infant ; *Pregnancy Complications, Infectious/prevention & control/drug therapy ; Tenofovir/administration & dosage ; *Pyrimidines/administration & dosage/adverse effects ; South Africa ; Uganda ; Emtricitabine/administration & dosage ; Male ; }, abstract = {BACKGROUND: HIV acquisition risk during pregnancy remains high and additional data supporting pre-exposure prophylaxis (PrEP) in pregnancy are needed. The aim of the MTN-042/DELIVER study was to evaluate the dapivirine vaginal ring (DVR) and daily oral tenofovir disoproxil fumarate plus emtricitabine use as PrEP during pregnancy. We report infant outcomes following confirmed in-utero exposure.
METHODS: This randomised, controlled, open-label, phase 3b study was conducted in four clinical research sites in Malawi, South Africa, Uganda, and Zimbabwe. Pregnant, HIV-negative, healthy women aged 18-40 years were enrolled at 36-37 weeks' (cohort 1), 30-35 weeks' (cohort 2), and 12-29 weeks' (cohort 3) gestation and randomly assigned 2:1 (cohorts 1 and 2) and 4:1 (cohort 3) to receive the DVR (dapivirine 25 mg) or oral PrEP (tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg). All infants born to maternal participants were enrolled and included in the primary infant analysis to evaluate infant safety with in-utero exposure to study product. Infant visits were conducted at less than 2 weeks, 6 weeks, 6 months, and 12 months of age. The primary infant composite safety outcome included serious adverse events and grade 3 or higher adverse events. Birth outcomes (livebirth or stillbirth, prematurity), adverse events (including frequency between each study visit), and growth up to 12 months were evaluated and collected. This study is registered with ClinicalTrials.gov (NCT03965923). The trial is completed and the database closed.
FINDINGS: The study was conducted between Feb 7, 2020, and May 13, 2024. In total, 545 infants were included: 147 in cohort 1, 154 in cohort 2, and 244 in cohort 3. Mean intrauterine exposure was 23·3, 59·7, and 113·8 days, respectively. Overall, 545 (99%) of 550 pregnancy outcomes were livebirths. Serious adverse events occurred in 66 (17%) of 398 infants in the DVR group and 15 (10%) of 147 in the oral PrEP group. Grade 3 or higher adverse events occurred in 95 (24%) of 398 and 29 (20%) of 147 infants, respectively, none related to product exposure. 41 (51%) of 81 new-onset serious adverse events occurred by age 6 weeks, and ten (91%) of 11 congenital anomalies were diagnosed by age 6 months. There were no maternal or infant HIV acquisitions.
INTERPRETATION: Over 12 months of follow-up of infants, the DVR and oral PrEP were generally safe, with no composite adverse events related to study product. Together with available maternal safety data, this supports use of the DVR and oral PrEP by pregnant women to prevent HIV.
FUNDING: US National Institutes of Health.}, }
@article {pmid41172559, year = {2025}, author = {Ebadi, M and Fan, X and Schoch, G and Gooley, T and Rashidi, A and Smith, SD and Shadman, M and Holmberg, L and Ujjani, C and Poh, C and Raghunathan, V and Ali, N and Vo, PT and Manjappa, S and Menon, M and Di, M and Lynch, R and Ho, C and Till, BG and Ermoian, R and Gopal, AK and Tseng, YD}, title = {Total Body Irradiation Versus Chemotherapy-Only Conditioning in Autologous Haematopoietic Stem Cell Transplantation for Relapsed/Refractory Large B-cell Lymphoma.}, journal = {Clinical oncology (Royal College of Radiologists (Great Britain))}, volume = {48}, number = {}, pages = {103959}, doi = {10.1016/j.clon.2025.103959}, pmid = {41172559}, issn = {1433-2981}, abstract = {AIMS: In the era of chimeric antigen receptor T-cell (CAR-T) therapy, there remains a role for autologous stem cell transplant (ASCT) for patients with large B-cell lymphoma (LBCL) without access to CAR T-cell therapy or who have late, chemosensitive relapse (>12 months). Typically, the ASCT conditioning regimen is chemotherapy only. Given the radioresponsiveness of LBCL, we retrospectively evaluated whether ASCT outcomes are improved with total body irradiation (TBI)-based conditioning compared to chemo-only conditioning.
MATERIALS AND METHODS: We included patients with relapsed/refractory (r/r) LBCL who underwent ASCT at our centre (2012-2021). As TBI is generally offered only to younger patients, we excluded patients in the chemo-only group who were older than the oldest patient in the TBI group, leaving 56 patients in the final dataset (TBI: 19; chemo: 37).
RESULTS: The TBI cohort had more adverse features including male sex (89.5% vs 62.2%), relapse ≤12 months (52.6% vs 32.4%), and shorter time between diagnosis and ASCT (median: 11.7 vs 21.8 months). Two-year progression-free survival (PFS) was 58% (95% confidence interval [CI]: 39%-85%) and 67% (53%-84%) in TBI and chemotherapy cohorts, respectively. Two-year overall survival (OS) was 79% (63%-100%) and 80% (68%-95%) in TBI and chemotherapy cohorts, respectively. Multivariable hazard ratio (HR) of PFS failure (TBI vs chemo) was 1.35 (95% CI: 0.59-3.12). The HR of death was 1.33 (95% CI: 0.49-3.58). While conditioning regimen was not associated with PFS, positron emission tomography (PET) positivity at time of ASCT (HR: 6.97, 95% CI: 2.98-16.27, P < 0.001) was associated with PFS failure.
CONCLUSION: Despite the presence of more adverse features among patients treated with TBI, there was no difference in PFS or OS among patients that underwent chemo-only vs TBI-based conditioning. Though hypothesis generating, this suggests that TBI may be able to partially compensate for adverse fatures.}, }
@article {pmid41171480, year = {2025}, author = {Mahdi, J and Gust, JA and Vitanza, NA and Scott, B and Monje, M and Ronsley, R}, title = {Neurotoxicity in central nervous system tumors treated with CAR T cell therapy: a review.}, journal = {Journal of neuro-oncology}, volume = {176}, number = {1}, pages = {60}, pmid = {41171480}, issn = {1573-7373}, }
@article {pmid41169120, year = {2025}, author = {Marzinke, MA and Hanscom, B and Haines, D and Scarsi, KK and Agyei, Y and Piwowar-Manning, E and Hendrix, CW and Gollings, R and Rose, S and Mathew, C and Panchia, R and Spooner, E and Singh, N and Bock, P and Rinehart, AR and Ford, SL and Rooney, JF and Soto-Torres, L and Cohen, MS and Hosseinipour, MC and Delany-Moretlwe, S and , }, title = {Evaluation of pharmacokinetic interactions between long-acting cabotegravir or emtricitabine/tenofovir disoproxil fumarate and hormonal contraceptive agents: a tertiary analysis of South African participants in HPTN 084.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {11}, pages = {e70056}, pmid = {41169120}, issn = {1758-2652}, support = {OPP1154174//Bill and Melinda Gates Foundation/ ; UM1AI068613/NH/NIH HHS/United States ; UM1AI068617/NH/NIH HHS/United States ; UM1AI068619/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; Adult ; *Emtricitabine/pharmacokinetics/administration & dosage ; Drug Interactions ; *HIV Infections/prevention & control ; *Tenofovir/pharmacokinetics/administration & dosage ; South Africa ; Young Adult ; *Pyridones/pharmacokinetics/administration & dosage ; Desogestrel/pharmacokinetics/blood ; *Contraceptive Agents, Hormonal/pharmacokinetics/administration & dosage ; Pre-Exposure Prophylaxis ; *Anti-HIV Agents/pharmacokinetics ; Norethindrone/analogs & derivatives/pharmacokinetics/blood ; Medroxyprogesterone Acetate/pharmacokinetics/blood ; Adolescent ; *Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/pharmacokinetics/administration & dosage ; Diketopiperazines ; }, abstract = {INTRODUCTION: HPTN 084 found that long-acting cabotegravir (CAB-LA) was well-tolerated and significantly reduced the risk of HIV acquisition in women compared to tenofovir disoproxil fumarate/emtricitabine (F/TDF). During the blinded phase of the trial, participants were required to use an effective method of contraception, including an injectable or implantable hormonal contraceptive (HC) agent. A contraceptive sub-study assessed the pharmacokinetic interactions between pre-exposure prophylaxis agents (CAB-LA or F/TDF) and etonogestrel (ENG), medroxyprogesterone acetate (MPA) or norethindrone enanthate (NET-EN).
METHODS: Participants were enrolled in a nested sub-study between 24 February 2020 and 26 October 2020. Via a convenience sampling strategy, plasma concentrations of ENG, MPA and NET-EN were evaluated at enrolment and weeks 25, 49 and 73; plasma tenofovir (TFV) and CAB concentrations were determined at contemporaneous visits. Participants were allowed to switch contraceptives, and HC assessments were adjusted accordingly. Geometric mean concentrations were calculated and compared using t-tests or Fisher's exact tests.
RESULTS: One hundred and seventy participants were included in this analysis. Hormone concentrations at all study visits were comparable between the CAB-LA and F/TDF study arms. Among participants randomized to the CAB-LA arm, geometric mean concentrations declined from enrolment to the follow-up period for ENG (335 to 202 pg/ml), MPA (1520 to 1138 pg/ml) and NET-EN (3715 to 1888 pg/ml); similar findings were observed among participants randomized to the F/TDF arm. Observed HC declines are likely attributed to the timing of contraceptive administration relative to sampling; the percentage of participants with hormone concentrations above thresholds associated with ovulation suppression was high (73-100%) and did not differ between arms. CAB concentrations were comparable across contraceptive types, with 97.8-98.1% of participants yielding trough CAB concentrations above the protocol-specified target threshold. TFV concentrations were unquantifiable for most participants, irrespective of contraceptive agent, rendering comparisons largely uninformative.
CONCLUSIONS: Given the comparable hormone concentrations between arms and the likely influence of the timing of sample collection on observed measurements, clinically significant interactions between CAB-LA and HC are not expected. Associations between F/TDF and hormone concentrations could not be effectively evaluated due to low adherence to F/TDF.
CLINICAL TRIAL REGISTRATION: NCT0316456.}, }
@article {pmid41168431, year = {2025}, author = {Jabbar, KS and Priya, S and Xu, J and Das Adhikari, U and Pishchany, G and Mohamed, ATM and Johansen, J and Thurimella, K and McCabe, C and Vlamakis, H and Okello, S and Delorey, TM and Lankowski, A and Mosepele, M and Siedner, MJ and Plichta, DR and Kwon, DS and Xavier, RJ}, title = {Human immunodeficiency virus and antiretroviral therapies exert distinct influences across diverse gut microbiomes.}, journal = {Nature microbiology}, volume = {10}, number = {11}, pages = {2720-2735}, pmid = {41168431}, issn = {2058-5276}, support = {P30 DK043351/DK/NIDDK NIH HHS/United States ; R01 HL141053/HL/NHLBI NIH HHS/United States ; K24 HL166024/HL/NHLBI NIH HHS/United States ; DK120485//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 DK043351/DK/NIDDK NIH HHS/United States ; R01 HL141053/HL/NHLBI NIH HHS/United States ; K24 HL166024/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome/drug effects ; *HIV Infections/drug therapy/microbiology ; Uganda ; Alkynes ; Metagenomics ; Benzoxazines/therapeutic use/adverse effects ; Male ; Female ; Feces/microbiology ; Cyclopropanes ; Adult ; Botswana ; *Anti-Retroviral Agents/therapeutic use ; Middle Aged ; United States ; Reverse Transcriptase Inhibitors/therapeutic use ; *Anti-HIV Agents/therapeutic use ; Bacteria/classification/genetics/drug effects/isolation & purification ; }, abstract = {Human immunodeficiency virus (HIV) infection alters gut microbiota composition and function, but the impact of geography and antiretroviral therapy remains unclear. Here we determined gut microbiome alterations linked to HIV infection and antiretroviral treatment in 327 individuals with HIV and 260 control participants in cohorts from Uganda, Botswana and the USA via faecal metagenomics. We found that while HIV-associated taxonomic differences were mostly site specific, changes in microbial functional pathways were broadly consistent across the cohorts and exacerbated in individuals with acquired immunodeficiency syndrome. Microbiome perturbations associated with antiretroviral medications were also geography dependent. In Botswana and Uganda, use of the non-nucleoside reverse transcriptase inhibitor efavirenz was linked to depletion of Prevotella, disruption of interspecies metabolic networks, exacerbation of systemic inflammation and atherosclerosis. Efavirenz-associated Prevotella depletion may occur through cross-inhibition of prokaryotic reverse transcriptases involved in antiphage defences, as shown by computational and in vitro experiments. These observations could inform future geography-specific and microbiome-guided therapy.}, }
@article {pmid41168411, year = {2025}, author = {Jiang, SJ and Thomas, M and Rosenthal, EA and Phipps, AI and Sakoda, LC and van Duijnhoven, FJB and Pellatt, AJ and Avery, CL and Berndt, SI and Bishop, DT and Castellví-Bel, S and Chan, AT and Grant, RC and Gignoux, C and Gsur, A and Gunter, MJ and Haiman, CA and Hoffmeister, M and Jarvik, GP and Jenkins, MA and Keku, TO and Küry, S and Lee, JK and Marchand, LL and Moreno, V and Newcomb, PA and Newton, CC and Ogino, S and Palmer, JR and Pearlman, R and Qu, C and Schoen, RE and Um, CY and Van Guelpen, B and Visvanathan, K and Vymetalkova, V and White, E and Woods, MO and Platz, EA and Brenner, H and Corley, DA and Vogelaar, IL and Hsu, L and Peters, U}, title = {Multiple polygenic score approach in colorectal cancer risk prediction.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {38006}, pmid = {41168411}, issn = {2045-2322}, support = {U01HG008657/HG/NHGRI NIH HHS/United States ; U01 CA164973, R01 CA126895, R01 CA060987, R01 CA072520, U24 CA074806/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Multifactorial Inheritance/genetics ; *Genetic Predisposition to Disease ; Female ; Male ; Machine Learning ; Aged ; Middle Aged ; Risk Factors ; Risk Assessment ; Genome-Wide Association Study ; ROC Curve ; Polymorphism, Single Nucleotide ; Case-Control Studies ; }, abstract = {Recent studies have demonstrated that for various diseases, incorporating polygenic risk scores (PRSs) for other traits and diseases into the PRS-based risk prediction model may improve predictive performance - known as Multiple Polygenic Score (MPS) approach. We aimed to examine whether the MPS approach improves colorectal cancer (CRC) risk prediction. We included 2,187 non-CRC PRSs from the polygenic Score (PGS) Catalog and used machine learning (ML) models to select the most predictive non-CRC PRSs, utilizing individual-level data from 31,257 CRC cases and 33,408 controls. An independent dataset from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (4,852 cases and 67,939 controls) was randomly split into subsets for model estimation and validation. The model combined MPS with two existing CRC-PRSs based on known loci and genome-wide genotyping. We then assessed model performance by calculating the area under the receiver operating curve (AUC) in the validation set and performed 1,000 bootstrapped iterations to evaluate AUC improvements. The ML model selected 337 non-CRC PRSs predictive of CRC risk. Adding MPS to the CRC-PRSs significantly improved AUC by 0.017 (95% CI: 0.011-0.022, p < 0.0001) when combined with known-loci CRC-PRS, 0.005 (95% CI: 0.002-0.007, p = 0.0005) with genome-wide CRC-PRS, and 0.004 (95% CI: 0.002-0.006, p = 0.0005) with both the known loci and genome-wide CRC-PRSs. These findings demonstrate MPS's potential to refine CRC risk prediction models and highlight opportunities for further advancements in risk prediction.}, }
@article {pmid41165705, year = {2025}, author = {MacKay, EJ and Talham, CJ and Szeto, WY and Brown, CR and Augoustides, JG and Desai, ND and Groeneveld, PW and Zhang, B}, title = {Surgical Volume and Outcomes of Intraoperative Transesophageal Echocardiography in Coronary Artery Bypass Graft.}, journal = {JAMA network open}, volume = {8}, number = {10}, pages = {e2540559}, pmid = {41165705}, issn = {2574-3805}, mesh = {Humans ; *Coronary Artery Bypass/mortality/statistics & numerical data/methods ; Male ; Female ; *Echocardiography, Transesophageal/statistics & numerical data/methods ; Retrospective Studies ; Aged ; Middle Aged ; Treatment Outcome ; *Intraoperative Care/methods ; }, abstract = {IMPORTANCE: The routine use of intraoperative transesophageal echocardiography (TEE) during coronary artery bypass graft (CABG) surgery remains controversial. Its benefit across different patient populations is unclear.
OBJECTIVES: To identify patient subgroups with the greatest or least likelihood to benefit from intraoperative TEE during CABG, stratified by hospital surgical volume.
This 2-stage, matched retrospective cohort study applied target trial emulation methodologies to the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) to quantify the conditional treatment effect of intraoperative TEE among subpopulations undergoing isolated CABG at low, medium, and high surgical volume hospitals. The study cohort consisted of patients aged 18 years or older who underwent isolated CABG surgery between July 1, 2014, and June 30, 2022. Data analysis was conducted from August 8, 2023, to December 15, 2024.
EXPOSURE: Receipt of an intraoperative TEE during CABG surgery.
MAIN OUTCOMES AND MEASURES: The primary outcome was mortality within 30 days of surgery. Statistical analyses included multivariable logistic regression and multiple TEE vs without TEE matched comparisons stratified by surgical volume and patient subpopulations.
RESULTS: Of 1 266 055 patients who underwent isolated CABG, 963 976 (76.1%) were male, and the mean (SD) age was 65.7 (10.0) years. Among these patients, 61.8% received TEE and 39.0% did not receive TEE. Intraoperative TEE use (vs without TEE) was associated with a significant survival benefit among patients treated at hospitals with low surgical volume (2.47% vs 2.94%; odds ratio [OR], 0.83 [95% CI, 0.78-0.89], P < .001) and medium surgical volume (2.09% vs 2.34%; OR, 0.89 [95% CI, 0.85-0.93], P < .001) but not high surgical volume (1.72% vs 1.77%; OR, 0.97 [95% CI, 0.91-1.03], P = .48). Among patients who underwent isolated CABG at low and medium surgical volume hospitals, TEE provided the greatest survival benefit to subpopulations with greater than 50% (vs ≤50%) left-main coronary stenosis, 3 or more (vs <3) diseased coronaries, and (3) a preoperative inotropic requirement.
CONCLUSIONS AND RELEVANCE: In isolated CABG, intraoperative TEE was associated with survival benefit at low- and medium-volume hospitals, particularly in patients with complex coronary disease or hemodynamic instability, but not at high-volume hospitals. These results highlight persistent equipoise and the need for randomized evaluation.}, }
@article {pmid41165693, year = {2025}, author = {Shadman, M and Gopal, AK}, title = {Bispecific antibodies in action: the reality of engagement.}, journal = {Blood}, volume = {146}, number = {18}, pages = {2148-2150}, doi = {10.1182/blood.2025030376}, pmid = {41165693}, issn = {1528-0020}, }
@article {pmid41162557, year = {2025}, author = {Damera, S and Lee, JR and Hong, YR and Nyame, YA and Hammarlund, N}, title = {Negative perceptions of the health system and racial inequities in PSA screening.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {41162557}, issn = {1476-5608}, abstract = {BACKGROUND: Black individuals in the U.S. experience significantly higher prostate cancer mortality and are more likely to be diagnosed at younger ages with aggressive disease. This disparity may be influenced by negative healthcare perceptions and racial discordance between patients and providers, impacting lower rates of prostate-specific antigen (PSA) screening. We hypothesized that these factors would be associated with reduced PSA screening uptake, particularly among Black men.
OBJECTIVES: This study aimed to examine the association between negative healthcare perceptions and PSA screening, assess whether this relationship differs by race, and evaluate the role of racial discordance in influencing screening behavior.
METHODS: We analyzed data from the 2018-2022 Medical Expenditure Panel Survey. The sample included 2373 men aged 45-70 who self-identified as non-Hispanic White or Black and had complete data on PSA screening, healthcare perceptions, and demographics. Negative healthcare perceptions were measured using a Health Perceptions Index (HePI), constructed from MEPS items (higher scores reflect more negative perceptions).
RESULTS: Higher HePI scores were significantly associated with lower PSA screening rates (p < 0.01). Interaction models indicated that Black men with higher HePI scores were disproportionately less likely to undergo screening. Racial discordance with providers was independently associated with reduced screening likelihood (~10.2 percentage points; p < 0.01). Models including interaction terms (age, race, and discordance) showed that older Black men with high HePI scores and discordant providers were least likely to be screened.
CONCLUSIONS: PSA screening disparities are shaped by negative healthcare perceptions and racial discordance, particularly among older Black men. Addressing these barriers through culturally tailored education, improved workforce diversity, and strengthened provider-patient relationships may help close screening gaps. These findings highlight the relevance of healthcare system perceptions in understanding screening disparities and may inform future strategies to identify at-risk individuals.}, }
@article {pmid41162424, year = {2025}, author = {Fergus, KB and Newberg, J and Greenstein, R and Fejerman, L and Carvajal-Carmona, L and Collisson, E and Dixit, N and Frampton, G and Huang, FW and Neuhausen, SL and Ziv, E}, title = {Association between ancestry and tumor somatic mutations in a large national cohort of women with breast cancer.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {117}, pmid = {41162424}, issn = {2374-4677}, support = {2023YIA-9977333099//American Society of Clinical Oncology/ ; R01CA223978, U54CA283766 and U54CA280811/CA/NCI NIH HHS/United States ; OPR18111//California Initiative to Advance Precision Medicine/ ; OPR18111//California Initiative to Advance Precision Medicine/ ; }, abstract = {Somatic mutations and copy number alterations in breast tumors are important to determine prognosis, predict treatment response, and identify targets for therapy. We utilized somatic sequencing data of breast tumors from Foundation Medicine Inc. to evaluate the association between genetic ancestry and somatic mutations. We used germline variants to infer genetic ancestry with both principal components analysis and ADMIXTURE. Overall, we identified 91 ancestry-specific somatic differences across 58 unique genes, which included potentially targetable genes such as PIK3CA found in higher frequency in European ancestry, and EGFR found in higher frequency in East Asian ancestry. Pan-cancer analysis of East Asian ancestry and EGFR also found higher frequency in prostate, thyroid, and kidney cancers. African ancestry was associated with increased frequency of copy number alterations overall and decreased frequency of multiple genes on the PI3K-AKT pathway. Future research is warranted to elicit the genetic and environmental conditions that underly these findings.}, }
@article {pmid41161984, year = {2025}, author = {Zhang, C and Lam, BD and Lucas, F and Foy, BH}, title = {Machine Learning and Artificial Intelligence-Based Clinical Decision Support for Modern Hematology.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {691-705}, doi = {10.1016/j.cll.2025.07.011}, pmid = {41161984}, issn = {1557-9832}, mesh = {*Machine Learning ; Humans ; *Hematology/methods ; *Decision Support Systems, Clinical ; *Artificial Intelligence ; *Hematologic Diseases/diagnosis ; }, abstract = {Hematology is one of the most data-rich areas of medicine and has consistently been at the forefront of technological innovation. With the increasing integration of machine learning (ML) into the diagnostic process, it is vital that both patient-facing and laboratory-facing members of the care team understand how these tools may interact with existing workflows and affect their work. We review the current landscape of ML research and clinical applications. We cover a wide variety of subdomains (eg, hematopathology, hemoglobinopathies, and coagulopathy) and explore both the success and limitations of corresponding research and deployments.}, }
@article {pmid41161982, year = {2025}, author = {Vishnu, P and Aboulafia, DM}, title = {Recent Advances in Extended Half-Life Products, Nonfactor Replacement Therapies, and Gene Therpy for the Treatment of Hemophilia.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {657-673}, doi = {10.1016/j.cll.2025.07.010}, pmid = {41161982}, issn = {1557-9832}, mesh = {*Hemophilia A/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Half-Life ; *Blood Coagulation Factors/therapeutic use/pharmacokinetics ; Factor VIII/therapeutic use/pharmacokinetics ; }, abstract = {Hemophilia, a rare X-linked hereditary bleeding disorder, is characterized by deficiency of coagulation factors. Symptoms range from spontaneous joint and muscle bleeds to life-threatening hemorrhage, for which patients require frequent infusion of coagulation factors, profoundly impacting their quality of life. Novel therapeutics and advances in gene therapy now offer patients long-term disease control and improved quality of life. Here, we focus on important developments in the use of extended half-life factor products, non-factor replacement therapies, and gene therapy. We also highlight the mechanism of action, clinical efficacy, and safety of these newer approaches.}, }
@article {pmid41161981, year = {2025}, author = {Vishnu, P and Aboulafia, DM}, title = {Hemostatic Disorders Following Severe Acute Respiratory Syndrome Coronavirus 2 Infection, COVID-19 Vaccination, and Long-COVID Syndrome: Current Evidence and Controversies in Clinical Practice.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {643-655}, doi = {10.1016/j.cll.2025.07.008}, pmid = {41161981}, issn = {1557-9832}, mesh = {Humans ; *COVID-19/complications/prevention & control ; *COVID-19 Vaccines/adverse effects ; *Hemostatic Disorders/etiology ; SARS-CoV-2 ; *Vaccination/adverse effects ; }, abstract = {The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented profound global health challenges. Beyond acute illness, a substantial proportion of individuals experience persistent symptoms including fatigue, brain fog, and post-exertional malaise, collectively known as Long-COVID. Among the complications associated with SARS-CoV-2 infection and vaccination, hemostatic disorders ranging from mild platelet dysfunction to severe thromboembolic events, and rare but serious coagulation-related adverse effects, such as vaccine-induced immune thrombotic thrombocytopenia, have emerged as a significant concern. Herein we provide an overview of current information and controversies surrounding hemostatic complications in SARS-CoV-2 infection and COVID-19 vaccination.}, }
@article {pmid41160804, year = {2025}, author = {Rashidi, A and Gao, F}, title = {Antibiotic risk score for acute graft-versus-host disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018317}, pmid = {41160804}, issn = {2473-9537}, abstract = {Certain antibiotic exposures have been associated with increased rates of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (alloHCT). Using data from 2,023 alloHCTs performed at our center (2010-2021), we recently developed an antibiotic risk score based on antibacterial antibiotic exposure between days -7 and +30 of alloHCT. The objective was to estimate the added risk for aGVHD due to exposures to antibiotics in the early peri-transplant period. Here, we validated the score in an independent, more recent cohort. Data from 297 alloHCT recipients (2022-2023) including 8,382 antibiotic use records (9 antibiotic classes) were analyzed. Median (range) age was 61 (19-78) years. 175 (59%) patients were male. Higher scores predicted a greater added antibiotic-related risk for grade III-IV (severe) aGVHD, with the upper 25% score quantile identifying a distinctly high-risk subset of patients (hazard ratio for the upper 25% risk quantile 2.37 compared to the lower 75%, 95% confidence interval 1.21-4.63, P = 0.01). A similar, though less strong pattern was observed for grade II-IV aGVHD. A free online antibiotic risk calculator was developed, identifying antibiotic exposures associated with higher added risk for severe aGVHD. In addition to its potential future use to identify higher-risk patients for aGVHD due to antibiotic exposures, the antibiotic-based risk score provided here can be included as a single continuous covariate in multivariable analysis of future GVHD prophylaxis trials.}, }
@article {pmid41160408, year = {2025}, author = {Nyquist, MD and Nelson, P}, title = {Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-3045}, pmid = {41160408}, issn = {1557-3265}, abstract = {The Androgen Receptor (AR) is the most important therapeutic target for metastatic prostate cancer. Though clinical responses to AR inhibition are nearly universal, so is progression, usually accompanied by reactivation of AR signaling. A new small molecule dual AR degrader/inhibitor shows promise in overcoming resistance and improving clinical outcomes.}, }
@article {pmid41159380, year = {2025}, author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Gujral, T and Holland, EC}, title = {Integrated transcriptomic landscape of medulloblastoma and ependymoma reveals novel tumor subtype-specific biology.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf251}, pmid = {41159380}, issn = {1523-5866}, abstract = {BACKGROUND: Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. While molecular subgrouping has enabled classification into molecular subtypes, the extent of heterogeneity within these subgroups remains poorly defined.
METHODS: We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. After rigorous batch effect correction, normalization, and dimensionality reduction, we generated a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations.
RESULTS: Our transcriptional analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. We also identified subtype-specific pathways and gene fusions, enriched in each group.
CONCLUSIONS: This transcriptomic landscape serves as a resource for biomarker discovery, diagnostic refinement, and prediction of tumor biology and outcome. By enabling projection of new patients' bulk RNA-seq data onto the reference map using nearest neighbor analysis, the framework supports accurate subtype classification. The landscape is publicly available via Oncoscape, an interactive platform for global exploration and application.}, }
@article {pmid41159377, year = {2025}, author = {Smith, AKS and Dhanda, SK and Billups, CA and Sioson, E and Lu, C and Peraza, AZ and Gangwani, K and Li, Y and Li, Q and Lin, T and Michalski, JM and Packer, RJ and Olson, JM and Leary, SES and Fouladi, M and Gajjar, A and Zhou, X and Onar-Thomas, A and Northcott, PA and Robinson, GW}, title = {An integrated analysis of three medulloblastoma clinical trials refines risk-stratification approaches for reducing toxicity and improving survival.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf250}, pmid = {41159377}, issn = {1523-5866}, abstract = {BACKGROUND: The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.
METHODS: Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3) and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.
RESULTS: 898 patients (WNT = 131, SHH = 151, G3 = 220, G4 = 396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (p = 0.048) and G3/G4 subgroup 2 (p = 0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk) and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).
CONCLUSIONS: Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.}, }
@article {pmid41159270, year = {2025}, author = {Farooq, MS and Amini, N and Sun, V and Deutsch, GB and Deneve, JL and Grant, M and Arnold, KB and Secord, AA and Anderson, G and Krouse, RS}, title = {Optimizing Palliative Cancer Surgery Trial Completion: Lessons Learned From Qualitative Content Analysis of S1316 - Comparative Effectiveness Trial for Malignant Bowel Obstruction.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091251391420}, doi = {10.1177/10499091251391420}, pmid = {41159270}, issn = {1938-2715}, abstract = {BackgroundMalignant bowel obstruction (MBO) is a complex clinical entity and there remains a relative lack of high-quality comparative trials on surgical management, in part due to a heterogeneous patient population and different treatment modalities which contribute to challenges in trial design and completion. SWOG S1316 is the only prospective randomized trial evaluating surgical vs non-surgical management of MBO and involved a trial framework in which patients were recruited for a randomization pathway as well as a patient choice pathway. Importantly, successful completion of S1316 required numerous amendment modifications to the trial during its course. We aimed to highlight aspects of S1316 trial design, execution, and modification that potentially contributed to trial completion.MethodsIterative qualitative content analysis of trial modification amendments through the course of the trial from 2015 to 2020.Results133 unique amendments were made to S1316 from 2015 to 2020. We found four dominant domains for the amendments: Accrual Barriers, Study Design Changes, Data Collection Issues, and Clarifications. Accrual amendments were essential to completing the trial and included increasing participating sites from six to 30 (including international sites) and the inclusion of Spanish-speaking participants (11% of final study population).ConclusionsContent analysis of S1316 trial amendments highlighted that Accrual amendments were important in trial completion. Future investigators may benefit from better anticipating trial modifications as they design their studies. It is likely that rapid initiation of trial amendments can lead to improved accrual and study completion.}, }
@article {pmid41158962, year = {2025}, author = {Cummings, CL and Stephan, SB and Fitzgerald, K and Stephan, MT}, title = {Bedside manufacturing of engineered stem cells using gene therapy foam.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {4}, pages = {101612}, pmid = {41158962}, issn = {2329-0501}, abstract = {Hematopoietic stem cell (HSC) gene therapies hold immense potential for treating a growing list of genetic disorders, but the field has reached an inflection point where novel technologies are needed to overcome significant challenges, including high costs, unequal access, and prolonged disruption of daily life. Here, we describe a bedside cell manufacturing strategy in which HSCs are genetically targeted within gene therapy foam that is mixed with freshly isolated bone marrow aspirate concentrate and then directly injected back into the marrow. We demonstrate that highly efficient genetic reprogramming of CD34+ HSCs can be accomplished within methylcellulose-based foam, using low vector doses that are inefficient with conventional liquid-based approaches. In an ex vivo model of perfused bone marrow, we show that foam retains vector at the injection site and locally boosts gene transfer into embedded CD34+ progenitor cells while minimizing off-target events. We also establish that this foam technology is compatible with freshly harvested human bone marrow aspirate. Once implemented in the clinic, this new method, which can be performed in an outpatient setting of any regional hospital, could improve the effectiveness of stem cell-based gene therapies, while concomitantly lowering costs to make these treatments accessible to all who need them.}, }
@article {pmid41155216, year = {2025}, author = {Qin, R and Hua, M and Wang, Y and Zhang, Q and Cao, Y and Dai, Y and Ma, C and Zheng, X and Ge, K and Zhang, H and Li, S and Liu, Y and Cao, L and Wang, L}, title = {Multiomics Investigation of Exhausted T Cells in Glioblastoma Tumor Microenvironment: CCL5 as a Prognostic and Therapeutic Target.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155216}, issn = {1422-0067}, support = {82304250//National Natural Science Foundation of China/ ; 82273734//National Natural Science Foundation of China/ ; 82173629//National Natural Science Foundation of China/ ; }, mesh = {*Glioblastoma/immunology/genetics/drug therapy/pathology/metabolism ; Humans ; *Tumor Microenvironment/immunology/genetics ; *Chemokine CCL5/genetics/metabolism ; Prognosis ; *T-Lymphocytes/immunology/metabolism ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; *Brain Neoplasms/immunology/genetics/drug therapy/pathology ; Multiomics ; }, abstract = {Glioblastoma multiforme (GBM) is a common malignancy with poor prognosis, and exhausted T (TEX) cells, a subset of T cells characterized by progressive loss of effector functions, play a critical role in its progression. This study aimed to investigate the impact of TEX-related genes on immune function, prognosis, and drug sensitivity in GBM through multiomics analysis. Initially, we identified a novel set of TEX-related genes specific to GBM and screened hub genes (CCL5, IL18, CXCR6, FCER1G, TNFSF13B) using conventional statistical methods combined with machine learning. A prognostic risk model was subsequently constructed based on TCGA data and validated in the CGGA cohort. Single-cell and pharmacogenomic analyses revealed significant differences in tumor microenvironment composition and drug sensitivity between risk groups. Notably, Palbociclib emerged as a potential therapeutic agent targeting the novel discovered biomarker CCL5. RT-qPCR results showed that T cells with low CCL5 expression exhibited reduced expression of immune checkpoint-related genes (PD1, TIM3, LAG3) and increased expression of CD28, suggesting enhanced immune function. In conclusion, our findings highlight five hub genes as prognostic markers that could stratify GBM patients with different immune landscapes and levels of drug sensitivity. Furthermore, experimental results suggest that low CCL5 expression could alleviate T cell exhaustion and represent a promising therapeutic target, offering new strategies for improving GBM prognosis.}, }
@article {pmid41152450, year = {2025}, author = {Ding, F and Liu, S and Sun, W}, title = {Exploration of the roles of HLAs when predicting infection status by T cell receptors.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {37638}, pmid = {41152450}, issn = {2045-2322}, support = {GM105785/GM/NIGMS NIH HHS/United States ; GM105785/GM/NIGMS NIH HHS/United States ; GM105785/GM/NIGMS NIH HHS/United States ; R56AI169192//National Institute of Allergy and Infectious Diseases/ ; R56AI169192//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Receptors, Antigen, T-Cell/genetics/immunology ; *HLA Antigens/genetics/immunology ; Alleles ; T-Lymphocytes/immunology ; *Virus Diseases/immunology/genetics ; }, abstract = {T cells are critical components of the human immune system. When a cell is infected by a virus, it presents viral peptides on its surface using human leukocyte antigen (HLA) proteins. These peptide-HLA complexes are recognized by T cells through interactions with T cell receptors (TCRs). A human blood sample can contain millions of unique TCRs, which is a sample from the individual's TCR repertoire. TCR repertoire-wide association studies (TReWAS) aim to evaluate the associations between individual TCRs and disease or exposure status. Previous studies have shown that TCRs associated with viral infections can be identified using TReWAS, and these TCRs can be used to predict current or past infection with high accuracy. Many TCRs are strongly associated with specific HLA alleles, suggesting that the incorporation of HLA information could improve the precision of TReWAS analyses and predictions based on TCRs. In this study, we evaluated TCR-based predictions while conditioning on individual HLA alleles or their k-nearest neighbors. We observed improved prediction accuracy for some HLA alleles. Furthermore, these HLA-specific predictions provide insight into the role of specific HLAs in coordinating immune response to immunogenic antigens, demonstrating the benefit of HLA-aware analysis of TCR data.}, }
@article {pmid41152111, year = {2025}, author = {Jindal, T and Jiang, CY and Alhalabi, O and Davidsohn, M and Freeman, D and Epstein, IY and Bakaloudi, DR and Talukder, R and Nizam, A and Nguyen, CB and Oh, E and Tsung, I and Glover, MJ and Khaki, AR and Taylor, AK and Jaime-Casas, S and Jang, A and Lemke, E and Pywell, C and Evans, ST and Shin, D and Bilen, MA and Basu, A and Kilari, D and Tripathi, A and Brown, J and Emamekhoo, H and Davis, NB and Shah, S and Gupta, S and Grivas, P and Bellmunt, J and Alva, A and Campbell, MT and Koshkin, VS}, title = {Efficacy of sacituzumab govitecan after enfortumab vedotin in advanced urothelial carcinoma: Analysis of the UNITE study.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.09.025}, pmid = {41152111}, issn = {1873-2496}, abstract = {BACKGROUND: Sacituzumab govitecan (SG) is an antibody-drug conjugate used for advanced urothelial carcinoma (aUC) refractory to platinum-based chemotherapy and immune checkpoint inhibitors (ICI). Real-world data are needed to better define SG outcomes, particularly following treatment with enfortumab vedotin (EV). In this analysis, we aim to evaluate efficacy of SG after EV and assess putative biomarkers associated with outcomes.
METHODS: In the UNITE retrospective study, we identified patients who received ≥1 SG cycle after therapy with EV. Observed response rate (ORR) was assessed in evaluable patients and correlated with baseline clinical characteristics and biomarkers. ORRs were compared using logistic regression, while progression free survival (PFS) and overall survival (OS) from SG start were estimated via Kaplan-Meier and Cox proportional hazard (PH) model. Biomarkers of response were evaluated in multivariate Cox PH models after accounting for relevant clinical variables.
RESULTS: Among 107 patients treated with SG after EV, 97 (91%) had NGS data. Median age was 69 years, 73% were male, 33% had ≥4 prior lines of therapy, and 42% received G-CSF. ORR was 18% (95% CI: 10%-26%), median PFS 3.2 months, and median OS 6.0 months. In patients with disease control on EV, ORR was 22% compared to 8% in primary progressors on EV. No significant associations were found between molecular biomarkers and SG outcomes in the multivariate analysis.
CONCLUSION: SG showed modest activity after EV in heavily pretreated patients with aUC. ORR with SG after EV was lower than reported in phase 2 and phase 3 clinical trials for SG in the postplatinum/ICI setting.}, }
@article {pmid41149505, year = {2025}, author = {Rios-Doria, E and Reichel, JB and Radke, MR and Manhardt, E and Rubin-Saika, M and Lockwood, C and Swisher, EM and Banda, K}, title = {Dynamic Monitoring of Recurrent Ovarian Cancer Using Serial ctDNA: A Real-World Case Series.}, journal = {Current oncology (Toronto, Ont.)}, volume = {32}, number = {10}, pages = {}, pmid = {41149505}, issn = {1718-7729}, support = {0000//Brotman Baty Institute/ ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/genetics/blood/pathology ; *Circulating Tumor DNA/blood/genetics ; *Neoplasm Recurrence, Local/blood/genetics ; Middle Aged ; Aged ; *Biomarkers, Tumor/blood/genetics ; Adult ; CA-125 Antigen/blood ; }, abstract = {Recurrent ovarian cancer (OC) is challenging to detect early using current methods like CA-125 and imaging. Circulating tumor DNA (ctDNA) may improve disease monitoring. Here, we assess the real-world clinical utility of serial ctDNA analyses in patients with recurrent OC. We analyzed serial plasma samples (N = 23) from six patients with recurrent OC using a tumor-informed next-generation sequencing assay targeting 68 cancer-related genes developed at the University of Washington. ctDNA variant allele frequencies (VAFs) were correlated with CA-125 levels, radiographic findings, and clinical outcomes. ctDNA levels generally reflected clinical status, accurately mirroring disease progression and therapeutic response. In one patient, rising ctDNA preceded clinical recurrence by four months, despite normal CA-125 and imaging, highlighting its potential advantage. Conversely, some patients exhibited clinical progression with undetectable ctDNA, indicating limitations in assay sensitivity, biological factors, or metastatic sites (e.g., brain metastases). ctDNA and CA-125 showed complementary value in most cases, suggesting potential combined use in clinical monitoring. Our findings demonstrate that ctDNA is a promising biomarker to complement existing monitoring approaches for recurrent OC. In some cases, capable of predicting relapse and treatment response ahead of current clinical indicators. However, identified discordances underscore technical and biological challenges that warrant further investigation. Larger prospective studies are necessary to refine ctDNA's clinical utility and integration into personalized OC care.}, }
@article {pmid41147516, year = {2025}, author = {Thomas, AB and Matthews, AL and Brooks, O and Winquist, A and Nelson, LA and Arias-Fontenot, R and Buchwald, D and Casaletto, KB and Weintraub, S and Heaton, RK and French, BF and Suchy-Dicey, A and Barbosa-Leiker, C}, title = {Psychometric properties of the NIH Toolbox Cognition Battery composites in older adults at risk for Alzheimer's disease and related dementias: A systematic review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70673}, pmid = {41147516}, issn = {1552-5279}, support = {1RF1AG071677-01//National Institute of Health/National Institute on Aging/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Psychometrics ; United States ; National Institutes of Health (U.S.) ; *Neuropsychological Tests ; *Dementia/diagnosis/psychology ; Aged ; *Cognition ; }, abstract = {This systematic review evaluated the psychometric performance of the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composite scores in older adults with and without Alzheimer's disease and related dementias (ADRD). A systematic literature search was conducted using MEDLINE, Embase, PsycINFO, and CINHAL databases. The evidence quality of NIHTB-CB measurement properties was assessed using integrated Consensus-based Standards for the Selection of Health Measurement Instrument (COSMIN) methodology and the Interpretation/Use Argument framework. Fourteen studies met inclusion criteria for this review of the NIHTB-CB. Evidence supporting the scoring, generalization, and extrapolation inferences of the Total, Crystallized, and Fluid composite scores in older adults ranged from developing through exemplary ratings. Findings indicate additional research is warranted on the NIHTB-CB in older adult and ADRD populations. The present study highlights the importance of continued use and research of the NIHTB-CB in diverse, older populations who are at risk for ADRD. HIGHLIGHTS: Limited research focuses on the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composites in older adults. The general psychometric robustness of the NIHTB-CB has been es. The Crystallized composite shows proficient psychometric evidence. The psychometric evidence of Fluid composite is developing due to limited data.}, }
@article {pmid41146877, year = {2025}, author = {Kuhlmann, AS and Madkhali, N and Moskovitz, E and Parrott, JE and Raman, SS and Riker, AO and Martinez-Reyes, J and Gupta, M and Jang, RA and Nelson, V and Gray, MD and Taylor, JJ and Peterson, CW and Kiem, HP}, title = {Heavy-chain immunoglobulin locus editing in rhesus macaque B cells to confer antibody production.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {4}, pages = {101598}, pmid = {41146877}, issn = {2329-0501}, abstract = {Antibody-based immunotherapies are promising; however, their application remains limited to acute diseases due to rapid clearance of antibodies in vivo. Some chronic conditions could benefit from sustained therapeutic antibody expression. One such instance is human immunodeficiency virus type 1 (HIV-1), where the efficiency of broadly neutralizing antibodies by passive immunization has been limited in clinical trials. B cell editing to enable sustained production of an antibody of interest in vivo could address this issue. However, the long-term potential of this approach and feasibility to perform editing in B cells from people living with HIV remain to be determined. We investigated editing of rhesus macaque B cells from healthy or simian/human immunodeficiency virus (SHIV)-infected animals to model this approach. An antibody-encoding cassette was inserted in the immunoglobulin locus by CRIPSR-Cas9-mediated ex vivo B cell editing. Similar indel efficiencies were achieved in B cells from both uninfected and infected animals, and expression of the antibody of interest was detected in up to 10% of uninfected B cells. This study paves the way for future in vivo work to assess the long-term potential of this approach and its impact on B cell development and function in an immunocompetent in vivo nonhuman primate model of HIV persistence and cure.}, }
@article {pmid41145253, year = {2025}, author = {Kataria, I and Selmouni, F and Duggan, C and Sullivan, R and Purushotham, A and Sankaranarayanan, R and Taghavi, K and Basu, P}, title = {Application of implementation science methods and theories for cancer control planning in low-income and middle-income countries: a scoping review.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e108755}, doi = {10.1136/bmjopen-2025-108755}, pmid = {41145253}, issn = {2044-6055}, mesh = {Humans ; *Neoplasms/prevention & control/therapy ; *Developing Countries ; *Implementation Science ; Health Policy ; Delivery of Health Care/organization & administration ; *Health Planning ; }, abstract = {INTRODUCTION: Implementation science (IS) is increasingly recognised as vital in cancer control planning and integrating evidence-based interventions across the cancer care continuum. Contextual differences often cause variability in delivering optimised healthcare, which IS approaches could mitigate. While IS improves planning effectiveness, many programme and policy planners remain unaware of its benefits. To address this, we examined IS theories applied to national cancer control plans (NCCPs)/strategies across five domains: stakeholder engagement, situational analysis, capacity assessment, economic evaluation and impact assessment.
METHODS: We conducted a scoping review using the Arksey and O'Malley framework to analyse NCCPs and strategies from 16 and 17 countries belonging to low and medium categories of Human Development Index (HDI), focusing on resource-constrained settings. We identified plans through the International Cancer Control Partnership portal, categorised them by WHO region and included only those available in English or French. We extracted data into a Microsoft Excel database and performed thematic analysis across five IS domains. Multiple IS experts, selected purposively based on their familiarity with resource-constrained settings, validated the findings, assessed policy relevance and helped develop a pathway for integrating IS into national cancer control planning. They reviewed structured questions in advance and provided feedback on analyses, practical utility, dissemination and simplifying IS application, which was used to refine the pathway and reach consensus.
RESULTS: While many NCCPs incorporated key IS elements such as stakeholder engagement, situational analysis and impact measurement, these often needed to be more explicit and consistently applied. None of the plans assessed health system capacity to determine readiness for implementing new interventions. Although most plans described stakeholder engagement, it was typically unstructured and incomplete. Four low HDI and nine medium HDI countries included costed plans, generally using an activity-based approach. All plans included impact measures (eg, key performance indicators), but five lacked mechanisms for engaging stakeholders or responsible entities to achieve the targets. These findings informed a proposed pathway to integrate IS principles into cancer control planning.
CONCLUSION: Integrating IS into national cancer control planning offers a structured framework for achieving equitable and feasible cancer control policies, particularly in resource-constrained settings, by enabling realistic goal setting and benchmarking against regional and global standards.}, }
@article {pmid41143136, year = {2025}, author = {Tanaka, K and Chikowore, TJB and Deeks, SG and Estes, JD and Ho, YC and Jiang, S and Lee, MJ and Li, C and Machinda, A and Martins, M and Mdletshe, P and Ndhlovu, ZM and Neogi, U and Ott, MM and Rasmussen, TA and Reddy, K and Rutishauser, RL and Farrell-Sherman, A and Tiemessen, CT and Voss, JE and Kityo, C and Lewin, SR and Ndung'u, T and McCune, JM}, title = {Meeting Summary for Keystone Symposia on HIV Cure: Antiretroviral Therapy (ART)-Free Control of HIV Infection in Durban, South Africa, 2025.}, journal = {Pathogens & immunity}, volume = {10}, number = {2}, pages = {196-229}, pmid = {41143136}, issn = {2469-2964}, abstract = {Antiretroviral therapy (ART) can effectively control human immunodeficiency virus (HIV) replication; however, lifelong treatment is required due to viral reservoirs, which fuel viral rebound. This necessitates curative interventions that can achieve either eradication of the reservoir or durable remission off ART. Advances in technology have fostered development of multi-omic techniques encompassing molecular tools, proteomic analyses, imaging, and artificial intelligence (AI)-driven data analysis to understand HIV reservoir biology and persistence. These have informed the investigation of therapeutic interventions such as broadly neutralizing antibodies, latency reversal, immune cell augmentation, antivirals, and gene therapy. From April 7-10, 2025, experts in the field convened at the Keystone Symposia conference, HIV Cure: Antiretroviral Therapy (ART)-Free Control of HIV Infection in Durban, South Africa, to discuss novel strategies for eradication and/or durable ART-free control of HIV.}, }
@article {pmid41141451, year = {2025}, author = {Reed, JC and Hall, L and McKhann, A and Kwak, G and Goecker, EA and Coombs, RW and Chen, H and Roa, J and Vecchio, A and Daar, ES and Hunt, PW and Marra, CM and Campbell, TB and Ma, Q and Swaminathan, S and Macatangay, BJC and Morse, GD and Miller, T and Rusin, D and Ha, B and Alston-Smith, B and Paul, R and Letendre, SL and Spudich, SS and Greninger, AL}, title = {Antiretroviral Therapy Intensification With Dolutegravir and/or Maraviroc Did Not Affect HIV-1 Cell-Associated DNA, RNA, and 2--LTR Circles Over 12 Weeks.}, journal = {Open forum infectious diseases}, volume = {12}, number = {10}, pages = {ofaf594}, pmid = {41141451}, issn = {2328-8957}, abstract = {BACKGROUND: Neurocognitive impairment (NCI) among people living with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) may result from residual viral replication. The A5324 trial found that ART intensification with dolutegravir (DTG) with or without maraviroc (MVC) did not affect NCI in PWH. We evaluated the impact of ART intensification on peripheral virological measures during the first 12 weeks of intensification.
METHODS: The A5324 study was a randomized, double-blind, placebo (PBO)-controlled, 96-week trial of ART intensification with either dual PBO, DTG + PBO, or DTG + MVC in PWH with NCI on ART who were naive to integrase strand transfer inhibitors and MVC. At baseline and weeks 2, 4, and 12, HIV-1 RNA was measured in plasma with a low-copy assay, while HIV-1 cell-associated DNA (caDNA), cell-associated unspliced RNA (caRNA), and cell-associated 2-long terminal repeat circles (ca2LTR) were quantified from peripheral blood mononuclear cells using droplet digital polymerase chain reaction.
RESULTS: Of the 171 participants, 59 were randomized to dual PBO, 57 to DTG + PBO, and 55 to DTG + MVC. Changes in caDNA and caRNA and detection of plasma RNA did not differ between treatment arms over 12 weeks (P > 0.05). Detection of ca2LTR was less frequent at weeks 2-4 in the DTG + MVC arm (40.4%) than in the dual-PBO (70.7%; P =0 .02) and DTG + PBO (68.4%; P = 0.03) arms. However, this difference diminished by week 12, and baseline ca2LTR detection in the DTG + MVC arm was lower than in the other groups.
CONCLUSIONS: DTG intensification had no effect on peripheral markers of HIV-1 persistence. DTG + MVC intensification reduced ca2LTR detection at weeks 2-4, though this effect did not persist through week 12. These findings indicate the minimal impact of intensification on the HIV-1 peripheral reservoir, consistent with prior studies.}, }
@article {pmid41141393, year = {2026}, author = {Choudhury, SR and Kaushal, A and Biswas, P and Padilla, C and Sarthy, JF and Chavan, A and Gonzalez, GA and Meshinchi, S and Farrar, JE}, title = {Transcriptional rewiring by enhancer methylation in CBFA2T3-GLIS2-driven pediatric acute megakaryoblastic leukemia.}, journal = {Genes & diseases}, volume = {13}, number = {1}, pages = {101843}, pmid = {41141393}, issn = {2352-3042}, abstract = {Resistance to chemotherapy and subsequent relapse remain the primary challenge in pediatric acute myeloid leukemia (pAML), particularly in CBFA2T3-GLIS2 (C/G) fusion-positive acute megakaryoblastic leukemia. Here we demonstrate that the C/G fusion drives extensive DNA methylation changes and oncogenic enhancer activation at cis-regulatory elements (CREs), reshaping gene expression. This multi-omics analysis reveals a distinct hypermethylation pattern at promoters of up-regulated genes in C/G[+] pAML across patient samples (n = 24) and representative cell lines, notably enriched in adhesion-related, TGFβ, or Wnt signaling pathways. Hypermethylated regions adjacent to transcription start sites (TSS) maintain open chromatin with H3K27ac enrichment, supporting a mechanism of de novo chromatin looping and active transcription in a non-canonical manner. Additionally, C/G fusion binding near the DNA methyltransferase 3B (DNMT3B) promoter correlates with elevated DNMT3B expression, implicating its role in aberrant DNA methylation changes at CREs. This study elucidates the epigenetic mechanisms driving C/G[+] pAML, showing how the fusion reshapes chromatin and DNA methylation landscapes by impacting the expression (and likely activity) of epigenetic modifiers like DNMT3B. Functionally, DNMT3B inhibition enhances apoptotic sensitivity to BCL2 blockade, indicating that targeting DNMT3B may overcome apoptotic resistance in C/G[+] leukemic cells and offer a therapeutic strategy for this high-risk subtype.}, }
@article {pmid41141367, year = {2025}, author = {Wick, BJ and Kluesner, MG and Slipek, NJ and Skeate, JG and Niemeyer, EM and Webber, BR and Moriarity, BS}, title = {Installation of dominant-negative mutations in FAS and TGFβR2 via base editing in primary T cells.}, journal = {Molecular therapy. Oncology}, volume = {33}, number = {4}, pages = {201063}, pmid = {41141367}, issn = {2950-3299}, abstract = {Adoptive cell transfer (ACT) of engineered T cells is effective against B cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FAS ligand (FASL) and transforming growth factor β (TGF-β) are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach that directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGF-β signaling. Chimeric antigen receptor (CAR)-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.}, }
@article {pmid41138914, year = {2025}, author = {Zhang, Y and Alver, S and Shan, Z and Mossavar-Rahmani, Y and Hu, J and Zhang, J and St-Onge, MP and Kaplan, R and Xue, X and Qi, Q}, title = {The timing of macronutrient and major food group intake and associations with mortality among US adults, 1999-March 2020: a serial cross-sectional study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.10.014}, pmid = {41138914}, issn = {1938-3207}, abstract = {BACKGROUND: Eating timing has been increasingly linked to health, yet national trends in macronutrient/food group timing and their health implications remain unclear.
OBJECTIVE: To characterize trends in timing of energy, macronutrient, and food group intake among US adults and examine their associations with mortality.
METHODS: In this serial cross-sectional study of adults aged ≥20 years with ≥1 valid 24-hour dietary recall (National Health and Nutrition Examination Survey, 1999-March 2020), we examined secular trends in timing of energy, macronutrients, and major food group intake. Associations with mortality (through December 2019) were examined using Cox models.
RESULTS: Among 50,264 adults, evening (6-10pm) accounted for the highest daily energy intake (weighted mean proportions across years, 31.9%-33.3%), followed by noon (10am-2pm, 24.7%-26.8%), afternoon (2-6pm, 19.9%-21.8%), morning (6-10am, 13.5%-14.9%), and overnight (10pm-6am, 5.6%-6.5%); midnight (10-2am) eating occurred in 23.4%-28.0% of the population. Macronutrient and food groups followed similar patterns, except whole grain (peaked in the morning) and fruit, egg, and dairy intake (more evenly distributed). Over years, noon and midnight energy intake proportions declined, while afternoon proportion increased; secular trends varied by macronutrients/food groups. Fasting started at 8:34-8:51pm and ended at 8:41-8:52am; intake midpoint was 2:38-2:48pm; intake duration was 11.9-12.2 hours. Male, non-Hispanic black, and socioeconomically disadvantaged groups had greater midnight intake proportions and later intake midpoints. Reallocating 5% of daily energy to midnight was associated with higher cardiovascular mortality (HR, 1.09; 95% CI, 1.02,1.17), driven by carbohydrates; reallocating 5% to predawn (2-6am) was associated with higher cancer mortality (1.22;1.05,1.41), driven by proteins. Each 1-hour delay in fasting and intake midpoint was associated with an 8%-9% higher cardiovascular mortality.
CONCLUSION: Overnight intake and delayed eating timing are prevalent among US adults, especially among socioeconomically disadvantaged groups, and were associated with higher mortality, particularly for specific macronutrients/foods, supporting eating timing recommendations integrating food composition.}, }
@article {pmid41138816, year = {2025}, author = {Shadman, M and Ahmed, S and Byrne, MT and Chavez, JC and Kamdar, M and Sorror, ML and Perales, MA and Hill, JA and Moslehi, J and Miklos, DB}, title = {Who Is Eligible for CAR T-Cell Therapy? Expert Perspectives on Overcoming Referral Barriers.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.10.025}, pmid = {41138816}, issn = {2666-6367}, abstract = {BACKGROUND: CD19-directed chimeric antigen receptor (CAR) T-cell therapies, including lisocabtagene maraleucel, axicabtagene ciloleucel, and tisagenlecleucel, have revolutionized the treatment landscape for patients with hematologic malignancies. However, identification and referral of patients who could benefit from treatment remains a significant challenge.
OBJECTIVE: To report expert recommendations for CAR T-cell therapy referral.
METHODS: Recommendations were gathered from 10 experts in oncology, hematology, cardiology, and infectious disease from a roundtable meeting and/or subsequent reviews from November 13, 2024, to June 9, 2025.
RESULTS: The authors considered the following potential factors: age, performance status, disease status, cardiovascular function, pulmonary function, renal function, hepatic function, infections, and psychological health. Based on existing evidence, the authors agreed that none of the factors discussed should preclude patients from receiving referrals/further evaluation for CAR T-cell therapy, particularly with current advances in supportive care and integration of services from other specialties. Timely referral should be made by the patient's primary oncologist to specialists as early as the disease is deemed relapsed or refractory, and preferably before the subsequent line of therapy is started to allow better access to care and to improve treatment outcomes. Before CAR T-cell therapy, holding therapy (before leukapheresis) and/or bridging therapy (after leukapheresis) may be given to patients with high-volume disease, in consultation with CAR T-cell therapy specialists. Based on the safety profile of CAR T-cell therapies, experts recommended flexible monitoring and transfer of care back to primary/community oncology physicians, starting from 2 weeks after infusion to improve access to this potentially curative therapy. Adaptations to clinical practice based on the most recent regulations, policy requirements, and institutional guidelines should be made as needed.
CONCLUSIONS: In summary, a panel of 10 experts provided recommendations for timely patient referral for CAR T-cell therapy upon occurrence of relapsed or refractory disease and before initiation of subsequent line of therapy to improve care access and treatment outcomes. Experts noted that with close collaboration between CAR T-cell therapy specialists and other medical disciplines, CAR T-cell therapy remains a feasible option for most patients despite their comorbidities.}, }
@article {pmid41138741, year = {2025}, author = {Anderson, BO and Duggan, C}, title = {Lessons from CONCORD and VENUSCANCER: closing global gaps in cancer care for women.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)01580-6}, pmid = {41138741}, issn = {1474-547X}, }
@article {pmid41137757, year = {2025}, author = {Fong, Y and Huang, Y and Huang, Y and Woo, W and McGarry, A and Áñez, G and Dunkle, LM and Cho, I and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Petropoulos, CJ and Leith, A and Haugaard, D and Webb, W and Lu, Y and Yu, C and Carpp, LN and Randhawa, AK and Andrasik, MP and Kublin, JG and Hutter, J and Keshtkar-Jahromi, M and Beresnev, TH and Rodriguez, CA and Tapia, M and Turley, CB and Zorrilla, CD and Cohen, SH and Kline, SE and Barranco, E and Corey, L and Neuzil, KM and Follmann, D and Ake, JA and Gay, CL and Kotloff, KL and Jones, T and Koup, RA and Donis, RO and Gilbert, PB}, title = {Analysis of antibody markers as immune correlates of risk of severe COVID-19 in the PREVENT-19 efficacy trial of the NVX-CoV2373 recombinant protein vaccine.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf558}, pmid = {41137757}, issn = {1537-6591}, abstract = {BACKGROUND: We previously showed that ancestral-specific anti-Spike binding IgG concentration and 50% inhibitory dilution neutralizing antibody titer (nAb-ID50) measured at 2 weeks post-dose 2 (∼peak) were inverse correlates of risk (CoRs) of COVID-19 over 2 months post ∼peak in the PREVENT-19 trial of the NVX-CoV2373 vaccine; there were not sufficient data to assess CoRs of severe COVID-19.
METHODS: Here we assessed, in the same vaccinated cohort, Delta- and ancestral-specific Spike IgG and nAb-ID50 at ∼peak and over time as CoRs of severe COVID-19 and of Delta COVID-19 over 3.5-10 months post ∼peak (287 breakthrough Delta cases, including 8 severe; 446 non-cases).
RESULTS: ∼Peak antibody levels were much higher for non-cases vs. severe cases (all inferred Delta), with nAb-ID50 Delta geometric mean 209.5 arbitrary units (AU)/mL (95% CI: 176.1, 249.1) vs. 9.6 AU/mL (95% CI: 2.4, 38.6), respectively. Frequency of detectable nAb-ID50 titer was 98.3% (97.2, 99.0) for non-cases vs. 62.5% (22.3, 93.9) for severe cases. All markers were inverse CoRs of severe COVID-19, with a ∼peak hazard ratio (HR) of 0.13 (95% CI: 0.03, 0.57) per 10-fold nAb-ID50 Delta increase. Severe COVID-19 risk through 305 days post-Day 35 was 0.0338 (0.0043, 0.206) at the nAb-ID50 Delta 2.5th percentile (8.4 AU/ml), and 0.002 (0.0000, 0.0108) and 0.0002 (0.0000, 0.0035) at the 50th and 95th percentiles (210, 2522 AU/ml).
CONCLUSIONS: Post-vaccination NVX-CoV2373 antibody levels are stronger predictors of severe COVID-19 than any-severity Delta COVID-19. Low antibody responses indicate vulnerability to severe COVID-19.}, }
@article {pmid41136629, year = {2025}, author = {Corey, L and Ratevosian, J and Beyrer, C and Currier, J and Eron, J and Cohen, MS and Deeks, SG}, title = {How HIV research drives health innovation in multiple diseases.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41136629}, issn = {1546-170X}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1AI068636//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068636//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068619//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, }
@article {pmid41136348, year = {2025}, author = {Duran, MC and Shah, PD and Bell-Brown, AM and Rojina, J and Glascock, M and Ramirez, M and Ibarra, G and Garza, L and Linde, S and Bishop, S and Garrison, MM and Pascoe, KM and Drain, PK and Zhou, C and Ko, LK}, title = {Back to school: a qualitative study evaluating a community-informed COVID-19 risk communication intervention for rural elementary school children and their families.}, journal = {Translational behavioral medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41136348}, issn = {1613-9860}, support = {OT2 HD107544/GF/NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/prevention & control ; Child ; Qualitative Research ; Female ; Male ; Rural Population ; Focus Groups ; Schools ; Parents/psychology ; SARS-CoV-2 ; *Students/psychology ; *Return to School ; Communication ; School Health Services ; Health Knowledge, Attitudes, Practice ; Adult ; }, abstract = {BACKGROUND: ReOpening Schools Safely and Educating Youth (ROSSEY) was a cluster randomized controlled trial of a risk communication intervention for COVID-19 prevention to promote safe return to school among students in a rural, agricultural community.
PURPOSE: This qualitative study evaluated the implementation of a risk communication intervention and a school district's COVID-19 testing program through parent focus groups and interviews with school staff and students.
METHODS: Parents (n = 37), students (n = 19), and school staff (n = 14) from seven schools that received the intervention shared their experience via focus groups and interviews informed by the RE-AIM framework. Deductive and inductive coding was conducted by four data analysts. Themes were validated with community members.
RESULTS: Parent focus groups, student and staff interviews provided insight into the ROSSEY study implementation. We identified five main themes: (i) social and financial drivers of participation; (ii) personal beliefs and unique challenges to research participation; (iii) intervention reinforced knowledge and shifted behavior; (iv) the appeal of comic books and videos supported adoption; and (v) multimodal communication and partnerships enhanced implementation.
CONCLUSIONS: The risk communication intervention was deemed culturally appropriate, reinforced previous knowledge, and encouraged adoption of preventive behaviors. The partnership with the school district and collaboration with the district's COVID-19 testing program ensured success of recruitment, study implementation, and adoption of preventive behaviors.}, }
@article {pmid41135920, year = {2025}, author = {Medlin, AR and Abrams, HR and Kent, EE and Ogunjesa, BA and Park, S and Tan, KR}, title = {Variations in mental distress among caregivers of individuals with chronic illnesses and comorbid cognitive impairment.}, journal = {American journal of preventive medicine}, volume = {}, number = {}, pages = {108165}, doi = {10.1016/j.amepre.2025.108165}, pmid = {41135920}, issn = {1873-2607}, abstract = {OBJECTIVES: To examine rates of mentally unhealthy days (MUDs) and frequent mentally unhealthy days (FMUDs) among caregivers of cancer, heart disease, mental illness, and ADRD based on caregiving intensity, and how cognitive impairment (CI) in non-ADRD caregiving moderates these relationships.
METHODS: Data from 22,550 caregivers in the 2019-2023 Behavioral Risk Factor Surveillance System were used to explore the relationship between caregiving intensity, MUDs, and the presence of CI. Zero-inflated negative binomial regressions assessed associations of caregiving intensity on MUDs, and logistic regressions examined patterns in FMUDs, controlling for demographics and survey weighting.
RESULTS: Caregivers of individuals with mental illness reported the highest FMUDs (27.53%) followed by cancer (20.3%), heart disease (18.57%), and ADRD (17.82%). Increased caregiving intensity correlated with higher MUD rates, particularly among cancer, heart disease, and ADRD caregivers. Cancer caregivers showed increased MUDs when moderating for CI. Higher caregiving intensity was linked to increased FMUDs in cancer and ADRD caregivers, with cancer caregivers showing more FMUDs when moderating for CI.
CONCLUSIONS: Caregiving intensity affects mental health outcomes differently across illnesses. Tailored support is needed for caregivers, especially those providing care for individuals with comorbid cognitive impairment.}, }
@article {pmid41135058, year = {2025}, author = {Adesina, O and Voutsinas, JM and Wu, QV and Teos, LY and Rokni, M and Nalbant, H and Nardo, L and Wun, T and Zemel, BS}, title = {Low bone mineral density and pain impact in adults with sickle cell disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025015957}, pmid = {41135058}, issn = {2473-9537}, abstract = {Low bone mineral density (BMD) is prevalent skeletal finding in people with sickle cell disease (SCD), but its clinical consequences are poorly understood. We hypothesized that low BMD, independent of osteonecrosis (ON), would associate with worse pain in SCD adults. In the SCD Bone Pain study, 53 ambulatory adults (64% females, mean age 38±11years, 66% Hb SS/Sβ0 thalassemia) underwent dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine, hip, forearm, and whole body. They also completed the Adult Sickle Cell Quality of Life Measurement Information System pain impact questionnaire. Twenty-three participants (43%) had low bone mass, defined as lumbar spine, total hip, or femoral neck BMD Z-scores ≤ -2. In multivariate linear regression, lumbar spine BMD Z-scores significantly changed by +0.31, -0.29, -0.14, and -1.3 for every unit increase in hemoglobin, indirect bilirubin, and white blood cell count, and with Crizanlizumab use, respectively. Pain impact T-scores significantly decreased (worsened) by 6.0 and 6.5 with reduced estimated glomerular filtration rate and chronic opioid therapy, respectively, but increased (improved) by 3.8 for every unit increase in serum phosphate. Median [interquartile range] pain impact T-scores were significantly lower in participants with low BMD and ON (38.3 [37.4, 40.1]), compared to those with either low BMD (49.5 [43.6, 54.4), p=3x10-5 or ON (52.7 [45.3, 57]), p=2x10-4 alone. Whether sickle cell-related low BMD results from impaired bone formation and/or accelerated bone loss remains unclear. Understanding how low bone density, with or without osteonecrosis, mediates SCD pain warrants further investigation. NCT05283148.}, }
@article {pmid41134118, year = {2025}, author = {Chua, KJ and Quilang, RC and Sallinger, K and Aktipis, CA and Arck, P and Bianchi, DW and Chang, HD and Cleaves, HJ and Eikmans, M and Fjeldstad, HES and Haig, D and Harrington, WE and Horsnell, W and Jacobsen, DP and Kamper-Jørgensen, M and Kanaan, SB and Khosrotehrani, K and Lambert, NC and Nelson, JL and Olsen, MB and Pan, TD and Prins, JR and Schildberg, FA and Staff, AC and Ståhlberg, A and Stelzer, IA and Urbschat, C and Way, SS and Wilson, MA and Ye, J and Kroneis, T and Boddy, AM}, title = {Identifying Key Questions and Challenges in Microchimerism Biology.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e14969}, doi = {10.1002/advs.202514969}, pmid = {41134118}, issn = {2198-3844}, support = {62214//John Templeton Foundation/ ; //Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health/ ; }, abstract = {Microchimerism research has recently gained renewed attention despite known existence of these rare cells for decades. Fetal and maternal microchimeric-derived cells may have functional capabilities, and are increasingly associated with both beneficial and adverse health outcomes. Yet, establishing the role of microchimerism in health has been largely constrained methodologically and theoretically. The Microchimerism, Human Health, and Evolution Project address these challenges by calling on 29 leading microchimerism experts to put forth key research questions that can substantially advance the field. Seven major categories are identified: function and mechanism; microchimerism in interventions, treatment, and transplant; mapping "generational microchimerism"; evolution; microchimerism detection; appropriate experimental model systems; and definition of microchimerism. Identifying these questions - and continuing to find answers - will be crucial for advancing the knowledge of microchimerism in health and disease.}, }
@article {pmid41130408, year = {2025}, author = {Le, X and Baik, C and Cho, BC and Riess, JW and Piotrowska, Z and Johannes de Langen, A and Goldberg, SB and Goldman, JW and Reguart, N and Shiraishi, Y and Ambrose, H and Fraenkel, PG and Ruiz, BM and Smith, PE and Tang, KH and Yu, HA}, title = {Osimertinib Plus Savolitinib in Patients With EGFR-Mutated Advanced NSCLC With MET Alterations After First-Line Osimertinib: Clinical Outcomes, Safety, and Biomarker Analysis: A Brief Report.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2025.10.009}, pmid = {41130408}, issn = {1556-1380}, abstract = {INTRODUCTION: The ORCHARD (NCT03944772) study was conducted to characterize resistance mechanisms and identify optimal treatments following progressive disease (PD) on first-line osimertinib. We report results from the osimertinib plus savolitinib module.
METHODS: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with PD on first-line osimertinib with MET gene amplification (≥4 copies of MET over tumor ploidy) per next-generation sequencing of a post-progression biopsy received osimertinib plus savolitinib. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DoR) and overall survival (OS), and safety. Correlation of ORR with baseline molecular alterations was an exploratory analysis.
RESULTS: Thirty-two patients were enrolled; all had tumors with MET amplification. At primary analysis cutoff (January 2023), confirmed ORR was 47% (80% confidence interval [CI]: 35-60). Median DoR was 14.5 months (95% CI: 5.6-18.7). Median PFS was 7.6 months (95% CI: 3.2-15.9). There was a trend towards increased ORR in patients with high MET gene copy number (≥10 versus <10). Fourteen patients (44%) had grade ≥3 treatment-emergent adverse events; most commonly pneumonia (n = 3; 9%). At final database lock (May 2024), 20 patients (63%) had died; median OS was 20.7 months (95% CI: 9.9-34.8).
CONCLUSIONS: Osimertinib plus savolitinib demonstrated encouraging clinical benefit in patients with EGFR-mutated advanced NSCLC and MET amplification following PD on first-line osimertinib. Safety was consistent with profiles of the individual drugs.}, }
@article {pmid41129763, year = {2025}, author = {Einstein, DJ and Abel, ML and Aragon-Ching, JB and Arlen, PM and Autio, KA and Bilusic, M and Carducci, MA and Choyke, PL and Citrin, DE and Figg, WD and Graff, JN and Gulley, JL and Halabi, S and Karzai, F and Lindenberg, L and Markowski, MC and Marshall, CH and McNeel, DG and Mena, E and Moon, H and Pachynski, RK and Paller, CJ and Patel, KR and Posadas, EM and Pienta, KJ and Regan, MM and Sena, LA and Walmsley, CS and Wei, XX and Yu, EY and Tran, PT and Madan, RA}, title = {National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501693}, doi = {10.1200/JCO-25-01693}, pmid = {41129763}, issn = {1527-7755}, abstract = {PURPOSE: Biochemical recurrence (BCR) of prostate cancer (PCa) after definitive surgery and/or radiation (including salvage strategies) is a burgeoning area of clinical research inspired by ultrasensitive next-generation imaging. Most phase III trials in PCa have focused on metastatic disease, defined by conventional imaging. Despite the emergence of new imaging, clinical trial principles from metastatic studies will not optimize future BCR trials.
METHODS: A Working Group convened at the National Cancer Institute on November 13, 2024 (NCI BCR WG). Key areas of discussion included nomenclature, baseline criteria for data capture, imaging considerations, delineation of high-risk populations to be targeted for trial development, requirements of metastasis-directed therapy (MDT) or hormonal therapy, quality-of-life considerations, and potential study end points.
RESULTS: The NCI BCR WG defined the novel term "prostate-specific membrane antigen (PSMA)+BCR" to identify the emerging concept of recurrent PCa identifiable only on PSMA positron emission tomography (PET), overlapping with BCR and distinct from metastatic hormone-sensitive PCa as traditionally defined by conventional imaging. The WG suggested defining high-risk BCR with a prostate-specific antigen doubling time of ≤6 months, regardless of PET findings. The WG provided recommendations for baseline data capture and imaging requirements. Neither systemic therapy nor MDT were considered mandatory for control arms. The WG also discussed novel end points and quality-of-life metrics in this disease space.
CONCLUSION: These discussions should inform future clinical BCR trials in this distinct disease space relative to metastatic disease defined by conventional imaging. The NCI BCR WG strongly advocates that future trials explore deintensification of treatment to minimize toxicity in this relatively indolent disease state.}, }
@article {pmid41129758, year = {2025}, author = {Bagshaw, P and Potter, JD and Griffiths, N and Hornblow, A and Cox, B and Gower, K}, title = {Nurse endoscopists: a rational response to rising rates of young-onset colorectal cancer in Aotearoa New Zealand.}, journal = {The New Zealand medical journal}, volume = {138}, number = {162}, pages = {76-86}, doi = {10.26635/6965.7100}, pmid = {41129758}, issn = {1175-8716}, mesh = {Humans ; New Zealand/epidemiology ; *Colorectal Neoplasms/epidemiology/diagnosis/nursing ; Middle Aged ; *Colonoscopy/nursing ; *Early Detection of Cancer ; Sigmoidoscopy/nursing ; Age of Onset ; Incidence ; *Mass Screening ; Aged ; Adult ; Female ; Male ; }, abstract = {Young-onset (<50 years) colorectal cancer (YOCRC) has been increasing in Aotearoa New Zealand since the birth cohort born around the mid-1950s. Possible responses include education and public health measures, none of which are likely to make a major impact in the foreseeable future. Many YOCRCs are presenting at late stages with predominantly distal cancers. Our current National Bowel Screening Programme (NBSP), screening people 60-75 years, was introduced with inadequate resources; as a result, some colonoscopy services have been moved from symptomatic cases to screening, resulting in diagnostic delays and poorer outcomes. Extending screening to 40 or 45 years will markedly increase the need for follow-up colonoscopies and stretch services beyond breaking point. Sigmoidoscopy is associated with a substantial and sustained reduction in risk of distal colorectal cancer incidence and mortality. As there are too few endoscopists for the existing workload, increasing the nurse endoscopist workforce is a rational step. Initial training would focus on flexible sigmoidoscopy (FS) and concentrate on symptomatic patients <50 years. Steadily increasing nurse endoscopist numbers will contribute to management of the rising incidence of YOCRC. Without disrupting the NBSP or putting much extra strain on need for follow-up colonoscopies, nurse-led FS clinical services can expand to anyone with relevant symptoms and, as a longer-term goal, eventually become part of an expanded screening programme that could include one-off FS at age 50. If we are agreed that this is essential, training and service must be adequately funded and accompanied by a public advocacy campaign to ensure sufficient resources.}, }
@article {pmid41129365, year = {2025}, author = {Watling, CZ and Campbell, PT and Graubard, BI and Wang, Y and Gewirtz, AT and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, JM and Hofmann, JN and Huang, WY and Kang, JH and Koshiol, J and Loftfield, E and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Purdue, MP and Sesso, HD and Shrubsole, M and Sinha, R and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Watts, EL and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Barupal, D and Petrick, JL and McGlynn, KA}, title = {Pre-diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case-control analysis of 12 prospective cohorts.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70201}, pmid = {41129365}, issn = {1097-0215}, support = {//American Cancer Society/ ; //National Institutes of Health Intramural/ ; 75N92021D00001/NH/NIH HHS/United States ; 75N92021D00002/NH/NIH HHS/United States ; 75N92021D00003/NH/NIH HHS/United States ; 75N92021D00004/NH/NIH HHS/United States ; 75N92021D00005/NH/NIH HHS/United States ; CA047988/NH/NIH HHS/United States ; CA182913/NH/NIH HHS/United States ; HL043851/NH/NIH HHS/United States ; HL080467/NH/NIH HHS/United States ; HL09935/NH/NIH HHS/United States ; CA34944/NH/NIH HHS/United States ; CA40360/NH/NIH HHS/United States ; CA097193/NH/NIH HHS/United States ; HL26490/NH/NIH HHS/United States ; HL34595/NH/NIH HHS/United States ; NCI U01 167552/NH/NIH HHS/United States ; U01CA202979/NH/NIH HHS/United States ; U01CA164974/NH/NIH HHS/United States ; U01CA63673/NH/NIH HHS/United States ; UM1CA167462/NH/NIH HHS/United States ; U01CA167462/NH/NIH HHS/United States ; U24ES035386/NH/NIH HHS/United States ; UM1CA186107/NH/NIH HHS/United States ; 187861/CAPMC/CIHR/Canada ; }, abstract = {The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case-control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23-1.79). Concentrations of anti-flagellin IgA (1.13, 1.01-1.28) and IgG (1.13, 1.01-1.28), anti-lipopolysaccharide IgG (1.20, 1.01-1.42), and soluble CD14 (1.12, 1.01-1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34-2.33) but not ICC (0.67, 0.37-1.22; p-heterogeneity = .003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.}, }
@article {pmid41129142, year = {2025}, author = {Jani, S and Bencomo, T and Shasha, C and Pulliam, T and Jojic, A and Church, CD and Gooley, TA and Koelle, DM and Newell, EW and Nghiem, P}, title = {Circulating neoantigen- and viral oncoprotein-specific CD8+ T cells share a transcriptional signature.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-25-0082}, pmid = {41129142}, issn = {2326-6074}, abstract = {Tumor-specific CD8+ T cells in blood appear to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, identification of tumor-specific CD8+ T cells is not routinely feasible. Here, we characterized polyomavirus-specific CD8+ T cells from blood of 17 patients with virus-driven Merkel cell carcinoma (MCC). We identified a 98-gene signature, SPoTT (Signature of Peripheral Tumor-specific CD8+ T cells), that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus from tumor. In validation cohorts of MCC, as well as neoantigen-driven cancers, SPoTT was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCR_PBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize MCPyV-specific T cells with sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally-driven cancers.}, }
@article {pmid41129124, year = {2025}, author = {Su, CT and Ramsey, SD and Shankaran, V}, title = {Can We Use Credit Data to Assess Cancer Financial Hardship?.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.4371}, pmid = {41129124}, issn = {2374-2445}, }
@article {pmid41128595, year = {2025}, author = {Albirair, M and Nyame, Y and Gulati, R and Etzioni, R}, title = {Age-Specific racial disparities in the incidence of fatal prostate cancer: an analytic deconstruction.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf103}, pmid = {41128595}, issn = {2515-5091}, abstract = {BACKGROUND: Black men in the United States bear a disproportionate share of the prostate cancer (PCa) burden, with more than 50% higher incidence and double the mortality compared with White men. Previous studies have examined racial disparities in the incidence of fatal PCa (fPCa), defined as diagnosis leading to disease-specific death within 10 years and found that they are greater in younger versus older men. However, the extent to which these trends are driven by disparities in incidence or survival is unknown.
METHODS: We conduct a retrospective analysis of data from the Surveillance, Epidemiology, and End Results program over the period 1980-2009 to decompose the incidence of fPCa into incidence and 10-year probability of death and quantify the relative disparities in these metrics by age at diagnosis.
FINDINGS: We find that relative PCa incidence for Black versus White men significantly decreases by 0.116 units with each successive five-year age group (95% CI = -0.183 to -0.049) but the relative probability of death within 10 years does not differ significantly by age (slope = -0.012, 95% CI = -0.060 to 0.035). Further, this deconstruction is similar before and after the introduction of prostate-specific antigen screening.
CONCLUSION: We conclude that higher relative incidence of fPCa in young Black men vs young White men appears to be largely driven by their significantly increased incidence of disease. This finding supports investigating targeted screening of Black men beginning at younger ages than White men.}, }
@article {pmid41125870, year = {2025}, author = {Sasaki, K and Bhatia, V and Asano, Y and Bakhtiari, J and Kaur, P and Wang, C and Matsuo, T and Dubois, O and Chiu, PC and Gun, D and Singh, C and Panagi, I and Noblecourt, L and Nikolaidi, M and Chong, T and Javier, G and Priceman, SJ and Chapuis, AG and Lee, JK and Ishihara, J}, title = {Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models.}, journal = {Nature biomedical engineering}, volume = {}, number = {}, pages = {}, pmid = {41125870}, issn = {2157-846X}, support = {W81XWH-21-1-0581//U.S. Department of Defense (United States Department of Defense)/ ; HT9425-23-1-0089//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH-21-1-0581//U.S. Department of Defense (United States Department of Defense)/ ; SBF007\100097/AMS_/Academy of Medical Sciences/United Kingdom ; RIA21-ST2-010/PCUK_/Prostate Cancer UK/United Kingdom ; TLD-CAF24-006/PCUK_/Prostate Cancer UK/United Kingdom ; RIA21-ST2-010/PCUK_/Prostate Cancer UK/United Kingdom ; 202160429//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; ALTF 56-2022//European Molecular Biology Organization (EMBO)/ ; Prostate Cancer Foundation Young Investigator Awards//Prostate Cancer Foundation (PCF)/ ; }, abstract = {Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimaeric antigen receptor (CAR)-T cell therapies applied to solid tumours. Previously, CAR-T cells were armoured with immunostimulatory molecules, such as interleukin 12 (IL-12), to overcome this issue, but faced high toxicity. Here we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of prostate 1 (STEAP1) is retained within murine prostate tumours. This leads to high intratumoural interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumour antigens after CBD-IL-12-armoured CAR-T cell treatment. A combination of CBD-IL-12-armoured CAR-T cells and immune checkpoint inhibitors eradicated large tumours in an established prostate cancer mouse model. In addition, human CBD-IL-12-armoured CAR-T cells showed potent anti-tumour efficacy in a 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armoured CAR-T cells. CBD fusion to potent payloads for CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumours.}, }
@article {pmid41124669, year = {2025}, author = {Berman, JN and Verma, A and Viola, SA and Alonzo, T and Wang, YC and Brodersen, LE and Loken, MR and Beckman, AK and Hirsch, BA and Raimondi, S and Chisholm, KM and Ma, X and Ries, RE and Meshinchi, S and Gamis, AS and Schore, RJ and Taub, JW and Kolb, EA and Cooper, TM and Hitzler, JK}, title = {Molecular Risk Markers Define Risk of Relapse in Myeloid Leukemia of Down syndrome Beyond Measurable Residual Disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017837}, pmid = {41124669}, issn = {2473-9537}, abstract = {Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric acute myeloid leukemia (AML) that responds to reduced intensity chemotherapy as compared to non-DS AML that requires intensive chemotherapy and often stem cell transplant. While most patients with ML-DS have a favorable prognosis, outcomes for those with refractory or relapsed disease are dismal. Children's Oncology Group (COG) study AAML1531 introduced the use of minimal residual disease measured by multi-parameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 ML-DS patients enrolled, 41 were classified as high risk (HR) due to positive EOI-1 MRD and treated with intensified chemotherapy similar to that used for pediatric non-DS AML. Treatment intensification did not improve the 2-year event-free survival compared to MRD-positive patients treated with reduced intensity therapy in predecessor study AAML0431(80.5 + 12.4% vs. 76%, p=0.247) or overall survival (80.5 + 12.4% vs. 76.2 + 18.6%, p=0.819), but significantly increased the frequency of febrile neutropenia and sepsis events. While stratification of treatment intensity based on MRD was not beneficial, molecular markers of relapse risk proposed by the Japan Children's Cancer Group for ML-DS (alterations of CDKN2A, ZBTB7A, JAK2, TP53) proved prognostic. Relapse risk was 50% in AAML1531 HR patients with any high risk molecular marker compared to 6.7% in those without. Similar relapse results were obtained in the MRD-negative AAML1531 group, suggesting molecular risk markers can predict outcome and thus be used to stratify therapy in ML-DS. https://clinicaltrials.gov/study/NCT02521493.}, }
@article {pmid41124233, year = {2025}, author = {Cortés, J and Punie, K and Barrios, C and Hurvitz, SA and Schneeweiss, A and Sohn, J and Tokunaga, E and Brufsky, A and Park, YH and Xu, B and Hegg, R and Oliveira, M and Fabi, A and Vaksman, N and Valdez, T and Zhang, X and Lai, C and Tolaney, SM and , }, title = {Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2511734}, pmid = {41124233}, issn = {1533-4406}, abstract = {BACKGROUND: Patients with previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer who are not candidates for inhibitors of programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) have limited treatment options.
METHODS: In this international, phase 3, open-label, randomized trial, we enrolled patients with previously untreated, advanced triple-negative breast cancer who were not candidates for PD-1 or PD-L1 inhibitors owing to previous use or coexisting conditions. Patients had either PD-L1-negative tumors with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells, multiplied by 100) of less than 10 or PD-L1-positive tumors with a CPS of 10 or higher and were assigned in a 1:1 ratio to receive sacituzumab govitecan or chemotherapy (paclitaxel, nanoparticle albumin-bound paclitaxel, or gemcitabine plus carboplatin). The primary end point was progression-free survival, assessed by blinded independent central review. Secondary end points included overall survival, objective response, the duration of response, and safety.
RESULTS: Among 558 patients, median progression-free survival was 9.7 months (95% confidence interval [CI], 8.1 to 11.1) with sacituzumab govitecan and 6.9 months (95% CI, 5.6 to 8.2) with chemotherapy (stratified hazard ratio for disease progression or death, 0.62; 95% CI, 0.50 to 0.77; P<0.001). An objective response was confirmed in 48% of patients (95% CI, 42 to 54) who received sacituzumab govitecan and 46% (95% CI, 40 to 52) who received chemotherapy; the median response duration was 12.2 months (95% CI, 9.7 to 13.8) and 7.2 months (95% CI, 5.7 to 8.4), respectively. Adverse events of grade 3 or higher occurred in 66% of patients who received sacituzumab govitecan (most frequently neutropenia [in 43%], diarrhea [in 9%], and leukopenia [in 7%]) and in 62% of patients who received chemotherapy (most frequently neutropenia [in 41%], anemia [in 16%], and leukopenia [in 13%]). The incidence of adverse events that led to discontinuation of sacituzumab govitecan or at least one chemotherapy drug was 4% and 12%, respectively.
CONCLUSIONS: Sacituzumab govitecan led to significantly longer progression-free survival than chemotherapy among patients with advanced triple-negative breast cancer who were not candidates for treatment with PD-1 or PD-L1 inhibitors. The incidence of adverse events of grade 3 or higher with sacituzumab govitecan was similar to that with chemotherapy, but adverse events were common. (Funded by Gilead Sciences; ASCENT-03 ClinicalTrials.gov number, NCT05382299.).}, }
@article {pmid41124032, year = {2025}, author = {Panian, J and Henderson, NC and Herchenhorn, D and Barata, PC and Bilen, MA and Graham, L and Heath, E and Hwang, C and Supernois, A and Kilari, D and Thapa, B and Koshkin, VS and Jindal, T and Nauseef, JT and Sokolova, A and Amery, T and Zakharia, Y and Schweizer, MT and Raychaudhuri, R and Reichert, ZR and Dorff, T and Armstrong, AJ and Wang, J and Alva, A and McKay, RR}, title = {Genomic Alterations and Associated Outcomes in Patients with PSMA-Positive Metastatic Castration-Resistant Prostate Cancer treated with 177Lu-PSMA-617.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyaf358}, pmid = {41124032}, issn = {1549-490X}, abstract = {BACKGROUND: 177Lu-PSMA-617 is approved for patients with metastatic castration-resistant prostate cancer (mCRPC). Although treatment is associated with improved outcomes, not all patients benefit and response is heterogeneous. We aim to characterize genomic alterations associated with benefit to 177Lu-PSMA-617.
METHODS: This study used the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n = 2445). The primary endpoint was ≥50% PSA decline (PSA50) from baseline with 177Lu-PSMA-617 in molecular subgroups. Secondary endpoints included 90% PSA decline (PSA90). Associations were assessed using Fisher's exact test and Cox regression in multivariable analysis.
RESULTS: We identified 183 mCRPC patients treated with 177Lu-PSMA-617. Median number of prior lines of mCRPC therapy was three. Overall, PSA50 was 49%, median progression-free survival was 7.6 months, and median overall survival was 13.9 months. NF1 (n = 8) and FOXA1 alterations (n = 5) were associated with increased PSA50 (88% vs. 47%, p = 0.03 for NF1; 100% vs. 47%, p = 0.03 for FOXA1). Among CRPC sequenced tumors (n = 119), androgen receptor (AR) alterations (n = 58) were associated with lower PSA50 (38% vs. 60%, p = 0.03). While any tumor suppressor genes (TSG) (PTEN, TP53, RB1) (n = 109) or TP53 (n = 83) alteration were associated with lower PSA90 (p = 0.02 for both), NF1 (n = 8) and FOXA1 alterations were associated with higher PSA90 (p = 0.03 and p = 0.003, respectively).
CONCLUSIONS: This analysis identifies potential genomic predictors of response to 177Lu-PSMA-617, with NF1 and FOXA1 alterations associated with favorable outcomes and AR and TSG alterations with diminished response. These hypothesis-generating findings suggest genomic profiling may inform selection for PSMA-targeted therapy and warrant prospective validation in larger cohorts.
IMPLICATIONS OF PRACTICE: In this study, we evaluate the use of genetic markers to predict response to treatment with 177Lu-PSMA-617 in patients with metastatic prostate cancer. We identified that alterations in the androgen receptor (AR) and tumor suppressor genes (TSG) were associated with a worse response to 177Lu-PSMA-617, which FOXA1 and NF1 alterations were associated with improved outcomes. These data are hypothesis generating and warrant validation in larger studies. Identifying predictive markers to 177Lu-PSMA-617 can better optimize treatment selection for this therapy.}, }
@article {pmid41120126, year = {2025}, author = {Patel, SP and Othus, M and Chae, YK and Azenkot, T and Wagner, MJ and Threlkel, S and Farley, JH and Magner, CM and Chen, HX and Sharon, E and Ryan, CW and Blanke, C and Kurzrock, R}, title = {Multicenter phase II trial of ipilimumab and nivolumab in metastatic or unresectable perivascular epithelioid cell tumor (PEComa): a substudy of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609 (Cohort 38).}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {10}, pages = {}, pmid = {41120126}, issn = {2051-1426}, mesh = {Humans ; Female ; *Nivolumab/pharmacology/therapeutic use ; Middle Aged ; Male ; *Ipilimumab/pharmacology/therapeutic use ; Adult ; Aged ; *Perivascular Epithelioid Cell Neoplasms/drug therapy/pathology/mortality ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology/adverse effects ; Young Adult ; *CTLA-4 Antigen/antagonists & inhibitors ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors ; }, abstract = {BACKGROUND: Malignant perivascular epithelioid cell tumors (PEComas) are ultra-rare, aggressive mesenchymal neoplasms associated with poor outcomes. Standard-of-care systemic therapy includes mammalian target of rapamycin (mTOR) inhibition and chemotherapy. Immune checkpoint inhibition has not been previously studied in patients with advanced PEComas in a prospective clinical trial.
METHODS: This is an open-label phase 2 trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors; here we report the cohort of patients with advanced malignant PEComa recruited from >1,000 sites across the USA. Primary end point was objective response rate, with progression-free survival, overall survival, and toxicity as secondary end points.
RESULTS: 17 patients were enrolled (N=16 evaluable). Median age was 59.5 years (range, 22-77 years) and the majority were female (81%). Best responses included partial response (18.8%), stable disease for <6 months (25.0%), and progressive disease (56.3%). Median OS was 7.5 months (95% CI 3.4 to 34.6) and median PFS was 1.9 months (95% CI 1.8 to 11.8). PFS in responding patients was 11.8, 18.9, and 34.6 months. Available genomic sequencing showed TSC, ATRX, and TP53 mutations; no TFE3 fusions were identified (N=7). Nearly all patients experienced a treatment-related adverse event (AE) of any grade, while 37.5% experienced a grade 3-4 AE. Most common AEs were fatigue (43.8%), pruritus (37.5%), rash (25.0%), and aspartate aminotransferase increase (25.0%). There were no grade 5 AEs.
CONCLUSIONS: The combination of ipilimumab and nivolumab demonstrated responses in 18.8% of patients with advanced malignant PEComas. Dual immunotherapy may be an alternative treatment option for certain patients, including those who are unable to tolerate or do not desire prolonged treatment with chemotherapy or mTOR inhibition or have failed to respond to other therapies. Ipilimumab and nivolumab warrants further investigation in this and other rare soft tissue sarcomas.}, }
@article {pmid41118367, year = {2025}, author = {Carter, JJ and Hurlburt, NK and Scherer, EM and Singh, S and Rodarte, JV and Smith, RA and Lewis, P and Kinzelman, R and Kieltyka, J and Cabãn, ME and Wipf, GC and Pancera, M and Galloway, DA}, title = {Human monoclonal antibodies to HPV16 show evidence for common developmental pathways and public epitopes.}, journal = {PLoS pathogens}, volume = {21}, number = {10}, pages = {e1013086}, doi = {10.1371/journal.ppat.1013086}, pmid = {41118367}, issn = {1553-7374}, mesh = {*Antibodies, Monoclonal/immunology ; Humans ; *Human papillomavirus 16/immunology ; *Antibodies, Viral/immunology ; *Epitopes/immunology ; Capsid Proteins/immunology ; Antibodies, Neutralizing/immunology ; *Papillomavirus Infections/immunology/prevention & control ; Papillomavirus Vaccines/immunology ; Oncogene Proteins, Viral/immunology ; }, abstract = {Antibodies to human papillomavirus (HPV) primarily recognize surface exposed residues on five loops of the major capsid protein (L1) that vary significantly among HPV types. We determined which loops were required for neutralization for 68 HPV16 specific human monoclonal antibodies (mAbs) cloned from participants who received an HPV vaccine and describe molecular features of those antibodies. Chimeric HPV16 pseudovirus (cpsV), each having one surface loop bearing multiple amino acid substitutions, were used to determine neutralization specificity. The HPV16-FG-loop was the loop most frequently required for neutralization (42 of 68, 61.8%), however, all surface loops were required for neutralization by multiple mAbs: HI (13, 19.1%), DE (15, 22.1%), EF (five, 7.4%), BC (four, 5.9%). Antibodies that required multiple loops were common (17, 25.0%). Three mAbs (4.4%) required sequences on the c-terminus of L1 and for another three mAbs the neutralization specificity could not be determined. Two types of mAbs appeared to be overrepresented: ten mAbs used immunoglobin heavy chain variable region 2-70 (IGHV2-70) with immunoglobin light chain variable region 1-40 (IGLV1-40), having characteristic mutations in complementarity determining region two (CDRL2) of the light chain. Cryogenic electron microscopy (Cryo-EM) revealed that two of these antibodies bound five Fabs per capsomer interacting with all five L1-surface loops. The other type of mAbs that appeared to be overrepresented were nine mAbs using IGHV4-34, six of which also used DH3-16*02 with conserved CDRH3 sequences. Cryo-EM for one of these mAbs, that required the FG-loop for neutralization, was shown to bind one Fab per capsomer at the apex, interacting with the DE- and FG-loops, with sequences of the Fab CDRH3 inserted between the DE- and FG-loops from two L1 proteins. These two types of mAbs were found in the four participants suggesting that these antibodies shared developmental pathways and bound to similar immunodominant epitopes on the virus.}, }
@article {pmid41117775, year = {2025}, author = {Lai, Y and Song, D and Xia, L and Li, JJ}, title = {PseudotimeDE-fast: fast testing of differential gene expression along cell pseudotime.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btaf573}, pmid = {41117775}, issn = {1367-4811}, abstract = {SUMMARY: Identifying differentially expressed (DE) genes along cell pseudotime is crucial for understanding dynamic biological processes captured by single-cell RNA sequencing. However, existing DE methods either produce invalid p-values by ignoring the uncertainty in pseudotime inference or struggle to scale with the growing size of modern datasets. To address these limitations, we introduce PseudotimeDE-fast, a scalable method for detecting DE genes along pseudotime with well-calibrated p-values. Through comprehensive simulations and real-data analyses, we demonstrate that PseudotimeDE-fast delivers comparable or superior performance to existing approaches while offering substantial improvements in computational efficiency.
AVAILABILITY: PseudotimeDE-fast is implemented in R with Rcpp acceleration and released under the MIT license. The source code is available at: https://github.com/dsong-lab/PseudotimeDE.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid41117635, year = {2025}, author = {Davis, JW and Aragaki, AK and Harrington, LB and Rossouw, JE and Wells, G and Shadyab, A and Schnatz, PF and Shufelt, CL and Warsinger-Martin, L and Wild, RA and Manson, JE}, title = {Baseline use of aspirin or statins with oral estrogen and progestogens to prevent incident arterial or venous thrombotic events: a secondary analysis of the Women's Health Initiative trial.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, pmid = {41117635}, issn = {1530-0374}, abstract = {OBJECTIVE: To evaluate whether effects of oral hormone therapy (HT) on risks of venous and arterial vascular events differ by baseline statin or aspirin use.
METHODS: We performed time-to-event analysis using data from the Women's Health Initiative menopausal HT randomized trials to assess risk of thrombotic events. Women were randomized to oral conjugated equine estrogens (CEEs) alone or placebo among women with prior hysterectomy (n = 10,739), and CEE with medroxyprogesterone acetate (MPA) or placebo among women with an intact uterus (n = 16,608), stratified by baseline personal use of statins and aspirin. We evaluated risk of prespecified, adjudicated thrombotic events, including coronary heart disease, stroke, venous thromboembolism, and/or composite major adverse cardiovascular events, at 2 and 5 years.
RESULTS: Baseline statin use (n = 827 in CEE-alone trial; n = 1,115 in CEE+MPA trial) or aspirin use (n = 2,212; n = 3,431) was limited. At 5-year follow-up, coronary heart disease risk for CEE-alone versus placebo was hazard ratio (HR) = 0.81 (95% CI: 0.44-1.49) in statin users, similar to nonusers, HR = 1.07 (95% CI: 0.82-1.40). For CEE+MPA, there was also no difference by statin use, HR = 1.02 (95% CI: 0.55-1.89) and HR = 1.47 (95% CI: 1.13-1.90), respectively. Neither statin nor aspirin exposure significantly modified effects of HT on any arterial or venous thrombotic outcome at 2 or 5 years.
CONCLUSIONS: In this secondary randomized clinical trial analysis, neither statins nor aspirin significantly modified effects of oral HT on key arterial or venous thrombotic outcomes at 2 or 5 years. Results, however, may be underpowered given low baseline exposure prevalence for both statins and aspirin.}, }
@article {pmid41117594, year = {2025}, author = {Bacsik, DJ and Mills, MG and Monroe, LD and Spring, C and Perez-Osorio, AC and Reed, JC and Fang, FC and Bourassa, L and Roychoudhury, P and Crawford, KHD and Snekvik, K and Greninger, AL}, title = {Validation of H5 influenza virus subtyping RT-qPCR assay and low prevalence of H5 detection in 2024-2025 influenza virus season.}, journal = {Journal of clinical microbiology}, volume = {}, number = {}, pages = {e0041525}, doi = {10.1128/jcm.00415-25}, pmid = {41117594}, issn = {1098-660X}, abstract = {A sustained outbreak of H5N1 influenza virus among wild fowl and domestic livestock has caused more than 70 zoonotic infections in humans in North America, including two deaths. The United States Centers for Disease Control and Prevention has recommended rapid H5 subtyping for all hospitalized cases with influenza A virus infection to enable prompt initiation of antiviral treatment, as well as infection prevention and implementation of public health measures to control spread. To address these needs, we developed a qualitative multiplex RT-qPCR assay to subtype H5 influenza virus in nasal, nasopharyngeal, and conjunctival specimens with a limit of detection of 250 copies/mL. No cross-reactivity was observed with other common respiratory viruses, including seasonal H3N2 and H1N1 influenza A viruses. We retrospectively subtyped 590 influenza A virus-positive clinical specimens with Ct values less than 31 processed by University of Washington labs between March 2024 and February 2025, including 512 specimens collected during the 2024-2025 influenza season, and detected no H5 positives. After clinical implementation, we performed 150 clinically ordered H5 subtyping tests between February and April 2025 and again detected no positives. This work enhances clinical pandemic preparedness activities and highlights the exceedingly low prevalence of H5N1 influenza virus during the 2024-2025 respiratory season.IMPORTANCEThe spread of H5N1 influenza virus in the United States has led to the culling of almost 200 million birds, infected cow herds across 17 states, and resulted in 70 human infections as of July 2025. Rapid PCR subtyping of H5 influenza virus is critical to inform hospital infection prevention and public health to enable containment of viral transmission. Here, we report the design, validation, and clinical implementation of a qualitative multiplex H5-subtyping RT-qPCR assay for nasopharyngeal, nasal, and conjunctival swab specimens. Additionally, we offer the largest reported study of H5 subtyping of influenza A virus-positive specimens in the United States to date. No H5 infections were detected in 740 samples collected between March 2024 and April 2025 from patients with confirmed influenza A virus infection in a large academic medical system in Seattle, WA.}, }
@article {pmid41117001, year = {2025}, author = {Gunn, CM and Boyer, N and Sheikh, S and Lee, JM and Woloshin, S and Specht, JM and Hubbard, RA and Bowles, EJA and Su, YR and Tosteson, ANA}, title = {Patient and Physician Perspectives on Using Risk Prediction to Support Breast Cancer Surveillance Decision Making.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {}, number = {}, pages = {272989X251379888}, doi = {10.1177/0272989X251379888}, pmid = {41117001}, issn = {1552-681X}, abstract = {IntroductionBreast cancer survivors have a higher risk of interval cancers relative to the screening population. Patient characteristics including features of the primary cancer and its treatment can help predict interval second breast cancer risk, but patient and physician perspectives on how risk prediction tools might enhance surveillance decision making are not well characterized.DesignWe conducted a qualitative study of women with breast cancer who had completed primary treatment and multispecialty physicians recruited through Breast Cancer Surveillance Consortium registries. We conducted semi-structured focus groups with 5 to 7 breast cancer survivors and individual physician interviews. All participants were presented with information about an interval cancer risk prediction tool. We elicited participant perspectives on aspects of the tool's design, relevance, and use for surveillance decision making. Data coding, thematic analysis, and interpretation were guided by the principles of theoretical thematic analysis.ResultsForty physician interviews and 4 focus groups involving 23 breast cancer survivors were analyzed. Two prominent areas of focus emerged: 1) perspectives on how a risk prediction tool would enhance and add value to patient-centered care and 2) risk prediction tools can be a means to improve communication about risk of in-breast recurrence or new breast cancer.ConclusionsThis study provides data on breast cancer survivor and physician perceptions of a new risk prediction tool to support surveillance imaging decisions among breast cancer survivors.ImplicationsAn interval second breast cancer risk prediction tool may promote evidence-based care across an array of physicians and different clinical settings. Future research should identify care delivery settings and features that promote adoption and support use in ways that improve shared decision making and patient outcomes.HighlightsThis qualitative study of breast cancer survivors and physicians found that risk prediction tools to support surveillance decisions were perceived positively when positioned as a supplement to the patient-physician relationship.Both patients and physicians said that a tool supported by strong evidence and accessible outputs would be valuable for shared decision making.}, }
@article {pmid41116172, year = {2025}, author = {Hemberg, M and Marini, F and Ghazanfar, S and Al Ajami, A and Abassi, N and Anchang, B and Benayoun, BA and Cao, Y and Chen, K and Cuesta-Astroz, Y and DeBruine, Z and Dendrou, CA and De Vlaminck, I and Imkeller, K and Korsunsky, I and Lederer, AR and Li, JJ and Meysman, P and Miller, CL and Mullan, KA and Ohler, U and Panwar, P and Patikas, N and Schuck, J and Siu, JHY and Triche, TJ and Tsankov, A and van der Laan, SW and Yajima, M and Yang, J and Zanini, F and Jelic, I}, title = {Insights, opportunities, and challenges provided by large cell atlases.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {358}, pmid = {41116172}, issn = {1474-760X}, mesh = {*Single-Cell Analysis/methods ; Humans ; Animals ; *Computational Biology/methods ; *Atlases as Topic ; Databases, Genetic ; }, abstract = {The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.}, }
@article {pmid41116168, year = {2025}, author = {Gramatges, MM and Sanclemente, LN and Hall, L and Taylor, OA and Nuño, MM and Bhatia, S and Chow, EJ and Getz, KD and Hitzler, JK and Li, AM and McCloskey, K and Nathan, PC and O'Brien, MM and Patel, S and Verma, A and Yarbrough, AR and Richard, MA and Rosser, TC and Jacola, LM and Lupo, PJ and Rabin, KR}, title = {A multicenter observational cohort study in survivors of Down Syndrome-associated acute leukemia (ALTE22C1): a report from the Children's Oncology Group.}, journal = {BMC cancer}, volume = {25}, number = {1}, pages = {1611}, pmid = {41116168}, issn = {1471-2407}, support = {R01CA263000/CA/NCI NIH HHS/United States ; R03HD108261//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {BACKGROUND: Down syndrome (DS) is a common genetic disorder resulting from an extra copy of genetic material from all or part of chromosome 21. Individuals with DS have a higher burden of co-occurring structural birth defects, neurocognitive delay, and chronic health conditions when compared to those without DS, as well as a 10 to 20-fold excess risk for acute leukemia (AL). Few studies have reported the late effects of cancer treatment in DS-AL survivors, and even fewer have compared outcomes to children with DS and no cancer history. The Children’s Oncology Group study ALTE22C1 was developed to address this knowledge gap.
METHODS: This study leverages both registry and site-based DS-AL survivor recruitment and a prospective/retrospective cohort design to compare chronic health conditions and neurocognitive outcomes experienced by DS-AL survivors to age and sex-matched individuals enrolled to a DS cohort for which cancer is exclusionary. Survivors 6–39 years old, ≥ 3 years from end of AL treatment, and in remission are eligible. Participants complete a medical conditions survey and neuropsychological battery by parent proxy and may also participate in an in-person physical and neurocognitive assessment. Biological samples are collected to evaluate molecular features associated with outcomes.
DISCUSSION: This cooperative group study will identify the prevalence and severity of medical and neurocognitive outcomes in DS-AL survivors compared with non-DS AL and DS controls without cancer history. Results are anticipated to inform clinical practice guidelines for DS-AL survivors and improve survivor outcomes through mitigation of outcome disparities in this vulnerable population.
TRIAL REGISTRATION: Children’s Oncology Group study ALTE22C1 is registered under the ClinicalTrials.gov identifier NCT05702645.}, }
@article {pmid41109336, year = {2025}, author = {Batista, MV and Chaer, FE and Englund, JA and Boeckh, M and Carpenter, PA and Dadwal, SS and Waghmare, A and Navarro, D and Hirsch, HH and Piñana, JL and Papanicolaou, GA and Chemaly, RF}, title = {Corrigendum to 'American Society for Transplantation and Cellular Therapy Series #10: Management of Parainfluenza and Human Metapneumovirus Infections in Hematopoietic Cell Transplantation and Cellular Therapy Recipients' [Transplantation and Cellular Therapy 31 (2025) 624-638/ https://doi.org/10.1016/j.jtct.2025.06.016].}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.027}, pmid = {41109336}, issn = {2666-6367}, }
@article {pmid41108951, year = {2025}, author = {Park, VY and Hippe, DS and Kazerouni, AS and Biswas, D and Bryant, ML and Li, I and Javid, SH and Kilgore, M and Kim, J and Kim, AG and Scheel, JR and Lowry, KP and Lam, DL and Partridge, S and Rahbar, H}, title = {Multiparametric breast MRI to problem-solve mammographically detected suspicious calcifications.}, journal = {European journal of radiology}, volume = {194}, number = {}, pages = {112467}, doi = {10.1016/j.ejrad.2025.112467}, pmid = {41108951}, issn = {1872-7727}, abstract = {OBJECTIVE: To evaluate the performance of multiparametric breast MRI to problem-solve mammographically-detected suspicious calcifications.
MATERIALS AND METHODS: Participants with mammographically-detected suspicious calcifications were prospectively enrolled between August 2017 to May 2023. Pre-biopsy multiparametric MRI (standard and high-temporal resolution dynamic contrast enhanced [DCE]-MRI acquisitions and diffusion-weighted imaging [DWI]) was performed. The associations of MRI features with outcomes - (1) any malignancy and (2) invasive or high-grade ductal carcinoma in situ [DCIS] only - were analyzed using univariable logistic regression. Multivariable models, sequentially incorporating clinical/mammographic, qualitative, and quantitative features, were developed using penalized logistic regression with the least absolute shrinkage and selection operator. Area under the receiver operating characteristic curves (AUC) were estimated via cross-validation and compared between models using bootstrap methods.
RESULTS: 81 women (mean age, 55 years ± 10 [standard deviation]) with 86 calcifications were included; 29 % (25/86) were malignant. Malignancy rates for non-enhancing mammographic Breast Imaging Reporting and Data System (BI-RADS) category 4a and 4b calcifications were 3.8 % (1/26) and 8.7 % (2/23), respectively, with no invasive cancer or high-grade DCIS. Mammographic BI-RADS category, MRI BI-RADS category, visibility on DWI, peak percent enhancement, functional tumor volume, and K[trans] values were associated with both outcomes (all p < 0.05). Multivariable models, including qualitative DCE-MRI assessments, showed higher AUCs (malignancy: 0.71-0.76; invasive cancer or high-grade DCIS: 0.78-0.91) than when including only clinical and mammographic features (malignancy: 0.57; invasive cancer or high-grade DCIS: 0.61, all p < 0.05). Further incorporation of DWI or quantitative MRI features did not improve AUCs (all ΔAUC ≤ 0).
CONCLUSION: Breast DCE-MRI aids in evaluating mammographic BI-RADS category 4a/4b calcifications without biopsy. DWI or quantitative MRI features may not further improve diagnostic performance.}, }
@article {pmid41108673, year = {2025}, author = {Gogebakan, KC and Elsisi, Z and Montano-Campos, F and Owens, L and Zhao, Y and Gulati, R and Ferdinandus, J and Fendler, WP and Calais, J and Hope, TA and Carlsson, S and Fainberg, J and Laudone, V and Kunst, N and Berlin, A and Schipper, M and Barbour, A and Iravani, A and Etzioni, R}, title = {Prostate-specific membrane antigen positron emission tomography/computed tomography imaging as a precision diagnostic at prostate cancer recurrence after radical prostatectomy: Modeling long-term survival.}, journal = {Cancer}, volume = {131}, number = {21}, pages = {e70131}, doi = {10.1002/cncr.70131}, pmid = {41108673}, issn = {1097-0142}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; CA097186/CA/NCI NIH HHS/United States ; CA253915/CA/NCI NIH HHS/United States ; R50:CA 221836/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/diagnostic imaging/mortality/surgery/pathology/therapy ; Prostatectomy ; *Positron Emission Tomography Computed Tomography/methods ; *Neoplasm Recurrence, Local/diagnostic imaging/mortality ; *Glutamate Carboxypeptidase II/metabolism ; *Antigens, Surface/metabolism ; Salvage Therapy ; Aged ; Middle Aged ; }, abstract = {BACKGROUND: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) is affecting the management of patients with prostate cancer with biochemical recurrence after radical prostatectomy. The long-term outcomes of tailoring salvage treatment on the basis of PSMA-PET/CT status remain to be determined.
METHODS: A decision-analytic model was developed to project incremental life-years of strategies that allocate treatments at biochemical recurrence after radical prostatectomy on the basis of PSMA-PET/CT status (PSMA-metastatic vs. PSMA-nonmetastatic). Modeled treatments are local/regional (radiation) or systemic (hormone therapy and doublet therapy), administered immediately or delayed. PSMA-metastatic status was assumed to lead to treatment intensification, whereas PSMA-nonmetastatic status would lead to deintensification. To project survival, data on progression to metastasis from a clinical cohort were combined with registry data on postmetastasis survival. Because of the lack of data on long-term treatment benefits by PSMA status, survival was projected by varying the hazard ratio (HR) for disease-specific death among PSMA-metastatic versus PSMA-nonmetastatic patients under delayed or local/regional regimens (HR1) and under immediate systemic regimens (HR2).
RESULTS: Mean life-years are projected to be 15.5 under the non-PSMA-tailored strategy, and mean incremental life-years range from 0.38 to 0.81 depending on HR1 and HR2. A greater benefit is projected when PSMA-metastatic status is more adverse under salvage regimens that do not include systemic agents.
CONCLUSIONS: This decision-analytic modeling study projects that PSMA-PET/CT-guided management at biochemical recurrence after radical prostatectomy yields a modest survival benefit under the specified model inputs and assumptions regarding treatment distributions. These findings may complement emerging data on the corresponding economic costs and health-related quality of life.}, }
@article {pmid41108088, year = {2025}, author = {Hurvitz, S and Simonelli, M and Yarza, R and Berz, D and Kitano, S and Del Conte, G and Acosta Eyzaguirre, D and Doger de Speville Uribe, BG and Maier, D and Erzen, D and Aykut Yazgili, S and Curigliano, G and Deng, T and Yan, M and Zhang, Q and Wang, X and Nakayama, I and Shitara, K}, title = {Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/14796694.2025.2569553}, pmid = {41108088}, issn = {1744-8301}, abstract = {BACKGROUND: Overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) is a recognized oncogenic driver in metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinomas (mGEAC). Although HER2-directed monoclonal antibodies, antibody - drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of HER2-positive tumors, additional combination regimens and/or novel agents are needed to expand sequential therapy options and improve patient outcomes - particularly following treatment with trastuzumab deruxtecan (T-DXd). Zongertinib is a novel, irreversible, HER2-selective TKI that spares EGFR.
STUDY DESIGN: Here, we detail the rationale and design of Beamion BCGC-1 (NCT06324357), an international Phase Ib/II open-label trial in which patients with previously treated HER2-positive mBC or mGEAC will receive zongertinib alone or in combination. Phase Ib (dose escalation) will determine the maximum tolerated dose of zongertinib plus trastuzumab emtansine (T-DM1), T-DXd, or trastuzumab ± capecitabine, in patients with HER2-positive mBC, and plus T-DXd in patients with HER2-positive mGEAC. Phase II (dose optimization) will assess two doses of zongertinib in combination regimens, or as monotherapy, in patients with mBC or mGEAC. The trial is actively recruiting in six countries globally.
CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06324357.}, }
@article {pmid40789020, year = {2025}, author = {Stolla, M and Cap, AP and Spinella, PC}, title = {Chilling controversy: cold-stored platelets for prophylactic transfusions.}, journal = {Blood}, volume = {146}, number = {17}, pages = {2023-2028}, doi = {10.1182/blood.2025029252}, pmid = {40789020}, issn = {1528-0020}, mesh = {Humans ; *Platelet Transfusion/methods ; *Blood Preservation/methods ; *Blood Platelets/cytology ; Cold Temperature ; *Hemorrhage/prevention & control/therapy ; Thrombocytopenia/therapy ; *Cryopreservation/methods ; Platelet Count ; }, abstract = {The US Food and Drug Administration recently licensed 14-day cold-stored platelets for bleeding patients. This policy change represents a reversal from the 1970s when cold-stored platelets were discontinued because of their short circulation time in healthy humans. This change will increase their availability in US hospitals with large trauma populations and in remote and rural settings in the United States. In some of these hospitals, cold-stored platelets will be the only platelets available. It is currently unclear whether patients with hypoproliferative thrombocytopenia who need platelet transfusion for prophylaxis benefit from cold-stored platelets. However, it is noteworthy that in recent clinical trials using room temperature-stored platelets, the transfusion interval in patients with hematologic and oncologic conditions can be as short as 1 transfusion per day, very similar to what one would expect to achieve with cold-stored platelets. Furthermore, the emphasis on the posttransfusion count increment and the platelet count as a transfusion trigger per se is questionable. In the PLADO trial, there was only a poor correlation between the morning platelet count and bleeding events, implicating other factors, such as red blood cells, coagulation factors, and vascular health, as possible culprits. In this perspective article, we review the history of cold platelets and the reason for their discontinuation, focus on recent clinical trial data using room temperature-stored platelets, and review the platelet count as a transfusion trigger. Overall, using cold platelets for prophylaxis may seem counterintuitive, but a closer look at the available data suggests that the indication expansion may hold more promise.}, }
@article {pmid40729699, year = {2025}, author = {Shadman, M and Davids, MS}, title = {How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor.}, journal = {Blood}, volume = {146}, number = {17}, pages = {2029-2036}, doi = {10.1182/blood.2024025482}, pmid = {40729699}, issn = {1528-0020}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/therapy ; *Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; *Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; *Protein Kinase Inhibitors/therapeutic use ; Male ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Female ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Sulfonamides ; }, abstract = {The treatment landscape for chronic lymphocytic leukemia (CLL) has been transformed by the advent of covalent Bruton tyrosine kinase (BTK) inhibitors (cBTKis) and B-cell lymphoma 2 (BCL-2) inhibitors, leading to markedly improved outcomes and, for many, near-normal life expectancy. However, patients progressing after both classes of therapy (double-refractory) have limited options and poor prognoses. This review outlines a practical approach to managing double-exposed or double-refractory CLL, incorporating clinical cases, trial data, and expert perspectives. For cBTKi intolerance, second-generation agents may remain effective. Venetoclax retreatment is reasonable after prior fixed-duration use. In true double-refractory disease, noncovalent BTK inhibitors (eg, pirtobrutinib) and CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (lisocabtagene maraleucel) are standard-of-care options. Pirtobrutinib induces rapid responses, though often of limited duration, underscoring the need for early consolidation planning with CAR-T or allogeneic stem cell transplant. Persistent disease after CAR-T therapy warrants close monitoring and timely transplant referral in eligible patients. Phosphoinositide 3-kinase inhibitors remain available but are limited by toxicity and modest benefit. Emerging agents, including BTK degraders, bispecific antibodies, and novel cellular therapies, offer promising future directions. Optimizing outcomes in double-refractory CLL requires an individualized, nuanced strategy integrating available treatments with innovative approaches under investigation.}, }
@article {pmid41107551, year = {2025}, author = {Prodanov, T and Plender, EG and Seebohm, G and Meuth, SG and Eichler, EE and Marschall, T}, title = {Locityper enables targeted genotyping of complex polymorphic genes.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {41107551}, issn = {1546-1718}, support = {R01 HG002385/HG/NHGRI NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; }, abstract = {The human genome contains many structurally variable polymorphic loci, including several hundred disease-associated genes, almost inaccessible for accurate variant calling. Here we present Locityper, a tool capable of genotyping such challenging genes using short-read and long-read whole-genome sequencing. For each target, Locityper recruits and aligns reads to locus haplotypes, for instance, extracted from a pangenome, and finds the likeliest haplotype pair by optimizing read alignment, insert size and read depth profiles. Across 256 challenging medically relevant loci, Locityper achieves a median quality value (QV) above 35 from both long-read and short-read data, outperforming state-of-the-art Illumina and PacBio HiFi variant calling pipelines by 10.9 and 1.7 points, respectively. Furthermore, Locityper provides access to hyperpolymorphic HLA genes and other gene families, including KIR, MUC and FCGR. With its low running time of 1 h 35 m per sample at eight threads, Locityper is scalable to biobank-sized cohorts, enabling association studies for previously intractable disease-relevant genes.}, }
@article {pmid41107178, year = {2025}, author = {Vigneswaran, HT and Palsdottir, T and Micoli, C and Tilki, D and Lin, D and Cooperberg, M and Eggener, S and Falagario, UG and Möller, A and Aly, M and Akre, O and Wiklund, P and Egevad, L and Grönberg, H and Nordström, T and Eklund, M}, title = {Stockholm3 Versus Prostate-specific Antigen in Prostate Cancer Screening: 9-year Outcomes Demonstrating Improved Detection of Aggressive Cancers and Reduced Overdiagnosis from the STHLM3 Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.10.001}, pmid = {41107178}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Prostate-specific antigen (PSA) thresholds (≥3 or 4 ng/ml) are used to balance prostate cancer (PCa) detection against false positives; yet, aggressive PCa can occur at a low PSA and indolent tumors at a high PSA level. Long-term data clarifying aggressiveness across PSA thresholds are limited.
METHODS: The STHLM3 screening trial enrolled 59 088 men. All received PSA testing; those with PSA ≥1 ng/ml underwent the multianalyte Stockholm3 blood test. We analyzed men treated with radical prostatectomy or radiotherapy (n = 968). Outcomes were any biochemical recurrence (BCR), high-risk BCR, and PCa-specific mortality. Incidence across four baseline groups-(1) elevated PSA (≥3 ng/ml) and Stockholm3 (≥11), (2) elevated Stockholm3 alone (≥11), (3) elevated PSA alone (≥3 ng/ml), and (4) neither elevated PSA (<3 ng/ml) nor elevated Stockholm3 (<11)-was compared using Gray's test and competing-risk regression.
KEY FINDINGS AND LIMITATIONS: Follow-up was 8.9 yr. The 5-yr cumulative rates of any/high-risk BCR were as follows: 13%/9.0% for both elevated Stockholm3 (≥11) and elevated PSA (≥3 ng/ml), 9.4%/5.3% for elevated Stockholm3 alone, 1.5%/0% for elevated PSA alone, and 0%/0% for nonelevated results on both tests (p < 0.001). Compared with PSA-only elevation, Stockholm3-only elevation showed a hazard ratio (HR) of 1.8 (95% confidence interval 0.8-3.9; p = 0.2) for any BCR and an HR of 8.8 (1.06-72; p = 0.044) for high-risk BCR.
Some men with PSA <3 ng/ml harbor aggressive PCa with a substantial risk of recurrence after upfront curative treatment. Risk predictive blood tests, such as Stockholm3, used at lower PSA thresholds, can identify these men, while few clinically important cancers are missed when biopsy is deferred with PSA ≥3 ng/ml but low Stockholm3 scores.}, }
@article {pmid41106548, year = {2025}, author = {Khor, S and Basu, A and Shankaran, V and Lee, K and Haupt, EC and Hahn, EE and Carlson, JJ and Bansal, A}, title = {Evaluating Long-term Health Disparity Impacts of Clinical Algorithms Using a Patient-level Simulation Framework.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jval.2025.09.3066}, pmid = {41106548}, issn = {1524-4733}, abstract = {OBJECTIVE: This study applies a simulation framework to evaluate the long-term effects of omitting race from a colon cancer decision algorithm for adjuvant chemotherapy, assessing impacts on health outcomes, costs, and disparities while accounting for measurement errors across racial groups.
METHODS: We developed a patient-level state-transition model using electronic health records from a large Southern California health system to project outcomes for 4,839 adults with stage II and III colon cancer post-surgery. We compared 30-year quality-adjusted life-years (QALYs), healthcare costs, and QALY distribution among racial groups under three chemotherapy treatment scenarios: 1) current practice, 2) treatment guided by an algorithm that includes race, and 3) the same algorithm with race omitted. An additional health state addressed racial bias in cancer recurrence ascertainment, and probabilistic sensitivity analysis (PSA) assessed uncertainty.
RESULTS: The clinical algorithm, compared to current practice, could improve average health by 0.048 QALYs and reduce racial health disparity by 0.20 QALYs at an incremental cost of $3,221, with the disparity gap decreasing in 96% of PSA iterations. Omitting race showed minimal effects on overall health or costs but resulted in 13% fewer Black patients receiving treatment, decreasing their QALYs by 0.07 and widening the disparity gap by 0.13 QALY. Health disparity increased in 94% of PSA iterations.
CONCLUSIONS: A cancer decision algorithm can improve population health and reduce health disparities, but omitting race may harm disadvantaged groups and limit reductions in disparities. Patient-level simulations can be routinely used to evaluate the potential health disparity impacts of algorithms before implementation.}, }
@article {pmid41106476, year = {2025}, author = {Chowdhury, S and Gasper, C and Lazar, AA and Allaire, K and Darragh, TM and Fong, L and Palefsky, JM}, title = {Expression of programmed death ligand-1 and programmed cell death-1 across the anal neoplasia disease continuum and association with survival in anal cancer.}, journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}, volume = {}, number = {}, pages = {100918}, doi = {10.1016/j.modpat.2025.100918}, pmid = {41106476}, issn = {1530-0285}, abstract = {High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of PD-L1 expression in aSCC and its impact on overall survival (OS) is controversial. ASCC can evade immune surveillance by co-opting the PD-L1/PD-1 immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells and immune cells by immunohistochemistry in non-lesional anal tissue (n=22), aHSIL (n=22), and aSCC (n=52) from HIV-negative participants and people living with HIV. PD-L1 expression on epithelial cells was restricted to tumor cells with no expression in non-lesional and HSIL tissues, while PD-L1-positive immune cells were present across all three diagnostic stages. PD-1 expression was absent on epithelial cells whereas PD-1-positive immune cells increased along the disease continuum from non-lesional to aSCC. The overall PD-L1 expression on epithelial cells and immune cells measured by the combined positive score (CPS) in aSCC and the aggregate PD-L1 score in non-lesional and HSIL showed a substantial increase from non-lesional to aHSIL to aSCC. In aSCC, PD-L1 expression on immune cells was more prominent than in tumor cells and correlated with increased immune cell infiltration and interferon-gamma secretion. 92% of aSCC exhibited an adaptive PD-L1 expression pattern characterized by PD-L1 expression on tumors cells, immune cells or both. HIV status did not affect PD-L1/PD-1 expression in non-lesional, aHSIL or aSCC. PD-L1 expression in treatment naïve aSCC was associated with improved OS. Those with CPS of 0 had a higher risk of death [Hazard ratio 15.2 (95% CI: 3.3-69, p=0.0004; log-rank p<0.0001)] compared to those with CPS > 0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.}, }
@article {pmid41106380, year = {2025}, author = {Galeano Niño, JL and Ponath, F and Ajisafe, VA and Becker, CR and Kempchinsky, AG and Zepeda-Rivera, MA and Gomez, JA and Wu, H and Terrazas, JG and Bouzek, H and Cromwell, E and Chanana, P and Wong, M and Damania, A and White, MG and You, YN and Kopetz, S and Ajami, NJ and Wargo, JA and Johnston, CD and Bullman, S}, title = {Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2025.09.010}, pmid = {41106380}, issn = {1878-3686}, abstract = {Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals downregulation of cell cycle, transcription, and antigen presentation genes in bacteria-enriched regions, consistent with a quiescent, immune-evasive phenotype. In an independent rectal cancer cohort, high Fusobacterium burden correlates with reduced therapy response. These results link extracellular bacteria to cancer cell quiescence and chemoresistance, highlighting microbial-tumor interactions as therapeutic targets.}, }
@article {pmid41106280, year = {2025}, author = {Tower, A and Owens, K and Esmaeili, S and Schiffer, JT and Reeves, DB and Schwartz, EJ}, title = {Quantitative viral dynamics: Methods for parameter estimation.}, journal = {Virology}, volume = {613}, number = {}, pages = {110631}, doi = {10.1016/j.virol.2025.110631}, pmid = {41106280}, issn = {1096-0341}, abstract = {Fitting mathematical models of viral dynamics to serial, quantitative viral load data provides inferences on the mechanisms in virus infection. This process can reveal the speed and magnitude of viral replication, cell proliferation and death, immune responses, and/or treatment efficacy. Viral dynamics modeling involves developing conceptual models, translating them into equations, and applying the appropriate statistical tools to determine the optimal parameters such that the model recapitulates observations from human and animal infections. In this review, we outline the theoretical foundations needed to understand model fitting, parameter estimation, and what it means to achieve a good fit. We provide examples and explain the strengths and limitations of three commonly used model fitting approaches: individual fitting, population mixed effects fitting, and feature fitting. We briefly review fitting algorithms and highlight powerful available computer software packages that can be used for fitting and parameter estimation. We discuss different model types, parameter identifiability, and how future modeling efforts can leverage advances in multi-dimensional data. Finally, we conclude with simple guidelines for choosing the best approach based on available data and scientific questions.}, }
@article {pmid41105919, year = {2025}, author = {Ji, X and Hu, X and Nathan, PC and Leisenring, WM and Armstrong, GT and Castellino, SM and Kirchhoff, AC}, title = {Changes in Medicaid Enrollment Among Adult Survivors of Childhood Cancer After Medicaid Expansion: A Report From the Childhood Cancer Survivor Study.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2401056}, doi = {10.1200/OP-24-01056}, pmid = {41105919}, issn = {2688-1535}, abstract = {PURPOSE: Little is known about whether Medicaid expansion under the Affordable Care Act affects insurance coverage among adult survivors of childhood cancer, a high-risk population requiring lifetime follow-up care. We examined the association of Medicaid expansion with Medicaid enrollment among participants in the Childhood Cancer Survivor Study.
METHODS: We identified 13,355 adult survivors (age 18-64 years) diagnosed with cancer at age <21 years between 1970 and 1999 and linked these survivors to Medicaid administrative data from 2010 to 2019. Outcomes included the percentage of survivors with any Medicaid enrollment and Medicaid-covered days (total number of days when a survivor was enrolled in Medicaid) each year. Multivariable difference-in-differences (DD) models were used to examine outcome changes (post- v pre-expansion) in expansion versus nonexpansion states.
RESULTS: Medicaid enrollment rates among survivors increased in expansion states (17.1% pre-expansion to 22.8% postexpansion) but decreased in nonexpansion states (16.6%-15.7%), leading to a net increase of 7.1 percentage points (ppts; 95% CI, 6.1 to 8.1). The DD model also showed a net mean increase of 18.7 days/year (95% CI, 15.0 to 22.4) in Medicaid-covered days in expansion relative to nonexpansion states. The expansion-associated increase in enrollment was greatest among survivors who were age 18-29 years (11.2 ppts; 95% CI, 8.3 to 14.1), non-Hispanic Black (13.6 ppts, 95% CI, 8.8 to 18.4) or Hispanic (13.4 ppts, 95% CI, 7.0 to 19.8), with <$20K in US dollars (USD) self-reported household income (13.5 ppts, 95% CI, 10.7 to 16.3), and noncollege graduates (9.3 ppts, 95% CI, 7.7 to 10.9). Similar patterns were observed when examining Medicaid-covered days.
CONCLUSION: To our knowledge, we provide the first evidence of increased Medicaid enrollment and longer coverage duration among adult survivors of childhood cancer after Medicaid expansion. Greater increases were seen among survivors from underrepresented racial/ethnic backgrounds, young adult survivors, and those with lower socioeconomic status, providing a mechanism to reduce disparities and ensure long-term medical care for childhood cancer survivors.}, }
@article {pmid41105890, year = {2025}, author = {Zwaan, CM and Tasian, SK and Aplenc, R and Brodersen, LE and Buldini, B and De Moerloose, B and Dworzak, MN and Fogelstrand, L and Gibson, BE and Goemans, BF and Hasle, H and Hirsch, BA and Kaspers, GJ and Klusmann, JH and Kutny, MA and Lehrnbecher, T and Locatelli, F and Meshinchi, S and Petit, A and Pigazzi, M and Tierens, A and Kolb, EA and Reinhardt, D and Tomizawa, D and Cooper, TM}, title = {Diagnosis and Management of AML in Pediatric Patients: Consensus Recommendations from an International Expert Panel.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027904}, pmid = {41105890}, issn = {1528-0020}, abstract = {The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Whilst similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.}, }
@article {pmid41105630, year = {2025}, author = {Beyrer, C and Remien, RH and Eshleman, SH and Gamble, TR and De Dieu Tapsoba, J and Labbett, RL and Sullivan, PA and Laeyendecker, O and Anderson, PL and Agravat, D and Hughes, JP and Driffin, DD and Hutchinson, CS and Hucks-Ortiz, C and Adair, M and Curry, M and Jones, SB and Haddock, IL and Boyd, D and Burwen, DR and Johnson, AS and Nelson, LE and , }, title = {Investigating the HIV epidemic among Black gay and bisexual men in the Southern United States: Results of the HPTN 096 pilot cross-sectional assessment.}, journal = {PloS one}, volume = {20}, number = {10}, pages = {e0334031}, pmid = {41105630}, issn = {1932-6203}, mesh = {Humans ; Male ; *HIV Infections/epidemiology/prevention & control/drug therapy ; Cross-Sectional Studies ; Adult ; *Homosexuality, Male/statistics & numerical data ; Pilot Projects ; *Black or African American/statistics & numerical data ; Middle Aged ; United States/epidemiology ; Pre-Exposure Prophylaxis ; *Bisexuality/statistics & numerical data ; Young Adult ; Adolescent ; Incidence ; *Epidemics ; White ; }, abstract = {BACKGROUND: The HIV Prevention Trials Network (HPTN) 096 study was designed to address the markedly higher rates of HIV incidence among Black men who have sex with men (MSM) in the Southern United States (US). A cross-sectional assessment was conducted during the pilot phase of the study to determine its feasibility and collect key HIV-related metrics for the study population.
METHODS AND FINDINGS: Four hundred and twenty-two Black MSM, ≥ 15 years old and living in the four pilot communities (Dallas, TX; Houston, TX; Montgomery, AL; Greenville, SC), were enrolled via starfish sampling into the cross-sectional assessment. Each participant completed two questionnaires and had blood samples collected at a single study visit. Laboratory testing was performed to determine HIV status and use of oral pre-exposure prophylaxis (PrEP). HIV drug resistance and viral suppression were also assessed for two of the four pilot communities (Dallas and Houston). Categorical variables were summarized using frequency and percentage. Continuous variables were summarized using mean, standard deviation, median and interquartile range. Univariable and multivariable logistic regression models were used to assess various associations. HIV status was determined for 403 of the 422 participants (95.5%); 212 (52.6%) men were living with HIV, including one with acute HIV. For these participants, 163 (76.9%) reported that they were in HIV care. In Dallas and Houston, 71 of the 101 living with HIV (70.3%) were virally suppressed. Of the 191 not living with HIV, 57 (29.8%) reported ever taking PrEP, 41 (21.5%) reported being currently on PrEP, and eight (4.2%) reported never having heard of PrEP. PrEP use was documented through laboratory testing in 36 (19.1%) of 188 participants tested; of the 41 participants reporting current PrEP use, five did not have laboratory evidence of PrEP use.
CONCLUSION: During the pilot, we successfully recruited Black MSM using starfish sampling and demonstrated the feasibility of collecting primary study outcomes using a cross-sectional assessment. We found a high burden of HIV and those living with HIV had only a moderate rate of viral suppression. In addition, PrEP use was uncommon among the men living without HIV. Reducing HIV incidence in Black MSM remains a key element to addressing the HIV epidemic in the US.}, }
@article {pmid41105497, year = {2025}, author = {Gavate, R and Zepeda-Rivera, MA and Jones, DS and LaCourse, KD and Bullman, S and Johnston, CD}, title = {Complete genome sequence of Peptostreptococcus anaerobius SB204, isolated from a human colonic adenocarcinoma.}, journal = {Microbiology resource announcements}, volume = {}, number = {}, pages = {e0080425}, doi = {10.1128/mra.00804-25}, pmid = {41105497}, issn = {2576-098X}, abstract = {We report the complete genome sequence of Peptostreptococcus anaerobius SB204, a strain isolated from the resected tumor of a treatment-naive patient with colorectal cancer. The genome comprises a single chromosomal contig of 2.15 Mbp with an overall GC content of 36.1%.}, }
@article {pmid41104107, year = {2025}, author = {Tom, A and Gomez-Acosta, C and Henderson, V and McDougall, J and Mendoza, JA and Carosso, E and Cohn, EB and Barrington, WE and Bigelow-Chavez, L and Nyame, YA and Lion, KC}, title = {Advancing equity in cancer care: a pilot explanatory mixed methods study of a racially, ethnically, and linguistically concordant model of patient navigation.}, journal = {Journal of health equity}, volume = {2}, number = {1}, pages = {}, pmid = {41104107}, issn = {2994-4694}, support = {F31 CA157045/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {Disparities in cancer outcomes persist among systemically marginalized patients. A new racially, ethnically, or linguistically concordant (RELC) model of patient navigation (PN) was piloted at Fred Hutchinson Cancer Center in 2019. An explanatory mixed-methods observational study assessed patient-centered outcomes of RELC PN, traditional PN, and no PN. Patients from these models completed surveys at baseline and follow-up to measure changes in satisfaction, discrimination, resilience, stress, trust, and discussion of clinical trials. Interviews with patients receiving RELC PN were analyzed using thematic analysis. A total of 118 participants completed surveys. Satisfaction with care improved by 4.2 points (SD 7.0) on an 18-item 5-point Likert scale for those receiving RELC navigation, with no change in traditional or no PN groups. Discrimination based on race dropped from 40% (n = 2) to 20% (n = 1) in the RELC model. A higher proportion of RELC PN patients (80%; n = 4) discussed clinical trials compared to traditional PN (17%; n = 3) and no PN (20% n = 19). Thematic analysis of 29 interviews indicated the model was crucial in overcoming racism, improving trust, and empowering patients. This study highlights the potential of RELC PN to improve patient satisfaction, increase participation in clinical trials, and reduce experiences of discrimination.}, }
@article {pmid41103457, year = {2025}, author = {Zhu, K and Zheng, Y and Chan, KCG}, title = {Weighted Brier Score - an Overall Summary Measure for Risk Prediction Models with Clinical Utility Consideration.}, journal = {Statistics in biosciences}, volume = {}, number = {}, pages = {}, pmid = {41103457}, issn = {1867-1764}, support = {R01 CA236558/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {As advancements in novel biomarker-based algorithms and models accelerate their use in disease risk prediction, it is crucial to evaluate these models within the context of their intended clinical application. Prediction models output the absolute risk of disease; subsequently, patient counseling and shared decision-making are based on the estimated individual risk and cost-benefit assessment. The overall impact of the application is referred to as clinical utility, which received significant attention and desire to incorporate into model assessment lately. The classic Brier score is a popular measure of prediction accuracy; however, it is insufficient for effectively assessing clinical utility. To address this limitation, we propose a class of weighted Brier scores that aligns with the decision-theoretic framework of clinical utility. Additionally, we decompose the weighted Brier score into discrimination and calibration components, and we link the weighted Brier score to the H measure, which has been proposed as an alternative to the area under the receiver operating characteristic curve. This theoretical link to the H measure further supports our weighting method and underscores the essential elements of discrimination and calibration in risk prediction evaluation. The practical use of the weighted Brier score as an overall summary is demonstrated using data from a prostate cancer study.}, }
@article {pmid41102612, year = {2025}, author = {Heldman, MR and Boeckh, MJ and Ison, MG}, title = {Influenza Antivirals for Prevention and Treatment in Immunocompromised People.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {Supplement_3}, pages = {S243-S253}, doi = {10.1093/infdis/jiaf217}, pmid = {41102612}, issn = {1537-6613}, mesh = {Humans ; *Immunocompromised Host ; *Influenza, Human/prevention & control/drug therapy ; *Antiviral Agents/therapeutic use ; Dibenzothiepins/therapeutic use ; Neuraminidase/antagonists & inhibitors ; Pyridones/therapeutic use ; Thiepins/therapeutic use ; Morpholines ; Pyridines/therapeutic use ; Drug Resistance, Viral ; Triazines ; }, abstract = {Antivirals form a foundation for protecting immunocompromised individuals (ICIs) from influenza complications. Neuraminidase inhibitors have demonstrated benefit for both prophylaxis and treatment in ICIs, including when given >48 hours after symptom onset. Baloxavir is a newer antiviral that has potent effects on viral kinetics in immunocompetent people, but data on baloxavir in ICIs are currently limited. Optimization of antiviral therapy to minimize viral replication within ICIs and reduce the risk of treatment-emergent antiviral resistance (eg, through combination regimens) may prevent viral evolution within ICIs and mitigate transmission of virulent or resistant variants to the general public. Unfortunately, ICIs have been excluded from most clinical trials evaluating novel influenza preventive and therapeutic strategies. Inclusion of ICIs in such clinical trials is essential to facilitate acquisition of clinical and virologic data in patients with specific immunocompromising conditions and ensure that ICIs have equitable access to valuable interventions.}, }
@article {pmid41102222, year = {2025}, author = {Ellison, ST and Hayman, I and Derr, K and Derr, P and Frebert, S and Itkin, Z and Shen, M and Jones, A and Olson, W and Corey, L and Wald, A and Johnston, C and Fong, Y and Ferrer, M and Zhu, J}, title = {Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9200}, pmid = {41102222}, issn = {2041-1723}, support = {U18 TR0033208//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; T32 AI007140/AI/NIAID NIH HHS/United States ; U18 TR003208/TR/NCATS NIH HHS/United States ; T32 AI07140//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI143773/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antiviral Agents/pharmacology ; *Acyclovir/pharmacology ; Keratinocytes/drug effects/virology ; *Skin/cytology/drug effects/virology ; Fibroblasts/drug effects/virology ; Printing, Three-Dimensional ; *Herpes Simplex/drug therapy/virology ; Bioprinting/methods ; *Simplexvirus/drug effects ; Virus Replication/drug effects ; }, abstract = {Herpes simplex virus (HSV) infection poses global public health concerns with lifelong impacts. Acyclovir, the standard therapy, has limited efficacy in preventing subclinical shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. Here we show that acyclovir is significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. Using 3D bioprinted human skin equivalents (HSEs) in a 96-well plate format, we have screened 738 compounds with broad targets and mechanisms of action, identifying potent antivirals, including 23 known or experimental HSV treatments. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways display similar potency across cell types and donor sources in both 2D and 3D models. The reduced potency in keratinocytes may explain acyclovir's limited clinical efficacy. Our 3D bioprinted HSE assay platform enables the integration of patient-derived cells early in drug development and offers a physiologically relevant approach for HSV drug discovery.}, }
@article {pmid41102182, year = {2025}, author = {Weinstock, JS and Chaudhry, SA and Ioannou, M and Viskadourou, M and Reventun, P and Jakubek, YA and Liggett, LA and Laurie, C and Broome, JG and Khan, A and Taylor, KD and Guo, X and Peyser, PA and Boerwinkle, E and Chami, N and Kenny, EE and Loos, RJ and Psaty, BM and Tracy, RP and Brody, JA and Yun, JH and Cho, MH and Vasan, RS and Kardia, SL and Smith, JA and Raffield, LM and Bidulescu, A and O'Brien, EC and de Andrade, M and Rotter, JI and Rich, SS and Tracy, RP and Chen, YI and Gu, CC and Hsiung, CA and Kooperberg, C and Haring, B and Nassir, R and Mathias, R and Reiner, A and Sankaran, VG and Lowenstein, CJ and Blackwell, TW and Abecasis, GR and Smith, AV and Kang, HM and Natarajan, P and Jaiswal, S and Bick, A and Post, WS and Scheet, P and Auer, P and Karantanos, T and Battle, A and Arvanitis, M}, title = {Genetic determinants and genomic consequences of non-leukemogenic somatic point mutations.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9194}, pmid = {41102182}, issn = {2041-1723}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; K08 HL166690/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R35 GM139580/GM/NIGMS NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Point Mutation/genetics ; Genome-Wide Association Study ; *Clonal Hematopoiesis/genetics ; Genomics/methods ; Germ-Line Mutation ; }, abstract = {Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantify CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we develop a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We perform a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. We identify seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1).Functional analyses of SMC4 and NRIP1 implicated altered hematopoietic stem cell self-renewal and proliferation as the primary mediator of mutation burden in blood. We then perform comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we perform phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.}, }
@article {pmid41101975, year = {2025}, author = {Miller, SR and Chung, DH and Gonzalez, RT and Jackson, WC and Caram, MEV and Tsao, PA and Stensland, K and Gulati, R and Shah, Y and Wale, D and Elliott, D and Caverly, T and Hofer, TP and Saini, S and Green, MD and Schipper, M and Dess, RT and Bryant, AK}, title = {Impact of PSMA PET Staging on Initial Treatment in Newly Diagnosed Prostate Cancer.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.270825}, pmid = {41101975}, issn = {1535-5667}, abstract = {Prostate-specific membrane antigen (PSMA) PET/CT has become a common staging modality for newly diagnosed high-risk and unfavorable intermediate-risk prostate cancer after showing improved sensitivity and specificity compared with conventional imaging in clinical trials. We aimed to assess the causal impact of PSMA PET staging on initial treatment selection in real-world practice. Methods: We used observational data from the U.S. Veterans Health Administration to emulate a randomized controlled trial in which patients with newly diagnosed, unfavorable intermediate-, high-, and very-high-risk prostate cancer from January 2022 to December 2023 would have been randomized to undergo either upfront [18]F- or [68]Ga-PSMA PET staging or conventional imaging ([99m]Tc bone scan and pelvic CT or MRI). Outcomes of interest included use of frontline androgen deprivation therapy (ADT), second-generation androgen receptor pathway inhibitors (ARPIs), radiotherapy, and radical prostatectomy. Weighted univariable Cox regression was performed to assess the effect of treatment group on each outcome, and 95% CIs were generated from 1,000 bootstrap replicates. Results: In total, 9,049 patients met the criteria for inclusion. PSMA PET staging was associated with higher rates of any ADT use relative to conventional staging (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.19-1.44), higher rates of ARPI use (aHR, 1.52; 95% CI, 1.33-1.78), lower rates of prostatectomy (aHR, 0.69; 95% CI, 0.56-0.83), and no significant effect on the use of radiotherapy (aHR, 1.10; 95% CI, 0.99-1.25). Compared with patients with PSMA stage N0M0, ARPI use was more common in patients with PSMA stage N1M0 (aHR, 6.87; 95% CI, 5.41-8.73) and PSMA stage M1 (aHR, 10.13; 95% CI, 8.16-1.2.58). Patients with PSMA N1M0 disease were much less likely to undergo prostatectomy compared with PSMA N0M0. Conclusion: PSMA PET staging may be leading to fewer prostatectomies and higher use rates of ADT and ARPIs in the Veterans Health Administration.}, }
@article {pmid41101869, year = {2025}, author = {Apisarnthanarax, S and Kim, EY}, title = {SBRT: The Most Precise and Least Invasive Tool in the Liver Cancer Toolbox.}, journal = {International journal of radiation oncology, biology, physics}, volume = {123}, number = {4}, pages = {919}, doi = {10.1016/j.ijrobp.2025.08.023}, pmid = {41101869}, issn = {1879-355X}, }
@article {pmid41101390, year = {2025}, author = {Chen, J and Belew, MD and Wei, J and Chow, EJ and Cheng, Z}, title = {Pediatric doxorubicin exposure induces persistent pathological changes in mice.}, journal = {Toxicology and applied pharmacology}, volume = {505}, number = {}, pages = {117600}, doi = {10.1016/j.taap.2025.117600}, pmid = {41101390}, issn = {1096-0333}, abstract = {Over 50 % of pediatric cancer patients undergo treatment with chemotherapy regimens containing anthracyclines, such as doxorubicin (DOX). However, the long-term effects of childhood DOX exposure remain poorly understood, and protective strategies are limited. To establish a mouse model that recapitulates the chronic health conditions in adult survivors of childhood cancer, 14-day-old C57BL/6N mice received DOX (2.5 mg/kg, twice weekly for 2 weeks, i.p.) and were monitored for 32 weeks. Pediatric DOX injection induced late cardiotoxicity including systolic and diastolic dysfunction, cardiac fibrosis and cardiomyocyte atrophy, which were alleviated by treatment with the CDK7/12/13 inhibitor THZ1. Pediatric DOX also reduced heart, liver and spleen weight, while sparing the lung and kidney. Mechanistically, DOX induced persistent activation of p38 in the heart and diminished physiological cardiomyocyte hypertrophy. Pediatric DOX caused slow body weight gain and late mortality, which were surprisingly exacerbated by THZ1. Notably, pediatric THZ1 exposure also hindered body weight gain and reduced heart and liver weight. In conclusion, pediatric DOX exposure resulted in chronic cardiac dysfunction, underweight and premature death during adulthood in mice. Pharmacologic inhibition of CDK7/12/13 with THZ1 partially protected against pediatric DOX-induced cardiotoxicity, but aggravated growth delay and accelerated mortality.}, }
@article {pmid41100801, year = {2025}, author = {Neelapu, SS and Chavez, JC and Sehgal, AR and Epperla, N and Ulrickson, ML and Bachy, E and Munshi, PN and Casulo, C and Maloney, DG and de Vos, S and Reshef, R and Leslie, LA and Oluwole, OO and Yakoub-Agha, I and Khanal, R and Rosenblatt, JD and Wulff, J and Shen, RR and Zhang, W and Poddar, S and Miao, H and Nikolajeva, O and Jacobson, CA}, title = {Five-Year Follow-Up Analysis of ZUMA-5: Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500668}, doi = {10.1200/JCO-25-00668}, pmid = {41100801}, issn = {1527-7755}, abstract = {Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 10[6] CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next treatment and overall survival were not reached (NR). At data cutoff, 55% of patients were alive without requiring subsequent anticancer therapy. Median lymphoma-specific PFS in patients with FL was NR; 34% had progression or death due to lymphoma or study treatment. Notably, after 30 months postinfusion, progression or lymphoma-related deaths were rare. Late-onset toxicities were infrequent and largely unrelated to axi-cel. Durable response and prolonged survival in FL were associated with robust early CAR T-cell expansion and naïve product phenotype. These findings confirm sustained responses and manageable safety with axi-cel in the long term among patients with R/R iNHL and its potential as a curative therapy in FL.}, }
@article {pmid41100668, year = {2025}, author = {Visani, GM and Pun, MN and Minervina, AA and Bradley, P and Thomas, PG and Nourmohammad, A}, title = {T cell receptor specificity landscape revealed through de novo peptide design.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {42}, pages = {e2504783122}, doi = {10.1073/pnas.2504783122}, pmid = {41100668}, issn = {1091-6490}, support = {R35GM142795//HHS | National Institutes of Health (NIH)/ ; R35 GM141457/GM/NIGMS NIH HHS/United States ; AI136514//HHS | National Institutes of Health (NIH)/ ; A153352//UW | Office of Research Central, University of Washington (ORC)/ ; 2045054//National Science Foundation (NSF)/ ; PHY-2210452//National Science Foundation (NSF)/ ; PHY-2309135//National Science Foundation (NSF)/ ; 2919.02//Gordon and Betty Moore Foundation (GBMF)/ ; }, mesh = {*Receptors, Antigen, T-Cell/immunology/metabolism/chemistry ; *Peptides/immunology/chemistry ; Humans ; Machine Learning ; T-Lymphocytes/immunology ; Major Histocompatibility Complex ; Histocompatibility Antigens Class I/immunology ; Protein Binding ; }, abstract = {T cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. Effective bindings between T cell receptors (TCRs) and pathogen derived peptides presented on major histocompatibility complexes (MHCs) mediate immune responses. However, predicting these interactions remains challenging due to limited functional data on T cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC-I alleles, and to design immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, HERMES's implicit physical reasoning enables us to make accurate predictions of both TCR-pMHC binding affinities and T cell activities across diverse viral and cancer epitopes, achieving up to 0.72 correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T cells at success rates of up to 50%. Last, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC's, offering key insights into T cell specificity. Our approach provides a platform for immunogenic peptide and neoantigen design, as well as for evaluating TCR specificity, offering a computational framework to inform design of engineered T cell therapies and vaccines.}, }
@article {pmid41099706, year = {2025}, author = {Hu, C and Popchock, AR and Latino, AA and Asbury, CL and Biggins, S}, title = {Direct observation of interdependent and hierarchical kinetochore assembly on individual centromeres.}, journal = {Nucleic acids research}, volume = {53}, number = {19}, pages = {}, pmid = {41099706}, issn = {1362-4962}, support = {P30 CA015704/CA/NCI/HH/HHS/United States ; R35 GM149357/GM/NIGMS/NH/NIH HHS/United States ; F32GM136010/NH/NIH HHS/United States ; //Jane Coffin Childs Memorial Fund/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {*Kinetochores/metabolism ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Centromere/metabolism/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Microtubules/metabolism ; Protein Binding ; Cell Cycle Proteins ; }, abstract = {Kinetochores are megadalton protein machines that harness microtubules to segregate chromosomes during cell division. The kinetochores must assemble after DNA replication during every cell cycle onto specialized regions of chromosomes called centromeres, but the order and regulation of their assembly remains unclear due to the complexity of kinetochore composition and the difficulty resolving individual kinetochores in vivo. Here, by adapting a prior single-molecule method for monitoring kinetochore assembly in budding yeast lysates, we identify a sequential order of assembly and uncover previously unknown interdependencies between subcomplexes. We show that inner kinetochore assembly depends partly on outer kinetochore components, and that outer kinetochore branches do not assemble independently of one another. Notably, Mif2 assembly is a rate-limiting step that can be accelerated by binding to the Mtw1 subcomplex, thereby promoting rapid assembly of many inner and outer kinetochore components. The importance of controlling kinetochore assembly kinetics is supported by a Mif2 mutant lacking both autoinhibition and Mtw1 subcomplex binding activity, which leads to defective kinetochore-microtubule attachments when the centromeric histone variant Cse4 is overexpressed. Altogether, our work provides a direct view of kinetochore assembly and reveals highly interdependent regulatory events that control its order and timing.}, }
@article {pmid41099265, year = {2025}, author = {McKenney, JK and Brooks, JD and Nguyen, JK and Ding, CKC and Newcomb, LF and Myles, JL and Alaghehbandan, R and Przybycin, CG and Chan, E and Simko, JP and Greenland, NY and Schwen, Z and Weight, CJ and Cooperberg, MR and Carroll, PR}, title = {In reply to: 'Prostate cancer with favorable histology is not synonymous with prostate cancer indolence'.}, journal = {Histopathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/his.70023}, pmid = {41099265}, issn = {1365-2559}, }
@article {pmid41098153, year = {2025}, author = {Ikoma-Colturato, MRV and Magalhães Furtado, F and Bertolucci, CM and Severino, AR and Souto, EX and Ferreira Dos Santos, TC and Dametto, APF and Beltrame, MP and Bacal, NS and Avelar, DMV and Fernandes, RA and Gomes, BE and da Costa, ES and Santos, BEFDS and Mendonça de Pontes, R and Périco, MDH and Gevert, F and de Siqueira, PFR and Marquezotti, F and Wagner, AOM and Soares, ACCV and Duarte, FB and Flowers, ME and Vigorito, AC}, title = {Standardization of Measurable Residual Disease in Acute Myeloid Leukemia by Flow Cytometry: A Multicenter Study.}, journal = {EJHaem}, volume = {6}, number = {5}, pages = {e70163}, pmid = {41098153}, issn = {2688-6146}, abstract = {INTRODUCTION: Measurable residual disease (MRD) is a strong predictor of the risk of relapse of acute myeloid leukemia (AML). Therefore, for use in clinical decision-making, methods for MRD assessment must achieve adequate accuracy, sensitivity, specificity, and reproducibility. Multiparametric flow cytometry (MFC) is the most widely used method for assessing AML-MRD, but its sensitivity varies considerably due to the differing approaches used across centers, in addition to the different experiences of flow cytometrists, especially during clonal evolution. This study aimed to standardize AML-MRD by MFC in a multicenter project involving 16 Brazilian laboratories.
METHODS: In the first phase, specialists were trained in pre-analytical standard operating procedures (SOPs) and analysis strategies of pre-validated 8- and 10-color protocols, followed by a data-only, that is, a Dry Phase of flow cytometry standard (FCS) file exchange by the coordinating laboratory in a comparability assessment. In the second or Wet Phase, laboratories prepared and analyzed their samples, and the FCS files were submitted for central analysis.
RESULTS: The agreement of MRD results was 81% and 80% between laboratories and central analysts in the Dry and Wet Phases, respectively. However, non-suitable application of pre-analytical SOPs hampered MRD interpretation for 30% of the laboratories in the Wet Phase.
CONCLUSIONS: This study demonstrated that standardized flow cytometry protocols are reproducible as long as rigorous SOPs are implemented. The project's results underscore that continuous education and external quality control are essential to build expertise and ensure reliable AML-MRD results in clinical practice. Trial Registration:The authors have confirmed clinical trial registration is not needed for this submission.}, }
@article {pmid41096533, year = {2025}, author = {Munarriz, D and López-Godino, O and Martinez-Cibrian, N and Albiol, N and Brillembourg, H and Navarro-Velázquez, S and Español-Rego, M and Casanueva, S and García-Tomás, L and Muñoz-Sanchez, G and Alserawan, L and Benitez-Ribas, D and Magnano, L and Correa, JG and Rivero, A and Mozas, P and Gine, E and Rodríguez-Lobato, LG and Martínez-Roca, A and Montoro-Lorite, M and Ayora, P and Esteve, J and Frutos, L and Balagué-Ponz, O and Urbano-Ispizua, A and González-Navarro, EA and Juan, M and Delgado, J and Ortiz-Maldonado, V}, title = {Combining CAR T-Cell Therapy and Nivolumab to Overcome Immune Resistance in THRLBCL: A Case Report.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096533}, issn = {1422-0067}, mesh = {Humans ; Female ; Adult ; *Nivolumab/therapeutic use ; *Lymphoma, Large B-Cell, Diffuse/therapy/immunology/pathology ; *Immunotherapy, Adoptive/methods ; *Antineoplastic Agents, Immunological/therapeutic use ; Antigens, CD19/immunology ; B7-H1 Antigen/metabolism ; Combined Modality Therapy ; Drug Resistance, Neoplasm ; Tumor Microenvironment ; }, abstract = {T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell therapy. We report a case of a 29-year-old woman with refractory stage IV-B THRLBCL treated with anti-CD19 CAR T-cell therapy (varnimcabtagene autoleucel), who achieved an initial response (day +28) but experienced disease progression by day +100 despite robust CAR T-cell expansion. Peripheral blood analysis revealed persistent absolute B-cell aplasia, while bone marrow biopsy confirmed CD19-positive disease. Comparative immunohistochemistry demonstrated markedly increased PD-L1 expression in post-CAR T-cell samples, suggesting adaptive immune resistance via PD-1/PD-L1-mediated CAR T-cell inhibition. Nivolumab was initiated at month +4 to overcome this checkpoint-mediated resistance. Notably, a complete metabolic response was documented on PET/CT after four doses of nivolumab (month +6). The patient remains in sustained remission, with persistent B-cell aplasia, four years post-intervention. This case provides clinical and pathological evidence supporting the use of immune checkpoint blockade to rescue CAR T-cell efficacy, highlighting the potential of this synergistic approach in THRLBCL and possibly other B-cell malignancies exhibiting similar immune evasion.}, }
@article {pmid41093689, year = {2025}, author = {Goetz, MP and Toi, M and Huober, J and Sohn, J and Trédan, O and Park, IH and Campone, M and Chen, SC and Manso, LM and Paluch-Shimon, S and Freedman, OC and O'Shaughnessy, J and Pivot, X and Tolaney, SM and Hurvitz, SA and Llombart-Cussac, A and André, V and Saha, A and van Hal, G and Shahir, A and Iwata, H and Johnston, SRD}, title = {Corrigendum to "Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3": [Ann Oncol 2024; 35: 718-727].}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.07.002}, pmid = {41093689}, issn = {1569-8041}, }
@article {pmid41092928, year = {2025}, author = {, }, title = {Global burden of 292 causes of death in 204 countries and territories and 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)01917-8}, pmid = {41092928}, issn = {1474-547X}, abstract = {BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations.
METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds.
FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value.
INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales.
FUNDING: Gates Foundation.}, }
@article {pmid41091803, year = {2025}, author = {Wiley, HS and Lopez, CF and Rodin, AS and Rockne, RC and Yankeelov, TE and Sauro, HM and Hassan, G and Prabhakaran, S and Demir, E and Hu, M and Fuxman Bass, J and Luddy, KA and Newman, H and Mochel, JP and Costello, JC and Xing, J and Afify, SM and Acar, A and Hayden Gephart, M and Feng, S and Banks, O and Banerjee, J and Clayton, A and Hill, DE and Sweis, RF and Umeh-Garcia, MC and Su, Y and Meyer, AS}, title = {A Roadmap for the Future of Systems Biology in Cancer Research.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-25-0700}, pmid = {41091803}, issn = {1538-7445}, abstract = {Cancer systems biology seeks to understand how cancer arises as a system of interconnected molecules, cells, and tissues, with the goal of understanding, predicting, and controlling the disease. In the last decade, the field has rapidly grown as advances in experimental, computational, and analytical technologies have improved our ability to capture and recapitulate the complexities of cancer at multiple scales. However, the field's promise to understand how specific molecular changes give rise to altered cancer outcomes remains incompletely fulfilled. Fortunately, an opportunity exists to accelerate progress by better coordinating modeling and data-gathering efforts across the cancer systems biology community. This will create the foundation for building accurate, multiscale cancer models that can better predict and identify improved therapeutic interventions. Here, we outline some of the current challenges in cancer systems biology research, how they can be addressed, and actions that the community can take to accelerate progress in the field.}, }
@article {pmid41088800, year = {2025}, author = {Fuhrman, J and Yun, J and Indorf, A}, title = {Practical considerations and emerging approaches for the management of vasomotor and sexual symptoms in breast cancer patients on endocrine therapies.}, journal = {Expert review of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1080/17512433.2025.2573780}, pmid = {41088800}, issn = {1751-2441}, abstract = {INTRODUCTION: Vasomotor symptoms (VMS) and decreased libido are common menopausal symptoms. Patients with breast cancer receiving endocrine therapy experience new or worsening menopausal symptoms. Pharmacologic therapy for VMS has been centered on selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, gabapentin, and clonidine. These therapeutic options fall short in obtaining adequate symptom relief, illustrating a therapeutic gap in efficacious treatment modalities. There are no historical systemic treatment options for low libido.
AREAS COVERED: This review summarizes the current pharmacologic therapy for VMS, focusing on the practical considerations for use of the novel VMS (fezolinetant, elinzanetant) and libido agents (flibanserin, bremelanotide). Literature search was completed with PUBMED, Cochrane Library, and Web of Science. Fezolinetant is a novel neurokinin 3 receptor antagonist that has demonstrated clinical benefit in patients without a history of breast cancer. For libido management, flibanserin and bremelanotide act as serotonin/dopaminergic modulators and melanocortin receptor agonists, respectively.
EXPERT OPINION: These novel agents are eagerly awaited therapeutic options; however, clinical trials excluded breast cancer patients. This review provides clinicians with relevant considerations to assess when recommending these therapies for patients with breast cancer, while awaiting ongoing research to give additional insights for best tailoring therapy for this patient population.}, }
@article {pmid41087806, year = {2025}, author = {Yi, JC and Lee, E and Duggan, C and Baker, KS and Blythe, N and Cole, AM and Cushing-Haugen, KL and Gutierrez, AI and Linden, H and Mendoza, JA and Ohlsen, TJD and Ortblad, KF and Schwartz, SM and Yung, R and Ceballos, R and Chow, EJ}, title = {Perspective of Hispanic Cancer Survivors on Survivorship Care Plans: A Qualitative Study.}, journal = {Journal of immigrant and minority health}, volume = {}, number = {}, pages = {}, pmid = {41087806}, issn = {1557-1920}, support = {75N91020C00005/NH/NIH HHS/United States ; HHSN261201800004I/NH/NIH HHS/United States ; R21 CA258105/NH/NIH HHS/United States ; R21 CA258105/NH/NIH HHS/United States ; }, abstract = {Explore Hispanic cancer survivors' thoughts about survivorship care plans (SCPs), lay health educator (LHE)-delivered survivorship information, and general survivorship care among Hispanic cancer survivors. A subset of N = 95 participants (≥ 18 years) enrolled in a randomized controlled trial (RCT; March 2023 to August 2023) assessing the feasibility of LHE-delivered survivorship information completed phone-based interviews in which semi-structured guides probed their views on SCPs, the LHE call, and survivorship more broadly. Twenty participants (21% of the total enrolled) completed interviews (11 in English, 9 in Spanish). Most participants were female (70%), half were born in the United States (50%), and the majority had breast cancer (55%); the remaining had colorectal (5%), lymphoma (15%), and prostate cancers (25%). The average time since cancer diagnosis was 3.1 years (SD 1.8). Participants reported few issues transitioning from oncology to primary care and perceived that this transition was supported by easily accessible medical records that also help delineate the care responsibilities of different providers. Most participants thought the SCPs were easy to understand and helped them manage their survivorship care with confidence. They also found information on nutrition and physical activity helpful. Participants liked the LHE call but did not necessarily think it assisted with care coordination. Hispanic cancer survivors reported that the SCPs were helpful and easy to understand but that benefits of a survivorship-focused LHE session were less clear. Additional research may help to determine how best to utilize SCPs and LHEs for these survivors and their providers. Clinical Trials Registration: clinicaltrials.gov NCT04081779.}, }
@article {pmid41087744, year = {2025}, author = {Abu-Shmais, AA and Freeman, G and Creanga, A and Vukovich, MJ and Malla, T and Mantus, GE and Shimberg, GD and Gillespie, RA and Guerra Canedo, V and Dadonaite, B and Rodgers, MD and Chopde, AJ and Bardwil-Lugones, E and Bylund, T and Henry, AR and Roberts-Torres, J and Johnston, TS and Smith, S and Yang, ES and Cheng, C and Walker, EL and Ravichandran, M and Gordon, IJ and Dittakavi, TS and Reed, DS and Pierson, TC and Dropulic, L and Bloom, JD and Tsybovsky, Y and Boritz, EA and Douek, DC and Zhou, T and Kanekiyo, M and Andrews, SF}, title = {Cross-neutralizing and potent human monoclonal antibodies against historical and emerging H5Nx influenza viruses.}, journal = {Nature microbiology}, volume = {}, number = {}, pages = {}, pmid = {41087744}, issn = {2058-5276}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; UC7AI180311//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UC7AI180311//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, abstract = {Highly pathogenic avian influenza H5Nx viruses are an emerging threat for global health, especially clade 2.3.4.4b H5N1 virus which causes panzootic infections. Here we describe the isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals who received a monovalent H5N1 vaccine 15 years ago. By screening over 500 mAbs, we identified 5 mAbs that neutralized the majority of H5 clades including 2.3.4.4b and target three distinct conserved epitopes within the HA globular head. Cryo-electron microscopy structures of these mAbs in complex with HA, deep mutational scanning and neutralization escape studies define the sites of vulnerability of H5 HA. These mAbs mediated stronger prophylactic protection against clade 2.3.4.4b H5N1 infection in mice than the best-in-class mAb targeting the HA stem. Our study identified several highly potent broadly neutralizing H5 mAbs from humans that either alone or in combination provide a pragmatic pandemic preparedness option against the threat of panzootic H5N1 influenza.}, }
@article {pmid41087376, year = {2025}, author = {Edge, R and Matthews, S and Ahani, B and Aksyuk, AA and Clegg, L and Perez, JL and Esser, MT and Chang, LJ and Hirsch, I and Villafana, T and Pura, J and Stepanov, O and Streicher, K and White, T and Cohen, TS and Follmann, D and Gilbert, PB and Seegobin, S}, title = {A SARS-CoV-2 variant‑adjusted threshold of protection model for monoclonal antibody pre-exposure prophylaxis against COVID-19.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9101}, pmid = {41087376}, issn = {2041-1723}, support = {Not applicable//AstraZeneca/ ; }, mesh = {Humans ; *COVID-19/prevention & control/immunology/virology ; *SARS-CoV-2/immunology/genetics/drug effects ; *Pre-Exposure Prophylaxis/methods ; *Antibodies, Monoclonal/immunology/therapeutic use/administration & dosage ; *Antibodies, Viral/immunology/blood ; Antibodies, Neutralizing/immunology/blood ; COVID-19 Drug Treatment ; Female ; Male ; Middle Aged ; Proportional Hazards Models ; Antibodies, Monoclonal, Humanized ; }, abstract = {Clinical development of monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is challenging due to rapid changes in the variant landscape. This study identified a threshold model for neutralising antibody (nAb) titres associated with clinically relevant protection against symptomatic COVID-19 for vulnerable populations. Using efficacy data from the phase 3 PROVENT pre-exposure prophylaxis trial of tixagevimab-cilgavimab (NCT04625725), individual nAb ID50 titres were predicted by dividing serum mAb concentration by prevalence-adjusted tixagevimab-cilgavimab potency (from in vitro IC50 values combined with viral surveillance data) and related to efficacy with a Cox model. The Threshold of Protection (ToP) Cox model was externally validated using data from the phase 3 SUPERNOVA trial (NCT05648110), which assessed sipavibart efficacy against symptomatic COVID-19 in immunocompromised participants. The PROVENT ToP model estimated the variant-specific observed efficacies from SUPERNOVA for 3 and 6 months post any dose with Lin's concordance of 0.86 and 0.75, respectively. This approach integrates predicted nAb ID50 titres against multiple SARS-CoV-2 variants into a ToP model that can be applied across different variants and could serve as a surrogate endpoint in immunobridging studies to expedite clinical evaluation and regulatory approval for mAbs targeting SARS-CoV-2.}, }
@article {pmid40763278, year = {2025}, author = {Simonin, M and Boissel, N and Petit, A and Mullighan, CG and Hunger, SP and Loh, ML and Winter, SS and Macintyre, E and Teachey, DT and Baruchel, A and Asnafi, V}, title = {Prognostic impact of the PredicT-ALL classifier in the AALL0434 trial: a model combining NGS, MRD, and WBC at diagnosis.}, journal = {Blood advances}, volume = {9}, number = {20}, pages = {5323-5326}, doi = {10.1182/bloodadvances.2025017399}, pmid = {40763278}, issn = {2473-9537}, }
@article {pmid41085624, year = {2026}, author = {Finton, KAK and Foote-McNabb, UN and Wilcox, EC and Jones, LA and Gafken, PR and Strong, RK}, title = {Artemis: Mass Spectrometry-Based Identification of MHC-Presented Peptides Across Alleles, Classes, and Species Using Soluble Single-Chain MHC Constructs.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2980}, number = {}, pages = {231-250}, pmid = {41085624}, issn = {1940-6029}, mesh = {Humans ; *Peptides/immunology/genetics ; Alleles ; *Mass Spectrometry/methods ; *Antigen Presentation/immunology ; Animals ; *Major Histocompatibility Complex ; }, abstract = {The current "gold standard" for the identification of MHC-restricted peptides is conventional immunoprecipitation/mass spectrometry (MS); however, this approach requires a relatively large amount of sample, complex purification procedures, and computational analyses to assign peptides to individual alleles. Here, we provide instructions for the expression, purification, and MS identification of MHC-presented peptides of human and non-human, classical and non-classical, class I and class II proteins using a readily expressible, soluble, and easily purifiable single-chain dimer construct. This procedure enables the identification of up to tens of thousands of allele-specific peptides per run for peptidomics, ligandomics, therapeutic targeting, and motif analyses. Also included are instructions for construct design, streamlined lentiviral transfection and transduction, and computational methods for high-throughput processing of MS results, yielding high confidence peptide lists, motifs, and multiple analytics.}, }
@article {pmid41085561, year = {2025}, author = {Fryer, E and Bishop, DT and Campbell, PT and Chan, AT and Le Marchand, L and Li, CI and Moreno, V and Gunter, MJ and Phipps, AI and Grant, RC and Schmit, SL and Martin, RM and Yarmolinsky, J and Haycock, P}, title = {Investigating the causal effect of potential therapeutic agents for colorectal cancer prevention: a Mendelian randomization analysis.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0875}, pmid = {41085561}, issn = {1538-7755}, abstract = {BACKGROUND: Conventional observational studies have identified several potential therapeutic agents that may lower risk of colorectal cancer development. However, these studies are susceptible to unmeasured and residual confounding and reverse causation, undermining robust causal inference.
METHODS: We used Mendelian randomization (MR), a genetic epidemiological method that can strengthen causal inference, to evaluate the effect of previously reported therapeutic agents on colorectal cancer risk, including medications, dietary micronutrients, and exogenous hormones. Genetic instruments were constructed using genome-wide association studies (GWASs) of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of micronutrients, circulating levels of endogenous hormones). Using summary statistics from these GWASs and a colorectal cancer risk GWAS (cases=78,473, controls=107,143), we employed Wald ratios and inverse-variance weighted models to estimate causal effects.
RESULTS: We found evidence for associations of genetically-proxied elevated omega-3 fatty acids (OR 1.10; 95% CI 1.03, 1.18; p=6.20x10-3) and reduced plasma ACE levels (OR 1.08; 95% CI 1.03, 1.13; p=9.36x10-4) with colorectal cancer risk. Findings for ACE inhibition were consistent across sensitivity analyses.
CONCLUSIONS: Reduced plasma ACE levels were robustly linked to increased colorectal cancer risk. Further work is required to better understand the mechanism behind this finding and whether this translates to adverse effects via medication use (i.e. ACE inhibitors).
IMPACT: These findings provide updated evidence on the role of previously reported therapeutic agents in colorectal cancer risk, helping to prioritise further evaluation of those agents with potential aetiological roles in cancer development.}, }
@article {pmid41084890, year = {2025}, author = {Fitzgerald, L and Ghosh, S and Bokun, A and Lax, A and Mu, F and Wu, E and Lin, Y and Shi, L and Qureshi, ZP and Graf, SA}, title = {Healthcare cost comparison between first-line ibrutinib and acalabrutinib in chronic lymphocytic leukemia patients in the Veterans Affairs.}, journal = {Journal of comparative effectiveness research}, volume = {}, number = {}, pages = {e250084}, doi = {10.57264/cer-2025-0084}, pmid = {41084890}, issn = {2042-6313}, abstract = {Aim: Bruton's tyrosine kinase inhibitors (BTKis), including ibrutinib and acalabrutinib, transformed the treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) by improving outcomes compared with chemoimmunotherapy. Real-world economic comparisons between BTKis are needed in diverse populations. This study aimed to compare healthcare costs in the Veterans Health Administration (VHA) among patients with CLL/SLL treated with, and remaining persistent on, first-line (1L) ibrutinib versus acalabrutinib monotherapy for 12 months. Materials & methods: This retrospective study used VHA electronic medical record data from January 2006 to July 2024. Eligible patients initiated 1L ibrutinib or acalabrutinib monotherapy on or after November 2019 and remained on continuous treatment for ≥12 months. All-cause and CLL/SLL-related costs were assessed over 12 months of follow-up. Generalized linear models were used to estimate adjusted costs and compare differences between treatment cohorts. Results: A total of 1059 patients were included (ibrutinib: n = 732; acalabrutinib: n = 327). During the 12-month follow-up of continuous 1L treatment, the annual adjusted all-cause total healthcare cost difference between ibrutinib and acalabrutinib was -$2422 (p = 0.46) (adjusted medical cost difference: $5259, p = 0.03; adjusted pharmacy cost difference: -$5886, p = 0.02). The annual adjusted CLL/SLL-related total healthcare cost difference between ibrutinib and acalabrutinib was -$3793 (p = 0.15) (adjusted medical cost difference: $2085, p = 0.05; adjusted pharmacy cost difference: -$5860, p = 0.02). Conclusion: Among VHA patients with CLL/SLL who initiated and remained on treatment with 1L BTKi monotherapy for 12 months, annual all-cause and CLL/SLL-related total healthcare costs were similar between ibrutinib and acalabrutinib. Pharmacy costs were lower for ibrutinib, while medical costs were lower for acalabrutinib, resulting in overall comparable total costs.}, }
@article {pmid41084727, year = {2025}, author = {Özcan, M and Cassaday, RD and Zarzycka, E and Vandendries, E and Zhang, F and Chen, Y and Nieto, A and Demirkan, F and Montesinos, P and Altuntas, F}, title = {Comparing two different doses of inotuzumab ozogamicin treatment in adult patients with acute lymphoblastic leukemia: a plain language summary of publication.}, journal = {Therapeutic advances in medical oncology}, volume = {17}, number = {}, pages = {17588359251370948}, doi = {10.1177/17588359251370948}, pmid = {41084727}, issn = {1758-8340}, abstract = {What is this summary about? This summary describes the results of a clinical study that compared two different doses of a treatment, called inotuzumab ozogamicin (inotuzumab for short), for acute lymphoblastic leukemia (ALL for short). This summary describes the results for people aged 18 years and older who took part in the study. Why was this study done? People who took part in the study had a higher risk of developing a side effect called sinusoidal obstruction syndrome (SOS for short), also known as veno-occlusive disease (VOD for short), which is a rare condition where some of the small blood vessels in the liver become blocked. Researchers wanted to find out if receiving a lower dose than the recommended dose of inotuzumab reduced the likelihood of people developing SOS after a stem cell transplant. Researchers wanted to find out if a lower dose of inotuzumab would also impact the efficacy (how well inotuzumab works to treat ALL) in people with ALL and what other side effects occurred.}, }
@article {pmid41083679, year = {2025}, author = {Salit, RB and Hexner, EO and Gagelmann, N and Kröger, N and McLornan, DP and Jain, T and Gupta, V and Hobbs, GS and Tamari, R and Robin, M and Scott, B and Saber, W}, title = {Defining remission following hematopoietic cell transplant for myelofibrosis: an international expert panel consensus.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {41083679}, issn = {1476-5551}, }
@article {pmid41082548, year = {2025}, author = {Matsuno, A and Tollefson, D and Cover, J and Obong'o, C and Gamba, H and Chen, YQ and Duerr, A}, title = {What drives adolescent girls and young women's decisions to persist on PrEP? Results of a comparative qualitative study from a DREAMS program in western Kenya.}, journal = {AIDS care}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/09540121.2025.2570098}, pmid = {41082548}, issn = {1360-0451}, abstract = {Oral pre-exposure prophylaxis (PrEP) is a valuable tool to help end HIV, but persistent PrEP use is low amongst adolescent girls and young women (AGYW) in sub-Saharan Africa (SSA), who are at high risk for HIV. To improve persistent PrEP use in AGYW, more research is needed to understand what drives their decisions to continue with PrEP. We conducted a thematic, comparative qualitative analysis of in-depth interviews with 32 AGYW who participated in PEPFAR's DREAMS program in western Kenya: 16 were randomly sampled among those who persisted with PrEP and 16 among those who discontinued. We compared results between these groups to explore drivers for the decision to persist with PrEP. We interpreted findings using the Integrated Behavior Model, which posits that the decision to persist is influenced by attitudes, social norms and personal agency. Three themes emerged that illuminated AGYW's decision to persist with PrEP. First, having positive attitudes towards PrEP was insufficient to ensure persistence in absence of correct knowledge. All AGYW were positive about PrEP, but those who discontinued often had insufficient/misinformation about PrEP, specifically on its appropriate use during pregnancy/breastfeeding. Second, support from family and friends was critical to overcome societal stigma and could counter lack of support from romantic partners. Third, strong mentors supported PrEP persistence by increasing self-agency, but this was secondary in importance to the need for robust knowledge and social support. To improve PrEP persistence amongst AGYW in SSA, PrEP programs may benefit from increasing education delivered to AGYWs and their communities, specifically family and friends. In particular, messages that PrEP may be used when pregnant/breastfeeding should be reinforced. Other health programs for AGYWs may also benefit from an increased focus on educational messaging to program recipients and people in their existing social networks.}, }
@article {pmid41081510, year = {2025}, author = {Dadonaite, B and Harari, S and Larsen, BB and Kampman, L and Harteloo, A and Elias-Warren, A and Chu, HY and Bloom, JD}, title = {Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0142325}, doi = {10.1128/jvi.01423-25}, pmid = {41081510}, issn = {1098-5514}, abstract = {SARS-CoV-2 is under strong evolutionary selection to acquire mutations in its spike protein that reduce neutralization by human polyclonal antibodies. Here, we use pseudovirus-based deep mutational scanning to measure how mutations to the spike from the recent KP.3.1.1 SARS-CoV-2 strain affect cell entry, binding to the ACE2 receptor, RBD up/down motion, and neutralization by human sera and clinically relevant antibodies. The spike mutations that most affect serum antibody neutralization sometimes differ between sera collected before versus after recent vaccination or infection, indicating that these exposures shift the neutralization immunodominance hierarchy. The sites where mutations cause the greatest reduction in neutralization by post-vaccination or infection sera include receptor-binding domain (RBD) sites 475, 478, and 487, all of which have mutated in recent SARS-CoV-2 variants. Multiple mutations outside the RBD affect sera neutralization as strongly as any RBD mutations by modulating the RBD up/down movement. Some sites that affect RBD up/down movement have mutated in recent SARS-CoV-2 variants. Finally, we measure how spike mutations affect neutralization by three clinically relevant SARS-CoV-2 antibodies: VYD222, BD55-1205, and SA55. Overall, these results illuminate the current constraints and pressures shaping SARS-CoV-2 evolution and can help with efforts to forecast possible future antigenic changes that may impact vaccines or clinical antibodies.IMPORTANCEThis study measures how mutations to the spike of a SARS-CoV-2 variant that circulated in early 2025 affect its function and recognition by both the polyclonal antibodies produced by the human immune system and monoclonal antibodies used as prophylactics. These measurements are made with a pseudovirus system that enables safe study of viral protein mutations using virions that can only infect cells once. The study identifies mutations that decrease recognition by current human antibody immunity; many of these mutations are increasingly being observed in new viral variants. It also shows the importance of mutations that move the spike's receptor-binding domain up or down. Overall, these results are useful for forecasting viral evolution and assessing which newly emerging variants have reduced recognition by immunity and antibody prophylactics.}, }
@article {pmid41081432, year = {2025}, author = {Avanessian, SC and van den Bijgaart, RJE and Chew, NW and Supper, VM and Tang, TT and Zhang, Y and Zhao, YQ and Abe, K and Gauthier, J and Barry, KC}, title = {IL-2/IL-15 signaling induces NK cell production of FLT3LG augmenting anti-PD-1 immunotherapy.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-24-1259}, pmid = {41081432}, issn = {2326-6074}, abstract = {Natural killer (NK) cells play a critical role in anti-cancer immunity through their direct cytotoxicity and production of cytokines, such as Flt3L. NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. Here, we show that NK cell production of Flt3l in the tumor is regulated by activation, and that activation by IL-2 and IL-15 uniquely induced Flt3L expression in NK cells. In melanoma, IL-2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Further, NK cell subsets differentially regulated Flt3L in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL-2-family signaling and upregulated Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.}, }
@article {pmid41077138, year = {2025}, author = {Akaike, T and Thakuria, M and Silk, AW and Hippe, DS and Ch'en, PY and Park, SY and Urman, NM and Chiu, MW and Kim, H and Kim, EY and Hall, ET and Bhatia, S and Reddy, S and Krainock, M and Aleshin, A and Choi, JS and Tsai, K and Yom, SS and Yu, SS and Choi, J and Chandra, S and Nghiem, PT and Zaba, LC}, title = {Circulating tumor DNA level is associated with time to clinical recurrence in Merkel cell carcinoma: Implications for patient management.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.10.032}, pmid = {41077138}, issn = {1097-6787}, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. Circulating tumor DNA (ctDNA) is an emerging blood-based biomarker for early MCC recurrence detection.
OBJECTIVE: To evaluate the timing and prognostic significance of ctDNA levels relative to clinical recurrence.
METHODS: This multicenter prospective study analyzed 669 tumor-informed ctDNA tests from 215 MCC patients (stage I-IV) without clinically evident disease after treatment.
RESULTS: Patients with at least one positive ctDNA test were more likely to experience recurrence compared to ctDNA-negative patients (hazard ratio: 18.1, 95% CI: 8.9-36.7), with 77% developing clinically evident disease by one year. The median interval between the first positive ctDNA and clinical recurrence was 2.7 months. Clinical recurrences usually occurred within 3 months for ctDNA levels above 10 molecules/mL, within 6 months for levels between 1-10 molecules/mL, and within 9 months for levels below 1 molecule/mL.
LIMITATIONS: In this real-world study, there was variability in timing and frequency of follow-up examinations, imaging, and ctDNA testing, although most patients were followed with both ctDNA and imaging.
CONCLUSIONS: A positive ctDNA test detects MCC recurrence approximately 3 months earlier than imaging. Negative ctDNA can help reduce imaging frequency through serial ctDNA monitoring, while positive ctDNA warrants closer patient follow-up.}, }
@article {pmid41076992, year = {2025}, author = {Bouras, E and Yu, R and Kim, AE and Markozannes, G and Murphy, N and Albanes, D and Anderson, LN and Barry, EL and Berndt, SI and Bishop, DT and Brenner, H and Burnett-Hartman, A and Campbell, PT and Carreras-Torres, R and Chan, AT and Cheng, I and Devall, MA and Diez-Obrero, V and Dimou, N and Drew, DA and Gruber, SB and Gsur, A and Hoffmeister, M and Hsu, L and Huyghe, JR and Kawaguchi, E and Keku, TO and Kundaje, A and Küry, S and Le Marchand, L and Lewinger, JP and Li, L and Lynch, BM and Moreno, V and Morrison, JL and Newton, CC and Obón-Santacana, M and Palmer, JR and Papadimitriou, N and Pellatt, AJ and Peoples, AR and Pharoah, PDP and Platz, EA and Qu, C and Ruiz-Narvaez, E and Mendez, JS and Schoen, RE and Stern, MC and Thomas, CE and Tian, Y and Um, CY and Visvanathan, K and Vodicka, P and Vymetalkova, V and White, E and Wolk, A and Woods, MO and Wu, AH and Gunter, MJ and Gauderman, WJ and Peters, U and Evangelou, M and Tsilidis, KK}, title = {Using gene-environment interactions to explore pathways for colorectal cancer risk.}, journal = {EBioMedicine}, volume = {121}, number = {}, pages = {105964}, doi = {10.1016/j.ebiom.2025.105964}, pmid = {41076992}, issn = {2352-3964}, abstract = {BACKGROUND: Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.
METHODS: We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].
FINDINGS: A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P < 0.05) for at least one exposure, as well as 1227 genes within the enriched pathways. Data were available for 811/1227 coding genes in the OTP, 241 of which were supported by strong relative abundance of prior evidence (overall OTP score > 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms.
INTERPRETATION: The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies.
FUNDING: This study was funded by Cancer Research UK (CRUK; grant number:PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements.}, }
@article {pmid41076366, year = {2025}, author = {Li, R and Hensley, PJ and Babjuk, M and Bukavina, L and Psutka, SP and Lerner, SP and O'Donnell, MA and Lotan, Y and Bree, KK and Redorta, JP and McConkey, DJ and Lee, BH and Mariappan, P and Mertens, LS and Soloway, MS and Svatek, RS and Tan, WS and Williams, SB and Gupta, S and Buckley, R and Kamat, AM}, title = {Intermediate-risk Non-muscle-invasive Bladder Cancer: Recommendations for Definitions, Risk Stratification, Management Strategies, and Clinical Trial Design from the International Bladder Cancer Group.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.08.003}, pmid = {41076366}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease, and standardized definitions and risk-guided management are critical for appropriate patient care and clinical trial development.
METHODS: A global committee of bladder cancer experts developed IR-NMIBC recommendations. Working groups reviewed literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During an August 2024 meeting, voting results and evidence were presented, and recommendations were refined. Final recommendations achieved >75% agreement.
KEY FINDINGS AND LIMITATIONS: The IBCG recommends inclusion of only low-grade (LG; G1 and G2) tumors in the IR-NMIBC category, risk stratified using the IBCG IR-NMIBC risk scoring system. Given the relatively indolent course and treatment burden of IR-NMIBC, therapeutic deintensification with active surveillance or office-based ablation is appropriate for select patients. Morbidity related to transurethral resection of a bladder tumor can be mitigated by forgoing restaging resection in completely resected LG tumors and not mandating muscularis propria sampling. Perioperative chemotherapy reduces recurrences, and additional adjuvant intravesical treatment should be risk stratified. Clinical trials evaluating novel IR-NMIBC therapies, including adjuvant and ablative designs, should incorporate patient-reported outcomes and risk-stratified controls. Ablative trials, as proof-of-concept studies for efficacy, require randomized controlled studies in the adjuvant setting to confirm superiority over the standard of care.
The IBCG consensus recommendations provide practical guidance for clinical care and clinical trial design for patients with IR-NMIBC.}, }
@article {pmid41076116, year = {2025}, author = {Louie, T and Snidarich, M and Hippe, DS and Wernli, KJ and Palazzo, L and Hansell, L and Brown, M and Coronado, GD and Lodhi, S and Leone, R and DeCell, K and Mardesich, K and Wysham, N and Triplette, M}, title = {A pragmatic pre-post intervention trial to address adherence to lung cancer screening follow-up in community settings (the ACCELL trial): Study protocol.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {108106}, doi = {10.1016/j.cct.2025.108106}, pmid = {41076116}, issn = {1559-2030}, abstract = {BACKGROUND: Lung cancer remains the leading cause of cancer death in the United States. Annual lung cancer screening (LCS) with low-dose chest CT (LDCT) can prevent lung cancer deaths in high-risk individuals; However, these benefits are tempered by low adherence to annual screening and low rates of follow-up for those with abnormal findings.
OBJECTIVE: To evaluate the impact of centralized approaches to care coordination on LCS follow-up in community settings through a hybrid implementation-effectiveness trial.
METHODS: This is a pre-post intervention trial of a pragmatic and flexible approach to LCS care coordination delivered at the system-level at two community LCS programs based at regional hospitals in Washington state. Care coordination approaches include standardized LCS follow-up workflows incorporating universal tracking of LCS results, universal results delivery to patients, stepped approaches to follow-up reminders and personalized approaches to positive findings. Participants who are eligible for and undergo LCS during either period (n ~ 6750) will be included. Primary outcomes include adjusted changes in screening adherence to annual follow-up and follow-up for positive findings between the pre- (August 2022-January 2025) and post- (January 2025-July 2027) intervention period. Secondary outcomes include assessing the impact of interventions by community site, patient ethnicity, socioeconomic status, and rurality. We will also assess the implementation of the intervention with attention to adaptation, sustainability and equity.
DISCUSSION: Implementing centralizing care coordination models may decrease barriers and improve adherence to LCS in community settings and serve as a model to improve LCS follow-up in clinical care settings.
REGISTRATION: ClinicalTrials.gov ID NCT06324110.}, }
@article {pmid41075386, year = {2025}, author = {Minnie, SA and Berrien-Elliott, MM and Smith, M and Biernacki, MA and Bleakley, M}, title = {Optimizing post-transplantation cell therapies to enhance graft-versus-leukemia effects in hematological malignancies.}, journal = {Current opinion in immunology}, volume = {97}, number = {}, pages = {102675}, doi = {10.1016/j.coi.2025.102675}, pmid = {41075386}, issn = {1879-0372}, abstract = {Allogeneic hematopoietic cell transplantation (HCT) can cure patients with high-risk hematologic malignancies. Donor T and natural killer (NK) cells contribute to graft-versus-leukemia (GVL) effects that provide relapse protection. Post-HCT relapses often represent inadequate GVL, but alloreactive lymphocytes that confer GVL may also cause graft-versus-host-disease (GVHD). Here, we review recent developments to selectively augment GVL while minimizing GVHD. Insights into the unique mechanisms of post-HCT T cell dysfunction highlight interventions to enhance GVL-mediating T cells. Early clinical data suggest that adoptive transfer of engineered donor T cells, expressing either transgenic T cell receptors specific for minor histocompatibility antigens presented exclusively on recipient hematopoietic cells or chimeric antigen receptors binding surface proteins on malignant cells, can mitigate post-HCT relapse. NK cells, key GVL mediators after haploidentical HCT, can be induced into a highly functional memory-like state and administered to HCT recipients to enhance GVL. These innovations promise much-needed improvements in post-HCT outcomes.}, }
@article {pmid41074700, year = {2025}, author = {Aldoss, I and Ali, A and Cassaday, RD and Curran, EK and Luskin, MR and Maese, LD and Orgel, E and Douer, D}, title = {Optimizing Asparaginase Treatment for Adolescent and Young Adult (AYA) Patients With Acute Lymphoblastic Leukemia: US Consensus Panel Recommendations.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70103}, pmid = {41074700}, issn = {1096-8652}, support = {//Jazz Pharmaceuticals/ ; }, abstract = {Asparaginase is an integral component of therapy for pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma. The success of asparaginase-containing regimens has led to trials of pediatric/pediatric-inspired regimens incorporating asparaginase for treating adolescent and young adult (AYA) and adult populations with acute lymphoblastic leukemia/lymphoblastic lymphoma. While treatment of AYA patients with these regimens is associated with improved clinical outcomes compared with adult-specific protocols, AYA patients face unique challenges with these treatments, further complicated by a rapidly evolving therapeutic landscape. In this article, we identify barriers and other feasibility issues associated with administering asparaginase-based treatment to AYA patients and provide recommendations from a consensus panel of experts to optimize AYA patient outcomes and experiences. Barriers identified include the limited access to clinical trials and specialized expertise in pediatric-inspired regimens for AYA patients compared with pediatric patients, the complex management of asparaginase toxicities, limited medical facilities and experienced staff to administer and manage pediatric-inspired regimens, and reduced AYA patient access/adherence to treatment due to lifestyle-related or psychosocial challenges. Recommendations are provided on addressing and managing these challenges to improve asparaginase-based treatment accessibility and safety in AYA patients, including specific recommendations for high-risk populations. Trial Registration: ClinicalTrials.gov: NCT04817761.}, }
@article {pmid41074685, year = {2025}, author = {Banerjee, R and Kaur, G and Razzo, BM and Portuguese, AJ and Sidana, S and Richards, T and Grajales-Cruz, A and Richard, S and Shune, L and Khouri, J and Dima, D and Lee, HC and Patel, KK and Pasvolsky, O and Vazquez-Martinez, M and Hansen, DK and Afrough, A and Davis, JA and Hashmi, H and Atrash, S and Ferreri, CJ and Julian, KL and Herr, MM and Midha, S and Costello, P and Forsberg, P and de Menezes Silva Corraes, A and Lin, Y and Cowan, AJ and Anderson, LD and Garfall, AL}, title = {Predictors of Delayed Responses to Teclistamab in Multiple Myeloma After Initial Non-Response.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70108}, pmid = {41074685}, issn = {1096-8652}, support = {//Leukemia and Lymphoma Society (Blood Cancer United)/ ; }, }
@article {pmid41073880, year = {2025}, author = {Koufigar, S and Ford, E and He, Y and Olsen, S and Fagerstrom, JM}, title = {A case study on SSD to SAD linear acceleartor calibration transition.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {10}, pages = {e70298}, pmid = {41073880}, issn = {1526-9914}, mesh = {Calibration/standards ; Humans ; *Radiotherapy Planning, Computer-Assisted/methods/standards ; *Particle Accelerators/instrumentation/standards ; Radiotherapy Dosage ; *Quality Assurance, Health Care/standards ; *Neoplasms/radiotherapy ; *Radiotherapy, Intensity-Modulated/methods ; Retrospective Studies ; *Phantoms, Imaging ; }, abstract = {PURPOSE: Modifying calibration conditions of linear accelerators is infrequent and potentially a high-risk procedure. This study outlines a systematic approach used to transition a linear accelerator's calibration condition in an active clinical environment from source-to-surface (SSD) to source-to-axis (SAD), while maintaining treatment accuracy and avoiding interruption of clinical operations.
METHODS: A satellite clinic within a university radiation oncology service operated an Elekta Versa HD linear accelerator with SSD calibration, while other system C-arm accelerators used SAD. With a single installation of the treatment planning system used across all sites, it was decided to convert the machine to SAD calibration. Representative plans with diverse delivery techniques were comprehensively evaluated in advance. Over a single weekend, beams were recommissioned in the treatment planning system (TPS), and output was adjusted per AAPM's TG-51 protocol. Monitor units (MUs) for on-treatment patients were scaled manually in the oncology information system, MOSAIQ. Quality assurance (QA) checks, as well as independent peer-reviewing of each field, were performed to ensure safety and quality for this high-risk procedure. A retrospective failure modes and effects analysis (FMEA) was subsequently conducted. To evaluate the clinical relevance and broader impact of this work, a targeted survey was conducted via the Wayne State MedPhysUSA LISTSERV.
RESULTS: As a result of the change in output calibration condition, field MU required scaling, ranging from 2.7% to 6.4%. Patient-specific QA measurements demonstrated consistent gamma pass rates, and both solid-water phantom and external audit results verified machine output accuracy within 2%. No patient treatments were interrupted during the process. The FMEA identified insufficient expertise and staffing as the highest-risk failure mode. Survey results indicated that 80% of respondents had never personally performed a calibration transition with patients on treatment, and the majority of respondents characterized the procedure as extremely rare and of higher risk than standard TG-51 annual QA.
CONCLUSIONS: The absolute output calibration condition was successfully transitioned from SSD to SAD without interruptions of patient treatments. Multiple verification steps were implemented to ensure quality and safety. This project contributed to improved standardization across multiple sites of practice.}, }
@article {pmid41073857, year = {2026}, author = {Cannon, V and Wright, JH and Yeung, CCS and Grady, WM and Yu, M}, title = {Multiplex Digital PCR Assay Targeting DNA Methylation for Early Detection of Cancer.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2969}, number = {}, pages = {29-42}, pmid = {41073857}, issn = {1940-6029}, mesh = {*DNA Methylation ; Humans ; *Multiplex Polymerase Chain Reaction/methods ; *Early Detection of Cancer/methods ; *Esophageal Neoplasms/genetics/diagnosis ; Biomarkers, Tumor/genetics ; *Adenocarcinoma/genetics/diagnosis ; }, abstract = {Digital PCR has been demonstrated to enable the precise nucleic acid absolute quantification across a wide range of applications. Historically, dPCR technology was limited to two channels for fluorescence detection. Recent advances in digital PCR have made it possible to multiplex and allow for simultaneous analysis of multiple targets within a PCR reaction. Here, we describe a multiplex dPCR assay for the detection and quantification of methylated DNA (also known as DNA-methylation-specific multiplex digital PCR, or DNA-methylation specific dPCR). We also demonstrate the application of this technology for the development of a candidate DNA methylation-based biomarker panel for the early detection of high-grade dysplasia and esophageal adenocarcinoma. Further, we discuss common technical challenges and troubleshooting for performing successful DNA-methylation-specific MS-dPCR assays.}, }
@article {pmid41072416, year = {2025}, author = {Di Meo, F and Albano, F and Cesarano, A and Wang, Y and Kale, B and Shain, K and Silva, A and Kurihara, N and Tenshin, H and Jellyman, D and Song, X and Ghaffari, S and Mesa, H and Creelan, B and Freeman, C and Zhao, X and Meads, MB and Rodriguez, PC and Marino, S and Locke, F and Hwu, P and Roodman, D and Mansilla-Soto, J and Perna, F}, title = {Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2025.09.007}, pmid = {41072416}, issn = {1878-3686}, abstract = {Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets. We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival. We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMA[low] tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells. This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.}, }
@article {pmid41071904, year = {2025}, author = {Malladi, SK and Jaiswal, D and Ying, B and Alsoussi, WB and Darling, TL and Dadonaite, B and Civljak, A and Horvath, SC and Zhou, JQ and Kim, W and Turner, JS and Schmitz, AJ and Han, F and Scheaffer, SM and Farnsworth, CW and Nachbagauer, R and Nestorova, B and Chalkias, S and Klebert, MK and Edwards, DK and Paris, R and Strnad, BS and Middleton, WD and O'Halloran, JA and Presti, RM and Bloom, JD and Boon, ACM and Diamond, MS and Bajic, G and Ellebedy, AH}, title = {Germinal center-mediated broadening of B cell responses to SARS-CoV-2 booster immunization.}, journal = {Science immunology}, volume = {10}, number = {112}, pages = {eadu4107}, doi = {10.1126/sciimmunol.adu4107}, pmid = {41071904}, issn = {2470-9468}, mesh = {*Germinal Center/immunology ; *SARS-CoV-2/immunology ; Humans ; Animals ; *B-Lymphocytes/immunology ; Immunization, Secondary ; *COVID-19/immunology/prevention & control ; Spike Glycoprotein, Coronavirus/immunology ; *COVID-19 Vaccines/immunology ; Antibodies, Viral/immunology ; Adult ; Antibodies, Neutralizing/immunology ; Cricetinae ; Antibodies, Monoclonal/immunology ; Male ; Female ; }, abstract = {Germinal centers (GCs) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 messenger RNA (mRNA) vaccines elicit robust GC B cell responses in humans, but how these responses influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults after mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 used the IGHV3-66 public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity after SARS-CoV-2 booster vaccination.}, }
@article {pmid41071741, year = {2025}, author = {Dionne, JA and Campbell, JD and Salim, J and Atmar, RL and Healy, CM and Posavad, CM and Flach, B and Brown, ER and Farley, MM and Stephens, DS}, title = {Baptism in a Pandemic: Infectious Diseases Clinical Research Consortium Network Design for Readiness and Response.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {81}, number = {Supplement_2}, pages = {S109-S116}, doi = {10.1093/cid/ciaf419}, pmid = {41071741}, issn = {1537-6591}, }
@article {pmid41071598, year = {2025}, author = {Corvera, S and Rajan, A and Townsend, KL and Shamsi, F and Wu, J and Svensson, KJ and Zeltser, LM and Collins, S and Reis, T and Tseng, YH and Goodyear, LJ}, title = {Advances in Adipose Tissue Biology.}, journal = {Endocrine reviews}, volume = {}, number = {}, pages = {}, doi = {10.1210/endrev/bnaf032}, pmid = {41071598}, issn = {1945-7189}, abstract = {Adipose tissue has emerged as a central regulator of human physiology, with its dysfunction driving the global rise in obesity-associated diseases, such as type 2 diabetes, cardiovascular and liver diseases, and several cancers. Once thought to be inert, adipocytes are now recognized as dynamic, responsive cells essential for energy homeostasis and interorgan communication, including the brain. Distinct adipose depots support specialized functions across development, sex, and aging. Technologies like single-cell RNA sequencing are unraveling depot-specific mechanisms, with the potential of identifying new therapeutic targets. This review highlights major scientific advancements leading to our current appreciation of the pivotal role of adipose tissue in health and disease. Many key discoveries in this field have been catalyzed by National Institutes of Health funding, particularly through the National Institute of Diabetes, Digestive and Kidney Diseases, now celebrating its 75th anniversary.}, }
@article {pmid38978671, year = {2025}, author = {Blechter, B and Wang, X and Dai, J and Karsonaki, C and Shi, J and Shiraishi, K and Choi, J and Matsuo, K and Chen, TY and Hung, RJ and Chen, K and Shu, XO and Kim, YT and Choudhury, PP and Williams, J and Landi, MT and Lin, D and Zheng, W and Yin, Z and Zhou, B and Wang, J and Seow, WJ and Song, L and Chang, IS and Hu, W and Chien, LH and Cai, Q and Hong, YC and Kim, HN and Wu, YL and Wong, MP and Richardson, BD and Li, S and Zhang, T and Breeze, C and Wang, Z and Bassig, BA and Kim, JH and Albanes, D and Wong, JY and Shin, MH and Chung, LP and Yang, Y and Zheng, H and Dai, H and Yatabe, Y and Zhang, XC and Kim, YC and Caporaso, NE and Chang, J and Man Ho, JC and Daigo, Y and Momozawa, Y and Kamatani, Y and Kobayashi, M and Okubo, K and Honda, T and Hosgood, HD and Kunitoh, H and Watanabe, SI and Miyagi, Y and Matsumoto, S and Horinouchi, H and Tsuboi, M and Hamamoto, R and Goto, K and Takahashi, A and Goto, A and Minamiya, Y and Hara, M and Nishida, Y and Takeuchi, K and Wakai, K and Matsuda, K and Murakami, Y and Shimizu, K and Suzuki, H and Saito, M and Ohtaki, Y and Tanaka, K and Wu, T and Wei, F and Machiela, MJ and Kim, YH and Oh, IJ and Fun Lee, VH and Chang, GC and Chen, KY and Su, WC and Chen, YM and Seow, A and Park, JY and Kweon, SS and Gao, YT and Liu, J and Schwartz, AG and Houlston, R and Gorlov, IP and Wu, X and Yang, P and Lam, S and Tardon, A and Chen, C and Bojesen, SE and Johansson, M and Risch, A and Bickeböller, H and Ji, BT and Wichmann, HE and Christiani, DC and Rennert, G and Arnold, SM and Brennan, P and McKay, J and Field, JK and Davies, MPA and Shete, SS and Le Marchand, L and Liu, G and Andrew, AS and Kiemeney, LA and Zienolddiny-Narui, S and Grankvist, K and Cox, A and Taylor, F and Yuan, JM and Lazarus, P and Schabath, MB and Aldrich, MC and Jeon, HS and Jiang, SS and Chen, CH and Hsiao, CF and Hu, Z and Burdett, L and Yeager, M and Hutchinson, A and Hicks, B and Liu, J and Berndt, SI and Wu, W and Wang, J and Li, Y and Choi, JE and Park, KH and Sung, SW and Kang, CH and Wang, WC and Xu, J and Guan, P and Tan, W and Yu, CJ and Yang, G and Loon Sihoe, AD and Choi, YY and Park, IK and Hung, HH and Vermeulen, RCH and Cheng, I and Wu, J and Tsai, FY and Chan, JKC and Li, J and Lin, HC and Liu, J and Song, B and Sawada, N and Yamaji, T and Wyatt, K and Ma, H and Zhu, M and Wang, Y and Qi, T and Li, X and Ren, Y and Chao, A and Iwasaki, M and Zhu, J and Wu, G and Chen, CY and Chen, CJ and Yang, PC and Stevens, VL and Fraumeni, JF and Lin, K and Walters, RG and Chen, Z and Chatterjee, N and Gorlova, OY and Amos, CI and Shen, H and Hsiung, CA and Chanock, SJ and Rothman, N and Kohno, T and Lan, Q and Zhang, H}, title = {Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38978671}, abstract = {BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction.
METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates.
RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier.
CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.}, }
@article {pmid41071311, year = {2025}, author = {Carballo, EV and Gonzalez-Ericsson, P and Lehmann, BD and Taylor, BC and Wulfkuhle, JD and Ocampo, A and Gallagher, RI and Huang, DS and Maxey, C and Steele, JA and Kleinberg, K and Sun, X and Marshall, JL and Sanchez, V and Opalenik, SR and Petricoin, E and Rimel, BJ and Balko, JM and Penn, CA}, title = {The impact of JAK1 pathogenic variants and MHC-I expression on response to immune checkpoint inhibition in endometrial cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-1442}, pmid = {41071311}, issn = {1557-3265}, abstract = {PURPOSE: Immune checkpoint inhibitors (ICI) have increasing application in endometrial cancer, underscoring the need for robust biomarkers for patient selection. JAK1 pathogenic variants (PV) have previously been implicated in immune evasion. Here, we identify biomarkers predictive of ICI response in endometrial cancer and the implications of JAK1 PV in this context.
EXPERIMENTAL DESIGN: This is a translational study of tumors from 84 endometrial cancer patients treated with ICI. High-throughput proteomic-based profiling was used to quantify 193 phospho-/protein expression levels, including key JAK/STAT signaling pathway components. Associations with clinical outcomes were assessed using multivariate regression analysis. The functional consequences of JAK1 PV were explored through in vitro signaling assays and analyses of TCGA database.
RESULTS: MHC-I expression correlated with improved progression-free survival (p = 0.035), validated in orthogonal approaches. Notably, a subset of patients harboring JAK1 PVs demonstrated exceptional survival on ICI. In TCGA cohort of microsatellite instability-high (MSI-H) and DNA polymerase epsilon (POLE)-mutated tumors, homozygous loss of JAK1 (JAK1Hom) trended toward decreased survival, whereas heterozygous loss of JAK1 (JAK1Het) was associated with significantly improved survival (p = 0.026), suggesting partial retention of antigen presentation pathways. Among our ICI-treated MSI-H tumor samples, NK cell marker NCAM1 was associated with improved survival (p=0.02).
CONCLUSIONS: These data support MHC-I as a potential predictive biomarker for ICI response in endometrial cancer. Additionally, we show that partial retention of JAK1 signaling in JAK1Het tumors is associated with improved survival, potentially attributable to enhanced NK cell activity in tumors with low MHC-I expression.}, }
@article {pmid41070684, year = {2025}, author = {Lynch, RC and Cassaday, RD and Smith, SD and Cowan, AJ and Warren, EH and Shadman, MS and Till, BG and Ujjani, CS and Morris, K and Rasmussen, H and Voutsinas, J and Gopal, AK}, title = {Long-term follow-up of dose-dense brentuximab vedotin, ifosfamide, carboplatin and etoposide in second-line treatment of relapsed/refractory classical Hodgkin lymphoma.}, journal = {British journal of haematology}, volume = {207}, number = {4}, pages = {1599-1603}, doi = {10.1111/bjh.70052}, pmid = {41070684}, issn = {1365-2141}, support = {//Seagen/ ; P30 CA015704/CA/NCI NIH HHS/United States ; K24 CA184039/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hodgkin Disease/drug therapy/mortality/therapy ; Brentuximab Vedotin/administration & dosage/adverse effects ; Etoposide/administration & dosage/adverse effects ; Carboplatin/administration & dosage/adverse effects ; Ifosfamide/administration & dosage/adverse effects ; Female ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration & dosage ; Adult ; Middle Aged ; Follow-Up Studies ; Adolescent ; Aged ; Young Adult ; Recurrence ; Salvage Therapy ; }, abstract = {This study presents the 5-year outcomes of a phase 1/2 trial (NCT02227199) evaluating dose-dense brentuximab vedotin (BV) combined with ifosfamide, carboplatin and etoposide (ICE) as second-line therapy in patients with relapsed classic Hodgkin lymphoma (cHL). Forty-five patients received at least one dose of BV-ICE, with the intention to proceed to autologous stem cell transplantation (ASCT). At a median follow-up of over 5 years, the progression-free survival was 77% (95% CI, 66%-91%) and overall survival was 91% (95% CI, 82%-100%). Of 37 patients who underwent ASCT, five relapsed; two received subsequent allogeneic transplantation and remain alive. Among eight patients who did not proceed to ASCT, four remain in complete remission long-term. Second malignancies developed in five patients post-ASCT, including two localized skin cancers and three non-skin cancers. These findings highlight BV-ICE as a highly active salvage regimen for relapsed cHL, with durable remissions in a majority of patients. The regimen may be especially relevant in the modern era for patients who relapse after Programmed Cell Death Protein 1 (PD-1) inhibitor-based front-line therapy and require additional treatment prior to planned ASCT.}, }
@article {pmid41068949, year = {2025}, author = {Cao, J and Ferguson, M and Sun, J and Shen, M and Small, R and Hippe, DS and Zhao, X and Zhang, D and Watase, H and Yuan, C and Gao, P and DeMarco, JK and Nicosia, RF and Wang, Y and Li, H and Li, Z and Wang, Y and Kohler, T and Hatsukami, T and Sui, B}, title = {Composition of carotid plaques differs between Chinese and US patients: a histology study.}, journal = {Chinese neurosurgical journal}, volume = {11}, number = {1}, pages = {23}, pmid = {41068949}, issn = {2057-4967}, support = {81361120402 and 62271061//National Natural Science Foundation of China/ ; R01 NS083503, R01 HL61851, R01-HL60213, RO1 HL073401, and R01 HL103609/NH/NIH HHS/United States ; L232130//Beijing Natural Science Foundation/ ; }, abstract = {BACKGROUND: The clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (US) populations as do the plaque features on imaging.
OBJECTIVES: The aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and US patients.
METHODS: Carotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10-µm thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallory's trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups.
RESULTS: A total of 1152 histological sections from 75 Chinese patients and 1843 sections from 111 US patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p = 0.046) and a larger percent wall volume (median: 74% vs. 70%, p = 0.018) than the US group. After adjusting for confounding factors, carotid plaques in the Chinese population had larger lipid pools (β = 10.0%, 95% CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; β = 8.4%, 95% CI: 4.5 to 12.7%), less late IPH (β = - 8.2%, 95% CI: - 11.3 to - 5.4), and fewer fibrous cap disruptions (45% vs. 67%, p = 0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did US plaques (20% vs 2.7%, p < 0.001).
CONCLUSIONS: The histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which indicates a need for a different management approach.}, }
@article {pmid41067857, year = {2025}, author = {Gyurkocza, B and Sandmaier, BM}, title = {Salvage Allogeneic Hematopoietic Cell Transplantation for Primary Graft Failure.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {725-726}, doi = {10.1016/j.jtct.2025.09.012}, pmid = {41067857}, issn = {2666-6367}, }
@article {pmid41067707, year = {2025}, author = {Hines, MR and Knight, TE and McNerney, KO and Leick, MB and Jain, T and Ahmed, S and Frigault, MJ and Hill, JA and Jain, MD and Johnson, WT and Lin, Y and Mahadeo, KM and Maron, GM and Marsh, RA and Neelapu, SS and Nikiforow, S and Ombrello, AK and Shah, NN and Talleur, AC and Turicek, D and Vatsayan, A and Wong, SW and Maus, MV and Komanduri, KV and Berliner, N and Henter, JI and Perales, MA and Frey, NV and Teachey, DT and Frank, MJ and Shah, NN}, title = {Erratum to <Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome><[Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. Epub 2023 Mar 9]>.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.016}, pmid = {41067707}, issn = {2666-6367}, }
@article {pmid41066125, year = {2025}, author = {Gogebakan, KC and Lange, J and Owens, L and Pinderup, A and Gulati, R and Kessler, LG and Lyratzopoulos, G and Etzioni, R}, title = {Clinical Significance of a Multicancer Screening Trial With Stage-Based End Points.}, journal = {JAMA network open}, volume = {8}, number = {10}, pages = {e2536247}, pmid = {41066125}, issn = {2574-3805}, mesh = {Humans ; *Early Detection of Cancer/methods/statistics & numerical data ; Female ; Male ; Middle Aged ; *Neoplasms/diagnosis/epidemiology/mortality ; Aged ; Incidence ; England/epidemiology ; Neoplasm Staging ; *Mass Screening/methods ; Randomized Controlled Trials as Topic ; Clinical Relevance ; }, abstract = {IMPORTANCE: The first randomized screening trial of a multicancer early detection test is ongoing, with the primary end point being the incidence of late-stage cancer. The unprecedented use of a stage-based end point and short 3-year follow-up raise questions about how results should be interpreted and used in developing multicancer screening policy.
OBJECTIVE: To estimate outcomes of the trial and to identify information from the estimates that may aid in interpreting results of short-term trials evaluating multicancer screening tests.
This multicancer decision-analytic model estimated outcomes from registry data from the England National Cancer Registration and Analysis Service for cases diagnosed between January 2013 and December 2018. This model simulated a population-based multicancer screening trial of average-risk participants without a prior cancer diagnosis. The analysis was performed between April 2024 and April 2025.
INTERVENTIONS: Three annual multicancer screenings at months 0, 12, and 24. Cancers were assumed detectable 1 or 2 years before clinical diagnosis based on a published analysis, and cancer-specific early-stage sensitivities were set to either 100% or 50% of published sensitivities among clinically diagnosed cases.
MAIN OUTCOMES AND MEASURES: Reductions in late-stage (stage III-IV) cancer incidence over 3 years, cancer mortality over 5 years, and contributions of each cancer type to reductions in late-stage incidence and cancer mortality across the range of detectable intervals and early-stage sensitivities.
RESULTS: The model simulated 70 000 participants per arm (screening and control; median age, 66 years), and estimated that the overall late-stage incidence reductions at 3 years ranged from 6% to 23%, with corresponding reductions in 5-year cancer mortality from 6% to 9%. Colorectal cancer contributed the most to the reduction in late-stage incidence (28% to 39%), while lung cancer contributed the most to mortality reduction (40% to 42%).
CONCLUSIONS AND RELEVANCE: This independent decision-analytic model study found that the trial could achieve nontrivial cancer downstaging over 3 years, but modest mortality reduction over 5 years. These results were due to a limited number of target cancer types, underscoring the importance of transparent reporting of outcomes by cancer type, consideration of mortality implications, and careful preplanning for subsequent evaluation steps by the cancer research community.}, }
@article {pmid41066089, year = {2025}, author = {O'Brien, KM and Keil, AP and Taylor, JA and Weinberg, CR and Polley, EC and Yadav, S and Boddicker, NJ and Hu, C and Ambrosone, CB and Anton-Culver, H and Auer, PL and Bodelon, C and Brantley, K and Burnside, ES and Chen, F and Domchek, SM and Eliassen, AH and Haiman, CA and Hodge, JM and Kraft, P and Lacey, JV and Lindstroem, S and Martinez, ME and Nathanson, KL and Neuhausen, SL and Olson, JE and Palmer, JR and Patel, AV and Penney, KL and Ruddy, KJ and Scott, CG and Teras, LR and Trentham-Dietz, A and Vachon, CM and Weitzel, JN and Yao, S and Zirpoli, G and Couch, FJ and Sandler, DP}, title = {Pathogenic Variants, Family History, and Cumulative Risk of Breast Cancer in US Women.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {41066089}, issn = {2374-2445}, abstract = {IMPORTANCE: Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described.
OBJECTIVE: To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors.
This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025.
EXPOSURES: PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors.
MAIN OUTCOMES AND MEASURES: Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated.
RESULTS: A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors.
CONCLUSIONS AND RELEVANCE: In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.}, }
@article {pmid41065373, year = {2025}, author = {Pradere, B and Schuit, M and Guerrero-Ramos, F and Shariat, SF and Kitamura, H and Jacob, JM and Bao, Y and Heesakkers, J and Peters, KM and Cahn, DJ and De Troyer, B and Herrera Imbroda, B and Morris, DS and Pieczonka, CM and Wei, Q and Bhanvadia, S and Somer, R and Jessner, W and Triantos, S and Sánchez de Llano, C and Maffeo, JC and Sweiti, H and Psutka, SP}, title = {Side effect management and procedural best practices with indwelling intravesical drug-releasing systems in the treatment of bladder cancer: recommendations from expert panels.}, journal = {Current opinion in urology}, volume = {}, number = {}, pages = {}, pmid = {41065373}, issn = {1473-6586}, abstract = {PURPOSE OF REVIEW: To provide expert recommendations for side effect management in patients with bladder cancer receiving intravesical-drug releasing system (iDRS) treatment and for optimizing iDRS insertion procedure success.
RECENT FINDINGS: Indwelling iDRS are designed to provide sustained local exposure to therapy. In clinical trials, frequent side effects of iDRS treatment were lower urinary tract symptoms (LUTS) (e.g., dysuria, pollakiuria, micturition urgency), urinary tract infections (UTIs), and hematuria. These side effects are generally low grade, but if not properly managed, may lead to treatment interruptions or discontinuations. As data are limited, practical recommendations based on expert opinion for the management of common side effects and best practices for iDRS insertion procedures may improve treatment adherence and optimize outcomes in patients with bladder cancer receiving iDRS.
SUMMARY: Two separate expert panels were convened to develop recommendations for side effect management with iDRS and optimizing iDRS insertion procedure success. Stepwise treatment-specific management strategies for LUTS, UTIs, and hematuria in patients receiving iDRS treatment that are familiar to practicing urologists are presented, including considerations for continuation or discontinuation of iDRS treatment. Several advanced techniques can be considered to improve iDRS insertions based on variations in patient anatomy.}, }
@article {pmid41065113, year = {2025}, author = {Palacios, N and Gordon, S and Wang, T and Burk, R and Qi, Q and Huttenhower, C and Gonzalez, HM and Knight, R and De Carli, C and Daviglus, M and Lamar, M and Telavera, G and Tarraf, W and Kosciolek, T and Cai, J and Kaplan, RC}, title = {Gut microbiome and cognitive function in the Hispanic Community Health Study/Study of Latinos.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251376911}, doi = {10.1177/13872877251376911}, pmid = {41065113}, issn = {1875-8908}, abstract = {BackgroundThere is limited work on the association between the gut microbiome and Alzheimer's disease and related dementia (AD/ADRD) in Latinos.ObjectiveWe examined, within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, the association between gut microbiome and cognitive function.MethodsWe analyzed the fecal metagenomes of 2471 HCHS/SOL participants to identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.ResultsEubacterium species (E. siraeum and E. eligens), and C phoceensis, among other species were associated with better cognition. Several KEGG modules, most strongly Ornithine, Serine biosynthesis and Urea Cycle, were associated with worse cognition.ConclusionsIn a large Hispanic/Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition.}, }
@article {pmid41063982, year = {2025}, author = {Mbuya, W and Horvath, A and Held, K and Maganga, L and Hoelscher, M and Bekker, LG and Duerr, A and Moodie, Z and Churchyard, G and Keefer, MC and Viegas, E and Moog, C and Geldmacher, C and Chachage, M}, title = {Effects of sex but not race and geographic origin on vaccine-induced HIV-specific antibody responses.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1601865}, pmid = {41063982}, issn = {1664-3224}, mesh = {Humans ; Female ; Male ; *AIDS Vaccines/immunology/administration & dosage ; *HIV Infections/immunology/prevention & control/virology ; Adult ; *HIV Antibodies/blood/immunology ; *HIV-1/immunology ; Sex Factors ; Immunoglobulin G/blood/immunology ; Young Adult ; Double-Blind Method ; Middle Aged ; White People ; South Africa ; Antibody Formation ; Immunoglobulin A/blood/immunology ; White ; }, abstract = {BACKGROUND: Sex, race and geographic location may affect vaccine-induced immune responses, yet few preventive HIV vaccine trials have systematically evaluated such effects. The main objective of this study was therefore to examine the role of these factors on vaccine-induced HIV-specific immune responses within the HVTN 204 trial. This randomized, double-blinded, placebo-controlled phase 2 trial enrolled 480 Black and Caucasian adults from Africa and the Americas, who received a trivalent DNA-HIV-1 vaccine prime followed by a rAd5 vector HIV-1 vaccine boost.
METHODS: Available serum samples from baseline and four weeks after the final vaccination boost from Black (n=85, 59% female) and Caucasian (n=49, 51% female) HVTN 204 vaccine recipients from South Africa and the United States of America were studied using an Enzyme-Linked Immunosorbent Assay to determine titers of Envelope-specific IgG1, IgG3 and IgA antibodies. Recognition of linear Envelope peptide-specific IgG responses was mapped in a randomly selected subgroup analysis using a custom-designed peptide microarray (n = 41, 49% female). Associations between vaccine-induced Envelope-specific antibody responses and sex assigned at birth (female or male), race and geographic location were then analyzed by the Mann-Whitney U test, Fisher's exact test and multivariate logistic regression.
RESULTS: Four weeks post-final vaccination boost, we observed that Envelope-specific antibody titers were significantly increased for IgG1 but reduced for IgA in females (female vs. male median titer: 900 vs. 300, p=0.030 and <100 vs. 100, p=0.007, respectively). Multivariate logistic regression confirmed that female sex increased the odds for higher Envelope-specific IgG1 and low IgA titers compared to males. In terms of antibody epitopes, the V2 region was more frequently recognized in females than males (p=0.008). Race and geographic location had no apparent influence on antibody isotype titers investigated.
CONCLUSION: Female sex was associated with higher vaccine-induced IgG Envelope-specific binding antibody titers and recognition of V2 region of HIV Envelope in HVTN 204 volunteers. No such associations were detected for race or geographic location. Understanding biological factors driving these sex-based differences may improve the design of a new generation of HIV vaccine candidates.}, }
@article {pmid41063661, year = {2025}, author = {Sesay, FA and Oware, K and Violette, LR and Donnell, D and Odoyo, JB and Omollo, V and Mogaka, FO and McClelland, RS and Balkus, JE and Bukusi, EA and Baeten, JM and Stewart, J}, title = {Trichomonas vaginalis Among Cisgender Women Taking Doxycycline Postexposure Prophylaxis.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf519}, pmid = {41063661}, issn = {1537-6613}, abstract = {Doxycycline treats and prevents several bacterial and parasitic infections and has been proposed as a possible treatment for Trichomonas vaginalis. Nested in a trial of doxycycline postexposure prophylaxis among cisgender women in Kenya, we conducted a secondary analysis of incident T. vaginalis infections. Among 224 cisgender women randomized to doxycycline postexposure prophylaxis and 225 to standard-of-care, there were 27 T. vaginalis diagnoses in the doxycycline postexposure prophylaxis group and 29 in the standard-of-care group (RR: 0.96, 95% CI: 0.54-1.73, p=0.9)). Understanding doxycycline postexposure prophylaxis's impact on T. vaginalis remains an important public health question that warrants further investigation.}, }
@article {pmid41063387, year = {2025}, author = {Chari, ST and Feng, Z and Wu, B and Fisher, W and Kambadakone, A and Zhao, YQ and Maitra, A and Kenner, B and Matrisian, LM}, title = {Heuriskance: a novel paradigm for systematic earlier detection of sporadic pancreatic cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf291}, pmid = {41063387}, issn = {1460-2105}, abstract = {Early detection is key to improving survival and mortality from pancreatic cancer. Traditional periodic screening for cancer in an asymptomatic population is infeasible and not recommended for this low-incidence disease. We describe a novel approach we call "heuriskance" (hyou-ris-kance) wherein a systematic search for and onetime workup of a "heurisk" (hyou-risk) leads to earlier detection of cancer. A heurisk is an early warning sign with three defining characteristics: i) indicates higher-than-threshold-probability of having prevalent invasive cancer, ii) is associated with a meaningful lead time to diagnosis, and iii) is identifiable by a systematic and scalable process in the population. Heuriskance aims to systematically detect cancer with clinically meaningful lead time to clinical diagnosis, minimize proportion of patients with advanced disease, and maximize treatment options leading to increases in lead time-adjusted 1-, 3- and eventually 5- year survival. A specific example of a heurisk for pancreatic cancer is glycemically defined new onset diabetes (GNOD) and the Early Detection Initiative (NCT04662879) an example of GNOD-based heuriskance. As heuriskance has no precedent, we provide i) a tiered risk stratification approach (Define-Enrich-Find), ii) metrics for choosing a heurisk, iii) success metrics for strategy and iv) Phases 1-5 for evaluating the strategy in retrospective and prospective studies. Like all current cancer therapies, heuriskance aims to iteratively improve survival from a fatal disease using a pragmatic, evidence-based systematic approach to its earlier detection. The concept of heuriskance is applied to pancreatic cancer but could be extended to other cancer types.}, }
@article {pmid41030929, year = {2025}, author = {Bents, SJ and Martin, ET and Steven-Ayers, T and Andrews, C and Adler, A and Perofsky, A and Krantz, EM and Blazevic, R and Kimball, L and Prentice, R and Hansen, C and Starita, L and Han, P and Englund, JA and Wolter, N and von Gottberg, A and Maake, L and Moyes, J and Cohen, C and Boeckh, M and Hay, JA and Waghmare, A and Viboud, C}, title = {Multiplex serology reveals age-specific immunodynamics of endemic respiratory pathogens in the wake of the COVID-19 pandemic.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41030929}, support = {/WT_/Wellcome Trust/United Kingdom ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, abstract = {The rebound of endemic respiratory viruses following the COVID-19 pandemic was marked by atypical transmission dynamics, with children experiencing increased disease burden and out-of-season epidemics as restrictions relaxed. Here we used serology from a newly developed quantitative multiplex assay to assess the post-pandemic immunity debt, a drop in immunity due to a lack of endemic virus circulation during COVID-19. We assessed age-specific antibody dynamics in Seattle, Washington, US, across a broad range of respiratory viruses, including influenza, respiratory syncytial virus, seasonal coronaviruses, and SARS-CoV-2. We found that respiratory virus immunodynamics differed between individuals <5 years of age and older individuals, with young children experiencing both larger boosts and quicker waning of antibodies across pathogens. We confirmed that these patterns are upheld in a non-pandemic setting by analyzing influenza serological data from South Africa. We incorporated our serological insights into an influenza transmission model calibrated to epidemiological data from Seattle and show that consideration of age-specific immunodynamics may be important to anticipate the effects of pandemic perturbations.}, }
@article {pmid41063102, year = {2025}, author = {Ebenezer, A and Iyaniwura, SA and Omame, A and Han, Q and Wang, X and Bragazzi, NL and Woldegerima, WA and Kong, JD}, title = {Understanding cholera dynamics in African countries with persistent outbreaks: a mathematical modeling approach.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {3395}, pmid = {41063102}, issn = {1471-2458}, support = {GPIN-2022-04559//NSERC Discovery Grant/ ; DGECR-2022-00454//NSERC Discovery Launch Supplement/ ; FRFE310 2021-00879//SSHRC-New Frontier in Research Fund- Exploratory/ ; 109981//Canada's International Development Research Centre (IDRC)/ ; }, mesh = {*Cholera/epidemiology/transmission ; Humans ; *Disease Outbreaks/statistics & numerical data ; Africa/epidemiology ; *Models, Theoretical ; Bayes Theorem ; Basic Reproduction Number ; Machine Learning ; }, abstract = {BACKGROUND: Cholera, caused by Vibrio cholerae, is a global health challenge, spreading through water in areas lacking clean water and sanitation. Since 2021, the reemergence of cholera cases has increased significantly in endemic regions in Africa. In particular, the continent experienced severe outbreaks between 2022 and 2024 due to droughts and cyclones, which have placed additional strain on healthcare systems.
OBJECTIVE: This study aims to investigate the dynamics of cholera outbreaks in eight African countries using mathematical modeling and machine learning and to provide information for public health decision making. By estimating key model parameters and epidemiological indicators, such as the basic reproduction number, we aim to identify and quantify the impacts of key transmission drivers. Using this together to socioeconomical factors, we will be classifying cholera persistent countries with similar dynamics using unsupervised learning. In addition, the study seeks to provide information on cholera outbreaks and management across the selected countries, identify key drivers of outbreak intensity, and propose targeted intervention strategies.
METHODS: A compartmentalized epidemiological model with indirect transmission routes is analyzed for cholera dynamics in eight African countries with persistent outbreaks. The key parameters and initial values of the model's variables were estimated using a Bayesian framework. We assessed some outcomes such as the reproduction number, "[Formula: see text]," outbreak peak duration and size. Moreover, environmental and socioeconomic data were used in hierarchical clustering to group countries by outbreak characteristics.
RESULTS: The study uncovered variation in cholera outbreak dynamics across the considered countries. Based on our model results, the median basic reproduction number ([Formula: see text]) across the endemic countries was 2.0 (SD : 0.454), which ranges from 1.41 in Zimbabwe to 2.80 in Mozambique. Furthermore, the results of the sensitivity analysis emphasized the significance of the maximum infection rate and the bacteria shedding rate in driving cholera outbreaks across the endemic regions in Africa. Hierarchical clustering revealed three distinct groups of countries based on outbreak dynamics and socioeconomic indicators: the chronic sanitation issues cluster (Somalia, Cameroon, and Comoros); the economic and infrastructure challenges cluster (Sudan, Zimbabwe, and Zambia); and the natural disaster cluster (Malawi and Mozambique).
CONCLUSION: This study highlights the drivers of cholera outbreaks across African countries, emphasizing the need for tailored interventions that consider underlying socio-demographic and environmental vulnerabilities. The findings underscore the importance of integrating data-driven approaches into cholera preparedness and response efforts to mitigate its impact.}, }
@article {pmid41062885, year = {2025}, author = {Nayak, P and Kosiorek, H and Pai, RK and Shivji, S and Hagen, CE and Graham, RP and Buchanan, DD and Jenkins, MA and Phipps, AI and Le Marchand, L and Wu, C and Samadder, NJ and Swallow, CJ and Gallinger, SJ and Grant, RC and Westerling-Bui, T and Conner, J and Cyr, DP and Kirsch, R and Pai, RK}, title = {Utility of quantitative pathologic analysis of pT1 colorectal carcinomas to improve prediction of lymph node metastasis.}, journal = {Virchows Archiv : an international journal of pathology}, volume = {}, number = {}, pages = {}, pmid = {41062885}, issn = {1432-2307}, support = {U01CA167551//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, abstract = {According to the National Comprehensive Cancer Network (NCCN), submucosally invasive (pT1) colorectal carcinomas (CRCs) should be evaluated for tumor grade, lymphatic invasion, and tumor budding to determine the risk of lymph node metastasis. The presence of any one of these high-risk features is an indication for surgery in endoscopically removed pT1 CRCs. In this study, we determined if quantitative pathologic analysis with the QuantCRC algorithm can augment NCCN risk stratification in a multi-institutional cohort of 512 surgically resected pT1 CRC. LASSO regression identified %high-grade, %inflammatory stroma (stromal area), and %tumor budding/poorly differentiated clusters (%TB/PDC) as important QuantCRC features and were used in subsequent logistic regression analysis. Five logistic regression models were built using NCCN and QuantCRC variables, with the combined NCCN + QuantCRC model providing the highest Area Under the Curve (AUC) of 0.74 (95% CI 0.68-0.81). A predicted probability cutoff of 0.092 provided a sensitivity of 78.3% and specificity of 62.1% in the NCCN + QuantCRC model with a 24.3% rate of lymph node positivity for high-risk (HR) tumors compared to 5.2% for low-risk (LR) CRCs. Fifteen pT1 CRCs were reclassified from NCCN LR to NCCN + QuantCRC HR and 3/15 (20%) demonstrated lymph node positivity. The median predicted probability of lymph node metastasis in the NCCN + QuantCRC model was used to define two HR groups (HR1: 0.092-0.218 and HR2: > 0.218). HR2 CRCs had a rate of lymph node positivity of 31.5% compared to 17.1% for HR1 CRCs (P = 0.02). Lastly, the NCCN + QuantCRC model was validated in a cohort of 29 endoscopically resected pT1 CRCs followed by surgical resection. In the NCCN + QuantCRC model, the 8 pN + CRCs in this cohort had a higher median predicted probability of lymph node metastasis compared to 21 pN0 CRCs (0.219 vs. 0.080, P = 0.04). In summary, the addition of variables from QuantCRC can improve risk stratification of pT1 CRCs over NCCN criteria alone.}, }
@article {pmid41062500, year = {2025}, author = {Jiménez-Vacas, JM and Westaby, D and Figueiredo, I and De Haven Brandon, A and Padilha, A and Yuan, W and Seed, G and Bogdan, D and Gurel, B and Bertan, C and Miranda, S and Lambros, M and Montero-Hidalgo, AJ and Coleman, I and Yu, IPL and Buroni, L and Zeng, W and Neeb, AJ and Welti, J and Rekowski, J and Paravati, R and Gabel, F and Pandell, N and Ferreira, A and Crespo, M and Riisnaes, R and Das, S and Taylor, J and Waldron, N and Hobern, E and Valenti, M and Ning, J and Bernett, I and Liodaki, K and Persse, T and Galipeau, P and Wilkinson, S and Trostel, SY and Karzai, F and Chau, CH and Beatson, EL and Zhang, X and Klumpp-Thomas, C and Varkaris, A and Luque, RM and Swain, A and Raynaud, F and Lack, NA and Thomas, CJ and Ha, G and Figg, WD and Bezzi, M and Sowalsky, AG and Nelson, PS and Carreira, S and Balk, SP and de Bono, JS and Sharp, A}, title = {Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8806}, pmid = {41062500}, issn = {2041-1723}, support = {IES\R3\213131//Royal Society of Medicine (RSM)/ ; Challenge Award//Prostate Cancer Foundation (PCF)/ ; Clinical Research Career Development Fellowship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism/antagonists & inhibitors ; Male ; Humans ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology/metabolism ; Animals ; Cell Line, Tumor ; Mice ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism ; Xenograft Model Antitumor Assays ; PTEN Phosphohydrolase/metabolism/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Apoptosis/drug effects ; bcl-Associated Death Protein/metabolism ; Bcl-2-Like Protein 11/metabolism ; }, abstract = {Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease requiring additional therapeutic strategies. MCL1, an anti-apoptotic BCL2 family member, promotes cancer-cell survival, but its role in mCRPC remains poorly understood. Here, we characterise MCL1 in multiple mCRPC biopsy cohorts and patient-derived models, assessing responses to MCL1 inhibition. MCL1 copy number gain (14%-34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in MCL1-gained mCRPC models. Co-inhibition of MCL1 and AKT induces cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo, modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with AKT inhibitor acquired resistance. Finally, CDK9-mediated MCL1 downregulation combined with AKT inhibition recapitulates these findings, providing further opportunities for clinical translation. These data support early phase clinical trials targeting MCL1, both as monotherapy for MCL1-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC.}, }
@article {pmid41062463, year = {2025}, author = {Ni, X and Richardson, RB and Godoy, AS and Ferla, MP and Kikawa, C and Scheen, J and Hannon, WW and Capkin, E and Lahav, N and Balcomb, BH and Marples, PG and Fairhead, M and Wang, S and Williams, EP and Tomlinson, CWE and Aschenbrenner, JC and Lithgo, RM and Winokan, M and Giroud, C and Dolci, I and Fernandes, RS and Oliva, G and Chandran, AV and Xavier, MA and Walsh, MA and Thompson, W and Bloom, JD and Kenton, NT and Lee, AA and von Delft, A and Barr, H and Kirkegaard, K and Koekemoer, L and Fearon, D and Evans, MJ and von Delft, F}, title = {Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8930}, pmid = {41062463}, issn = {2041-1723}, support = {U19AI171399//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*Zika Virus/drug effects/enzymology/genetics ; *Viral Nonstructural Proteins/genetics/antagonists & inhibitors/chemistry/metabolism ; *Protease Inhibitors/pharmacology/chemistry ; *Serine Endopeptidases/genetics/metabolism/chemistry ; Crystallography, X-Ray ; *Antiviral Agents/pharmacology/chemistry ; Mutation ; Drug Discovery/methods ; Binding Sites ; Models, Molecular ; Catalytic Domain ; Humans ; RNA Helicases/genetics/antagonists & inhibitors/chemistry/metabolism ; Protein Binding ; Viral Proteases ; Nucleoside-Triphosphatase ; DEAD-box RNA Helicases ; }, abstract = {The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 46 fragments with diverse scaffolds are identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we perform deep mutational scanning of the NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points. In this work, we maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.}, }
@article {pmid41061233, year = {2025}, author = {Dean, NE and Crisp, AM and Che-Mendoza, A and Kirstein, OD and Barrera-Fuentes, GA and Earnest, JT and Puerta-Guardo, HN and Collins, MH and Pavia-Ruz, N and Ayora-Talavera, G and González-Olvera, G and Medina-Barreiro, A and Bibiano-Marín, W and Jabbarzadeh, S and Halloran, ME and Longini, IM and Lenhart, A and Waller, LA and Correa-Morales, F and Palacio-Vargas, J and Gomez-Dantes, H and Manrique-Saide, P and Vazquez-Prokopec, GM}, title = {Randomized Trial of Targeted Indoor Spraying to Prevent Aedes-Borne Diseases.}, journal = {The New England journal of medicine}, volume = {393}, number = {14}, pages = {1387-1398}, doi = {10.1056/NEJMoa2501069}, pmid = {41061233}, issn = {1533-4406}, support = {U54 GM111274/GM/NIGMS NIH HHS/United States ; R37 AI032042/AI/NIAID NIH HHS/United States ; U01 AI148069/AI/NIAID NIH HHS/United States ; DFID: 30041-105//Bill and Melinda Gates Foundation/ ; }, mesh = {Humans ; Animals ; *Aedes ; Child ; Child, Preschool ; *Insecticides/administration & dosage ; *Mosquito Control/methods ; *Dengue/prevention & control/epidemiology ; Mexico/epidemiology ; *Zika Virus Infection/prevention & control/epidemiology ; Adolescent ; *Chikungunya Fever/prevention & control/epidemiology ; Female ; Male ; *Mosquito Vectors ; Housing ; Seasons ; Mosquito-Borne Diseases ; }, abstract = {BACKGROUND: Targeted indoor residual spraying focuses insecticide applications on common resting surfaces of Aedes aegypti mosquitoes (an arboviral disease vector) in houses, such as exposed lower sections of walls and under furniture.
METHODS: We conducted a two-group, parallel, unblinded, cluster-randomized trial in Merida, Mexico, to quantify the efficacy of targeted indoor residual spraying for preventing aedes-borne diseases (chikungunya, dengue, or Zika). Children 2 to 15 years of age were enrolled from households in 50 clusters of five-by-five city blocks. Households in 25 clusters received an annual application of targeted indoor residual spraying (intervention) before each season of aedes-borne disease (July through December). All clusters received routine Ministry of Health vector control. The primary end point was laboratory-confirmed, symptomatic aedes-borne disease. Community effects were assessed with the use of geolocated national surveillance data.
RESULTS: A total of 4461 children were monitored for up to three seasons (2021, 2022, and 2023). The indoor density of A. aegypti mosquitoes was 59% (95% confidence interval [CI], 51 to 65) lower with the intervention than with control. A total of 422 cases of aedes-borne disease were confirmed, primarily dengue in 2023. In the per-protocol analysis of cluster centers, 91 cases occurred among 1038 participants in the intervention group and 89 cases among 1037 participants in the control group (efficacy, -12.8%; 95% CI, -60.7 to 23.0). In an intention-to-treat analysis of entire clusters, 198 cases occurred among 2239 participants in the intervention group and 199 cases among 2222 participants in the control group (efficacy, 3.9%; 95% CI, -28.1 to 26.7). Adjustment of analyses for mobility or demographic characteristics did not change results. On the basis of 150 cases in the intervention clusters and 202 in the control clusters that were geolocated, the estimated community effect of the intervention was 24.0% (95% CI, 6.0 to 38.6). Two cases of multisymptom adverse events (e.g., nausea, watery eyes, diarrhea, and vomiting) were associated with the intervention.
CONCLUSIONS: Despite lower entomologic indexes with targeted indoor residual spraying than with routine vector control, the cumulative incidence of aedes-borne diseases was not significantly lower with targeted indoor residual spraying. (Funded by the National Institutes of Health and the Innovative Vector Control Consortium; ClinicalTrials.gov number, NCT04343521.).}, }
@article {pmid41061214, year = {2025}, author = {McMurtry, CL and Givens, ML and Bailey, ZD and Graetz, N and Fleming, PJ and Petteway, RJ and Pacheco, J and Gollust, SE and Heller, JC and Lee, HE and Porter, KMP and Johnson, S and Michener, JD and LeBrón, AMW and Bailey, AK and Bloyd, J and Creary, M and Ornelas, IJ}, title = {Why Building Power Is Key to Protecting Academic Public Health and Advancing Health Equity.}, journal = {American journal of public health}, volume = {115}, number = {11}, pages = {1783-1788}, pmid = {41061214}, issn = {1541-0048}, }
@article {pmid41061155, year = {2025}, author = {Banerjee, R and Raje, NS}, title = {Vaccination during bispecific antibody treatment for myeloma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018225}, pmid = {41061155}, issn = {2473-9537}, }
@article {pmid41060772, year = {2025}, author = {Sedovy, MW and Renton, MC and Roberts, K and Leng, X and Dennison, CL and Toler, CO and Leaf, M and Lampe, PD and Best, AK and Isakson, BE and Johnstone, SR}, title = {Injury-Induced Connexin 43 Expression Regulates Endothelial Wound Healing.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpheart.00153.2025}, pmid = {41060772}, issn = {1522-1539}, support = {AHA23PRE1010870//American Heart Association (AHA)/ ; NIH-F31HL170721//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; AHA25POST1410066//American Heart Association (AHA)/ ; AHA19CDA34630036//American Heart Association (AHA)/ ; NIH-R215R21HL168614-02//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; NIH-HL120840//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; NIH-HL137112//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, abstract = {Endothelial cell (EC) injury is a major contributing factor to vascular surgical failure. As such, understanding the mechanisms of endothelial healing is essential to the development of vascular therapeutics and procedures. Gap junctions formed by connexin 43 (Cx43) are implicated in regulating skin wound healing, but their role in endothelial healing is unknown. Secondary analysis of RNAseq data from in vivo injured mouse aortas (GEO: GSE115618), identified significant Cx43 upregulation in EC post-injury. We developed a novel in vivo model of EC injury using mouse carotid artery ligation to test the role of Cx43. We identified that EC immediately adjacent to the wound edge upregulate Cx43 protein expression, predominantly at cell-cell junctions. We show significantly delayed EC healing in a mouse model of inducible EC-specific Cx43 deletion (EC-Cx43 KO) at 24 hr post ligation. Single cell RNAseq analysis of 10,829 cells from 18 hr injured EC-WT and EC-Cx43 KO carotids revealed a Cx43-associated reduction in enrichment of EC pathways associated with migration, proliferation, and ERK/MAPK signaling pathways. Finally, the importance of Cx43 phosphorylation on EC healing was tested in mice with single-point alanine mutations (phospho-null) in known phosphorylation sites that alter Cx43 channel assembly and opening. Mice containing alanine mutations at ERK phosphorylated Cx43 serines (Cx43[S255/262/279/282A]) have reduced healing rates similar to EC-Cx43 KO mice. These data suggest that EC injury-induced Cx43 upregulation, and subsequent Cx43 gap junction-mediated cell-to-cell communication are required for normal EC migration during wound healing after vascular injury.}, }
@article {pmid41060040, year = {2025}, author = {Nagarajan, R and Klotzman, V and Kondo, M and Godambe, S and Gold, A and Henderson, J and Martel, S}, title = {Taxonomy Portraits: Deciphering the Hierarchical Relationships of Medical Large Language Models.}, journal = {JMIR medical informatics}, volume = {13}, number = {}, pages = {e72918}, pmid = {41060040}, issn = {2291-9694}, mesh = {Humans ; *Language ; *Artificial Intelligence ; Benchmarking ; *Classification/methods ; Large Language Models ; }, abstract = {BACKGROUND: Large language models (LLMs) continue to enjoy enterprise-wide adoption in health care while evolving in number, size, complexity, cost, and most importantly performance. Performance benchmarks play a critical role in their ranking across community leaderboards and subsequent adoption.
OBJECTIVE: Given the small operating margins of health care organizations and growing interest in LLMs and conversational artificial intelligence (AI), there is an urgent need for objective approaches that can assist in identifying viable LLMs without compromising their performance. The objective of the present study is to generate taxonomy portraits of medical LLMs (n=33) whose domain-specific and domain non-specific multivariate performance benchmarks were available from Open-Medical LLM and Open LLM leaderboards on Hugging Face.
METHODS: Hierarchical clustering of multivariate performance benchmarks is used to generate taxonomy portraits revealing inherent partitioning of the medical LLMs across diverse tasks. While domain-specific taxonomy is generated using nine performance benchmarks related to medicine from the Hugging Face Open-Medical LLM initiative, domain non-specific taxonomy is presented in tandem to assess their performance on a set of six benchmarks and generic tasks from the Hugging Face Open LLM initiative. Subsequently, non-parametric Wilcoxon rank-sum test and linear correlation are used to assess differential changes in the performance benchmarks between two broad groups of LLMs and potential redundancies between the benchmarks.
RESULTS: Two broad families of LLMs with statistically significant differences (α=.05) in performance benchmarks are identified for each of the taxonomies. Consensus in their performance on the domain-specific and domain non-specific tasks revealed robustness of these LLMs across diverse tasks. Subsequently, statistically significant correlations between performance benchmarks revealed redundancies, indicating that a subset of these benchmarks may be sufficient in assessing the domain-specific performance of medical LLMs.
CONCLUSIONS: Understanding medical LLM taxonomies is an important step in identifying LLMs with similar performance while aligning with the needs, economics, and other demands of health care organizations. While the focus of the present study is on a subset of medical LLMs from the Hugging Face initiative, enhanced transparency of performance benchmarks and economics across a larger family of medical LLMs is needed to generate more comprehensive taxonomy portraits for accelerating their strategic and equitable adoption in health care.}, }
@article {pmid41058545, year = {2025}, author = {Haneda, E and Peters, N and Zhang, J and Karageorgos, G and Xia, W and Paganetti, H and Wang, G and Guo, Y and Ma, J and Park, HS and Jeon, K and Fan, F and Thies, M and De Man, B}, title = {AAPM CT metal artifact reduction grand challenge.}, journal = {Medical physics}, volume = {52}, number = {10}, pages = {e70050}, doi = {10.1002/mp.70050}, pmid = {41058545}, issn = {2473-4209}, mesh = {*Artifacts ; *Metals ; *Tomography, X-Ray Computed ; *Image Processing, Computer-Assisted/methods ; Humans ; Algorithms ; }, abstract = {BACKGROUND: Metal artifact reduction (MAR) is a long-standing challenge in CT imaging. The presence of highly attenuating objects, such as dental fillings, hip prostheses, spinal screws/rods, and gold fiducial markers, can introduce severe streak artifacts in CT images, often reducing their diagnostic value. Existing CT MAR studies typically define their own test cases and evaluation metrics, making it difficult to objectively and comprehensively compare the performance of different MAR methods. There is a widespread need for a universal CT MAR image quality benchmark to evaluate the clinical impact of new MAR methods and compare them to state-of-the-art techniques.
PURPOSE: The goal of the AAPM CT Metal Artifact Reduction (CT-MAR) grand challenge was to create and distribute a clinically representative 2D MAR performance benchmark, and to invite participants to objectively compare the performance of their MAR methods based on this benchmark. A secondary goal was to facilitate MAR development by disseminating a MAR training database and tools. After completion of the grand challenge, the MAR benchmark and the MAR training database will remain publicly accessible for future MAR developments and benchmarking.
METHODS: Grand challenge participants were invited to submit results for their MAR algorithm. The challenge organizers provided 14,000 CT training datasets generated using a hybrid data simulation framework that combined real patient images-including lung, abdomen, liver, head, and pelvis-with virtual metal objects. Each training dataset included five types of data: CT sinograms (uncorrected and metal-free), CT reconstructed images (uncorrected and metal-free), and metal masks. In the final evaluation phase, 29 clinical uncorrected datasets with metal were provided in both the sinogram and image domains for participants to process with their MAR algorithms. Their results were evaluated using eight clinically relevant image quality metrics. The final ranking was determined and compared to an established normalized metal artifact reduction (NMAR) reference method. Additionally, we conducted a survey to better understand the methodologies used by participants.
RESULTS: A total of 106 teams registered for the challenge, with 26 teams completing all phases of the challenge. 92% of these-including all top ten teams-used a deep learning (DL) approach, employing a variety of network architectures such as UNet, ResNet, GAN, diffusion models, and transformers. Additionally, 22% of the teams-including the top three teams-utilized a combination of sinogram- and image-domain approaches. The results showed a broad distribution of the scores. Overall, the competition was marked by diverse methods and a wide range of results, including some truly exceptional results. More than 70% of the teams achieved a better overall score than the popular baseline NMAR method.
CONCLUSIONS: The CT-MAR grand challenge provided an opportunity to benchmark state-of-the-art MAR algorithms. Our hybrid data generation framework was a powerful tool for simulating large-scale realistic datasets for MAR algorithm development. A clinically relevant universal MAR benchmark offered an objective and meaningful way to compare different approaches. The training data and benchmark were published online to support future MAR development.}, }
@article {pmid41058534, year = {2025}, author = {Peters, N and Haneda, E and Zhang, J and Karageorgos, G and Xia, W and Verburg, J and Wang, G and Paganetti, H and De Man, B}, title = {A hybrid training database and evaluation benchmark for assessing metal artifact reduction methods for X-ray CT imaging.}, journal = {Medical physics}, volume = {52}, number = {10}, pages = {e70020}, doi = {10.1002/mp.70020}, pmid = {41058534}, issn = {2473-4209}, mesh = {*Artifacts ; *Tomography, X-Ray Computed ; *Metals ; Benchmarking ; *Databases, Factual ; *Image Processing, Computer-Assisted/methods ; Humans ; Phantoms, Imaging ; Deep Learning ; Algorithms ; }, abstract = {BACKGROUND: Metal artifacts significantly degrade the image quality in computed tomography (CT) imaging, obscuring or even feigning pathology. While many different algorithms for metal artifact reduction (MAR) have been proposed, no comprehensive, clinically relevant evaluation benchmark exists. A major contributing factor to this is the lack of artifact-free ground truth data in clinical cases. Similarly, deep-learning based algorithms are hindered by the lack of paired training datasets with and without artifacts.
PURPOSE: We propose the simulation of a large training database for deep-learning based MAR algorithms as well as the definition of a comprehensive evaluation benchmark for MAR. For this we utilize and validate a framework for the realistic simulation of metal artifacts on clinical CT data.
METHODS: A clinical and a generic CT scanner geometry is modelled in the CatSim CT simulator within the open-access toolkit XCIST. Since most MAR research is performed in 2D, all datasets are simulated in 2D. The metal artifact simulation capability is experimentally validated in CT phantom scans containing various metal types and -geometries. The tool is then used to simulate metal artifact scenarios as training data for deep-learning algorithms utilizing two public CT databases. Lastly, a benchmark is defined for clinically realistic metal artifact scenarios and applied to a numerical and a deep-learning based MAR algorithm, respectively.
RESULTS: Within specified regions of interest, the mean CT number deviation between simulation and real data was less than 2%, making the simulation tool suitable for the aspired tasks. In total, 14,000 metal scenarios in the head, thorax and pelvis regions were simulated. For the clinical benchmark, a set of metrics covering CT number accuracy, noise, image sharpness, streak amplitude, structural integrity, and the effect on range in proton therapy, were defined for a range of clinical scenarios. Metal scenarios covered the most relevant clinical use cases, covering small metal implants such as fiducial markers up to large metal implants such as hip replacements. Both the simulation tools and the benchmark with the test cases were made publicly available.
CONCLUSIONS: We developed and distributed tools and datasets for the development and evaluation of MAR algorithms. This is the first comprehensive evaluation benchmark covering a large number of clinically realistic metal artifact scenarios.}, }
@article {pmid41057655, year = {2025}, author = {Attard, G and Agarwal, N and Graff, JN and Sandhu, S and Efstathiou, E and Özgüroğlu, M and Pereira de Santana Gomes, AJ and Vianna, K and Luo, H and Gotto, GT and Cheng, HH and Kim, W and Varela, CR and Schaeffer, D and Kramer, K and Li, S and Baron, B and Shen, F and Mundle, SD and McCarthy, SA and Olmos, D and Chi, KN and Rathkopf, DE}, title = {Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41057655}, issn = {1546-170X}, abstract = {Inhibition of poly(ADP-ribose) polymerase (PARP) after relapse on hormone therapy is well established for patients with prostate cancer with homologous recombination repair (HRR) gene alterations, but resistance often develops. We hypothesized that PARP inhibition within 6 months of starting androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) could be effective and improve radiographic progression-free survival when added to standard-of-care treatments. The double-blind AMPLITUDE trial evaluated combining niraparib, a potent and specific PARP inhibitor, with abiraterone acetate and prednisone (AAP) versus placebo and AAP in mCSPC with HRR gene alterations. Patients (n = 696) were randomized in a 1:1 ratio (348 per group). Median age was 68 years; 56% had BRCA1 or BRCA2 alterations; 78% had high-volume metastases; and 16% had received docetaxel. The primary endpoint was met, with a significant improvement in radiographic progression-free survival observed first in the BRCA subgroup (median not reached at the time of analysis for the niraparib and AAP group versus 26 months for the AAP group; hazard ratio = 0.52; 95% confidence interval: 0.37-0.72; P < 0.0001) and then in the intention-to-treat population (hazard ratio = 0.63; 95% confidence interval: 0.49-0.80; P = 0.0001). The data for overall survival, a key secondary endpoint, are immature (193/389 events) but favor niraparib (hazard ratio = 0.79 (95% confidence interval: 0.59-1.04); BRCA subgroup: hazard ratio = 0.75 (95% confidence interval: 0.51-1.11)). Incidence of grade 3 or 4 adverse events was 75% in the niraparib and AAP group and 59% in the AAP group; most frequent in the niraparib and AAP group were anemia (29%), with 25% of patients requiring a blood transfusion, and hypertension (27%). There were 14 treatment-emergent adverse events leading to deaths in the niraparib group and seven in the placebo group. Combining niraparib with AAP significantly improved radiographic progression-free survival in patients with mCSPC harboring BRCA1/BRCA2 or other HRR gene alterations, suggesting clinical benefit with this combination for these patients. ClinicalTrials.gov identifier: NCT04497844 .}, }
@article {pmid41057532, year = {2025}, author = {Masterson, JM and Zheng, R and Luu, M and Murphy, A and Nyame, YA and Ritch, C and Gale, R and Spiegel, B and Freedland, SJ and Daskivich, TJ}, title = {Racial and ethnic differences in valuation of life expectancy in prostate cancer treatment decision making.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {41057532}, issn = {1476-5608}, support = {K08 CA230155/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Life expectancy (LE) is essential for triage between aggressive and conservative management for all prostate cancer risk subtypes. We sought to investigate differences in how Black and Hispanic men interpret LE in treatment decision-making.
METHODS: We used targeted crowdsourcing to sample a cohort reflecting sociodemographics of a US prostate cancer population. Subjects completed a conjoint analysis exercise where they iteratively chose between aggressive treatment versus conservative management across levels of 4 tradeoffs-tumor risk (lives saved by aggressive treatment at 5/10/20 year); erectile dysfunction; urinary incontinence; and irritative urinary symptoms-while considering their LE as calculated by the Prostate Cancer Comorbidity Index. Multinomial conditional logistic regression compared odds of choosing aggressive vs. conservative treatment across LEs ranging from 0 to 20 years overall and across racial/ethnic subgroups.
RESULTS: Of 2046 men, 435 (22%) were Black and 230 (11%) were Hispanic. Across all men, the odds of aggressive treatment choice increased by 17% for every 5 years of additional LE (OR = 1.17, 95%CI = 1.12-1.22, p < 0.001). Men were significantly more likely to choose aggressive treatment at LE > 13 y and non-aggressive treatment at LE ≤ 10 y. Among Black men, LE was not associated with treatment choice, as they consistently preferred aggressive treatment across all LE categories. Among Hispanic men, increased LE was associated with a higher likelihood of choosing aggressive treatment, with significant preference for aggressive treatment observed only when LE > 10 years. These patterns remained consistent when further stratified by tumor risk.
CONCLUSIONS: LE had no impact on treatment decisions in Black men, in contrast to other races and ethnicities. Future research is needed to identify reasons for this phenomenon and to inform culturally relevant approaches to communicating competing mortality risks.}, }
@article {pmid41056754, year = {2025}, author = {Laing, KJ and Sholukh, AM and MacPhee, KJ and McClurkan, CL and Pagnon, A and Ruiz, J and Bchir, S and Oualim, A and Hyrien, O and Corey, L and Wald, A and Gurunathan, S and Noriega, F and Coronel, D and Koelle, DM}, title = {Safety and immunogenicity of investigational herpes simplex virus-2 vaccines in adults with recurrent genital infection.}, journal = {Vaccine}, volume = {65}, number = {}, pages = {127821}, doi = {10.1016/j.vaccine.2025.127821}, pmid = {41056754}, issn = {1873-2518}, abstract = {HSV529 and G103 are investigational therapeutic vaccines for genital herpes. HSV529 is a replication-defective HSV-2. G103 contains three recombinant HSV-2 proteins: truncated UL19 and gD2 and full-length UL25. A randomized, placebo-controlled clinical trial was conducted over a two-dose schedule to assess various combinations of G103 and HSV529 with GLA-SE adjuvant in 24 participants. No immediate unsolicited adverse reactions were observed. Most injection site reactions (>50 %) were grade 2 with one reported grade 3 swelling. Grade 2 systemic reactions (headache and myalgia) were independent of GLA-SE dose. The vaccine candidates showed adequate safety profiles. All participants had baseline immune responses to HSV-2. gD2, UL19, and UL25-specific CD4 T cells increased in G103 recipients after the first dose and were most robust for gD2. Binding antibody levels increased most markedly for UL25, as did neutralizing antibodies.}, }
@article {pmid41056445, year = {2025}, author = {Jiang, CY and Hwang, H and Epstein, IY and Bakaloudi, DR and Talukder, R and Taylor, AK and Nizam, A and Jindal, T and Glover, MJ and Khaki, AR and Barata, PC and Nguyen, CB and Oh, E and Davis, NB and Mabey, H and Hoimes, CJ and Evans, ST and Abuqayas, B and Lemke, E and Tsung, I and Qiao, W and Kilari, D and Zakharia, Y and Bilen, MA and Milowsky, MI and Shah, SA and Gupta, S and Emamekhoo, H and Bellmunt, J and Alva, AS and Grivas, P and Msaouel, P and Koshkin, VS and Campbell, MT and Alhalabi, O}, title = {Efficacy of erdafitinib before or after enfortumab vedotin in FGFR3-altered advanced urothelial cancer: analysis of the UNITE collaborative study.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyaf342}, pmid = {41056445}, issn = {1549-490X}, abstract = {BACKGROUND: Erdafitinib is approved for locally advanced/metastatic urothelial cancer (LA/mUC). As enfortumab vedotin (EV) plus pembrolizumab enters frontline management, outcomes with erdafitinib pre- and post-EV are clinically relevant but not specifically evaluated in clinical trials.
METHODS: UNITE is a multi-institutional retrospective study of patients with LA/mUC treated with novel targeted agents. All patients with FGFR3 alterations treated with EV only, erdafitinib then EV (Erda->EV), and EV then erdafitinib (EV->Erda) were included. Sequential treatment with EV and Erda was not required. Primary endpoints were observed response rates (ORR) and progression-free survival (PFS); secondary endpoint was overall survival (OS).
RESULTS: We identified 83 patients with FGFR3 alterations and separated them into three cohorts: EV only (n = 44), Erda->EV (n = 24), and EV->Erda (n = 15). Most (72%) received ≥2 lines of therapy before erdafitinib (checkpoint inhibitor [87%], platinum-based chemotherapy [64%]). Median PFS with erdafitinib for EV-naïve cohort was 7.5 months and in EV-treated cohort 4.0 months (HR 0.78; 95% CI 0.35-1.7). ORR with erdafitinib for EV-naïve was 33% and EV-treated 31% (OR 1.1; 95%CI 0.29-4.1). Median PFS with EV for patients who were erdafitinib-naïve was 6 months and in erdafitinib-treated 5.3 months (HR 0.61; 95%CI 0.34-1.09). ORR with EV was 54% in erdafitinib-naïve cohort and 32% in erdafitinib-treated cohort (OR 2.5; 95%CI 0.87-6.3).
CONCLUSION: In patients with FGFR3-altered LA/mUC, erdafitinib is active pre- and post-EV. Outcomes with erdafitinib were consistent with clinical trial data generated prior to broader frontline use of EV. Findings are hypothesis-generating and given small sample size should be interpreted with caution.
IMPLICATIONS FOR PRACTICE: Non-trial outcomes of erdafitinib in FGFR3-altered locally advanced/metastatic urothelial cancer are consistent with reported clinical trial data. Erdafitinib therapy is effective in the pre- and post- EV setting.}, }
@article {pmid41056200, year = {2025}, author = {Lee, T and Buchanan, AL and Katenka, N and Forastiere, L and Halloran, ME and Nikolopoulos, G}, title = {Assessing spillover effects: Handling missing outcomes in network-based studies.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {9622802251382586}, doi = {10.1177/09622802251382586}, pmid = {41056200}, issn = {1477-0334}, abstract = {Estimating causal effects in the presence of spillover among individuals within a social network poses challenges due to missing information. Spillover effects refer to the impact of an intervention on individuals not directly exposed themselves but connected to intervention recipients within the network. In network-based studies, outcomes may be missing due to study termination or participant dropout, termed censoring. We introduce an inverse probability censoring weighted estimator which extends the inverse probability weighted estimator for network-based observational studies to handle possible outcome censoring. We prove the consistency and asymptotic normality of the proposed estimator and derive a closed-form estimator for its asymptotic variance. Applying the inverse probability censoring weighted estimator, we assess spillover effects in a network-based study of a nonrandomized intervention with outcome censoring. A simulation study evaluates the finite-sample performance of the inverse probability censoring weighted estimator, demonstrating its effectiveness with sufficiently large sample sizes and number of connected subnetworks. We then employ the method to assess spillover effects of community alerts on self-reported human immunodeficiency virus risk behavior among people who inject drugs and their contacts in the Transmission Reduction Intervention Project (TRIP), from 2013 to 2015, Athens, Greece. Results suggest that community alerts may help reduce human immunodeficiency virus risk behavior for both the individuals who receive them and others in their network, possibly through shared information. In this study, we found that the risk of human immunodeficiency virus behavior was reduced by increasing the proportion of a participant's immediate contacts exposed to community alerts.}, }
@article {pmid41040260, year = {2025}, author = {Bhattacharya, T and Freeman, TS and Alleman, EM and Wang, F and Chechik, L and Emerman, M and Myles, KM and Malik, HS}, title = {The Sindbis virus nsP3 opal codon protects viral RNA and fitness by maintaining replication spherule integrity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41040260}, issn = {2692-8205}, abstract = {Most alphaviruses encode an in-frame opal stop codon between nsP3 and nsP4 in their nsP ORF. This opal stop codon mediates a temperature-dependent balance between viral polymerase production and proteolytic processing in vertebrate hosts. Yet, why this opal codon is maintained in insect hosts is unknown. Here, we show that the nsP3 opal stop codon confers a replicative advantage to Sindbis virus (SINV) in RNAi-competent mosquito cells, but not in cells lacking RNAi. Through delays in nsP processing, the lack of opal stop codon disrupts viral replication spherule integrity and increases Dicer 2-dependent cleavage of viral RNA, resulting in higher antiviral siRNA responses to the virus. Moreover, in mammalian cells, the opal codon-mediated spherule integrity also blocks MDA5-dependent viral RNA detection and interferon signaling. Thus, the highly conserved alphavirus opal codon mediates a multipotent viral defensive strategy.}, }
@article {pmid41055680, year = {2025}, author = {Halm, EA and Del Vecchio, NJ and Rendle, KA and Tiro, JA and Zheng, Y and Winer, RL and Haas, JS and Corley, DA and Skinner, CS and Schottinger, J and Ghai, NR and Chubak, J}, title = {Longitudinal Adherence to Screening for Colorectal, Cervical, and Lung Cancer in a US Consortium.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {41055680}, issn = {1525-1497}, abstract = {BACKGROUND: Effective screening for colorectal, cervical, and lung cancer requires adherence over time, but little is known about repeat testing in real-world practice.
OBJECTIVE: Describe patterns of longitudinal screening adherence and identify patient and system factors associated with repeat testing.
DESIGN: Retrospective cohort study of colorectal, cervical, or lung cancer screening in 2010-2019.
PARTICIPANTS: Adults eligible for repeat colorectal (stool-based), cervical, or lung cancer screening following a negative index test in ten regional health systems comprising the US PROSPR consortium.
MAIN MEASURES: Repeat screening based on guideline-recommended intervals. For the colorectal and lung cohorts with opportunities for multiple annual screening rounds, the main outcome was repeat screening categorized as none, inconsistent, or consistent.
RESULTS: The sample size was: 1,566,346 for colorectal, 216,344 for cervical, and 6,209 for lung cancer screening. For colorectal, cervical, and lung screeners, mean age at index was 58.2, 39.4, and 64.6 years, respectively, and 49%, 55% and 30% were Hispanic and/or non-white. Completion of the next screening round was 62% for colorectal, 56% for cervical, and 56% for lung cancer. For colorectal, over the next two rounds of testing, 53% were consistent, 33% inconsistent, and 14% no repeat screeners. The comparable percentages over 3 + rounds for colorectal were 40% consistent, 50% inconsistent, and 11% no repeat screeners. For lung, over the next two rounds, 47% were consistent, 31% inconsistent, and 22% no repeat screeners. The proportions over 3 + rounds for lung were 44% consistent, 42% inconsistent, and 14% no repeat screening. The health system was the strongest predictor of repeat and consistent testing with three- to ten-fold variation.
CONCLUSIONS: Adherence to longitudinal screening for colorectal, cervical and lung cancer was suboptimal, particularly as the number of testing rounds increased. System-level strategies are needed to increase screening adherence given the strong relationship between health system and outcomes.}, }
@article {pmid41055602, year = {2025}, author = {Song, X and Wang, CY}, title = {A Corrected Score Approach for Proportional Hazards Model With Error-Contaminated Covariates Subject to Detection Limits.}, journal = {Statistics in medicine}, volume = {44}, number = {23-24}, pages = {e70243}, pmid = {41055602}, issn = {1097-0258}, support = {R21CA239168/NH/NIH HHS/United States ; R21AI176947/NH/NIH HHS/United States ; R01AG085616/NH/NIH HHS/United States ; R03CA235122/NH/NIH HHS/United States ; R01HL130483/NH/NIH HHS/United States ; UL1TR002378/NH/NIH HHS/United States ; 1916411//National Science Foundation/ ; }, mesh = {Humans ; Proportional Hazards Models ; Computer Simulation ; Bias ; Likelihood Functions ; Survival Analysis ; Acquired Immunodeficiency Syndrome/drug therapy ; Clinical Trials as Topic/statistics & numerical data ; }, abstract = {In survival analysis under the proportional hazards model, covariates may be subject to both measurement error and detection limits. Most existing approaches only address one of these two complications and can lead to substantial bias and erroneous inference when dealing with both simultaneously. There is very limited research that addresses both these problems at the same time. These approaches are exclusively based on likelihood and require distribution assumptions on the underlying true covariates, as well as restricted independence assumptions on the censoring time. We propose a novel corrected score approach that relieves such stringent assumptions and is simpler in computation. The estimator is shown to be consistent and asymptotically normal. The finite sample performance of the proposed estimator is assessed through simulation studies and illustrated by application to data from an AIDS clinical trial. The approach can be used in the case of replicate data or instrumental data. It can also be extended to more general models and outcomes.}, }
@article {pmid41055541, year = {2025}, author = {Salerno, S and Roberts, EK and Needham, BL and McCormick, TH and Li, F and Mukherjee, B and Shi, X}, title = {What's the Weight? Estimating Controlled Outcome Differences in Complex Surveys for Health Disparities Research.}, journal = {Statistics in medicine}, volume = {44}, number = {23-24}, pages = {e70289}, doi = {10.1002/sim.70289}, pmid = {41055541}, issn = {1097-0258}, support = {R35 GM144128/GM/NIGMS NIH HHS/United States ; R01 GM139926/GM/NIGMS NIH HHS/United States ; DP2 MH122405/MH/NIMH NIH HHS/United States ; R01 HD107015/MH/NIMH NIH HHS/United States ; P2C HD042828/MH/NIMH NIH HHS/United States ; 1712933//Division of Mathematical Sciences/ ; UG3 CA267907/CA/NCI NIH HHS/United States ; //Fred Hutchinson Cancer Center/ ; }, mesh = {Humans ; Nutrition Surveys/statistics & numerical data ; *Health Status Disparities ; White People/statistics & numerical data/genetics ; Propensity Score ; Black or African American/statistics & numerical data/genetics ; Female ; Male ; Computer Simulation ; Bias ; Telomere/genetics ; Middle Aged ; Socioeconomic Factors ; United States ; White ; }, abstract = {In this work, we are motivated by the problem of estimating racial disparities in health outcomes, specifically the average controlled difference (ACD) in telomere length between Black and White individuals, using data from the National Health and Nutrition Examination Survey (NHANES). To do so, we build a propensity for race to properly adjust for other social determinants while characterizing the controlled effect of race on telomere length. Propensity score methods are broadly employed with observational data as a tool to achieve covariate balance, but how to implement them in complex surveys is less studied-in particular, when the survey weights depend on the group variable under comparison (as the NHANES sampling scheme depends on self-reported race). We propose identification formulas to properly estimate the ACD in outcomes between Black and White individuals, with appropriate weighting for both covariate imbalance across the two racial groups and generalizability. Via extensive simulation, we show that our proposed methods outperform traditional analytic approaches in terms of bias, mean squared error, and coverage when estimating the ACD for our setting of interest. In our data, we find that evidence of racial differences in telomere length between Black and White individuals attenuates after accounting for confounding by socioeconomic factors and utilizing appropriate propensity score and survey weighting techniques. Software to implement these methods and code to reproduce our results can be found in the R package svycdiff, available through the Comprehensive R Archive Network (CRAN) at cran.r-project.org/web/packages/svycdiff/, or in a development version on GitHub at github.com/salernos/svycdiff.}, }
@article {pmid41054394, year = {2025}, author = {Schuurmans, F and Wittner, A and van den Bijgaart, RJE and Tahk, S and Boros, MGM and Looman, MWG and Fenn, NC and Humpe, A and Hopfner, KP and Adema, GJ}, title = {Development of aGD2-SIRPα fusion antibodies targeting neuroblastoma and the innate immune checkpoint receptor CD47.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1158/1535-7163.MCT-24-1090}, pmid = {41054394}, issn = {1538-8514}, abstract = {Neuroblastoma (NB) is a childhood malignancy characterized by overexpression of disialoganglioside GD2. Treatment with anti-GD2 monoclonal antibodies (aGD2 mAbs) has prolonged the survival of NB patients, however, long-term efficacy needs further improvement. NB tumor cells upregulate expression of the innate immune checkpoint and don't eat me signal CD47 to evade immune recognition and phagocytosis by Signal regulatory protein alpha (SIRPα) expressing myeloid cells. Targeting of CD47 remains challenging because ubiquitous CD47 expression on healthy cells causes on-target off-tumor related toxicities and functions as an antigen sink. To locally restrict CD47 blockade to the NB tumor site, we successfully developed aGD2-SIRPα fusion mAbs for the murine and human setting. These fusion mAbs are equipped with a functional Fc-domain and the extracellular SIRPα domain 1 either fused to the N-terminus of the light chain or to the C-terminus of the heavy chain. Both aGD2-SIRPα fusion mAbs selectively bind NB tumor cells and provide GD2-dependent SIRPα domain-mediated CD47 blockade (Fig. 1a). Furthermore, they potently induce innate immune effector mechanisms through the interaction of the mAbs Fc-domain with Fcγ receptors. Functional analysis of the fusion mAbs demonstrated enhanced phagocytosis and NK cell-mediated killing of NB tumor cells compared to the conventional aGD2 mAb. In addition, these novel antibodies modulate the cytokine production by primary macrophages. The aGD2-SIRPα fusion mAbs outperformed aGD2 mAb across a broad range of CD47/GD2 co-expressing tumor cells. This research shows the successful development of aGD2-SIRPα fusion mAbs to provide targeted blockade of CD47 for the treatment of solid NB tumors.}, }
@article {pmid41053791, year = {2025}, author = {Kim, D and Highland, HM and Smit, RAJ and Hysong, MR and Buchanan, VL and Young, KL and Zhao, C and Spracklen, CN and Kilpeläinen, TO and Guo, B and Darst, BF and Cai, Y and Wang, Z and Lundin, J and Berndt, SI and Manson, JE and Marouli, E and Lange, L and Lange, E and Fornage, M and Gignoux, CR and Haiman, CA and Rich, SS and Buyske, S and Loos, RJF and Kooperberg, C and Peters, U and Avery, CL and Gordon-Larsen, P and Graff, M and Raffield, LM and North, KE}, title = {Genetic underpinnings of the heterogeneous impact of obesity on lipid levels and cardiovascular disease.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {113}, pmid = {41053791}, issn = {1756-994X}, support = {903805//American Heart Association/ ; NNF22OC0074128//Novo Nordisk Foundation Center for Basic Metabolic Research/ ; Intramural Research Program/CP/NCI NIH HHS/United States ; R01HL142302/HL/NHLBI NIH HHS/United States ; R01DK122503/DK/NIDDK NIH HHS/United States ; R01HD057194//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HG010297/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Obesity/genetics/complications/blood ; *Cardiovascular Diseases/genetics/etiology/blood ; Genome-Wide Association Study ; Body Mass Index ; Male ; Female ; Middle Aged ; *Lipids/blood ; Mendelian Randomization Analysis ; Genetic Predisposition to Disease ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Triglycerides/blood ; }, abstract = {BACKGROUND: Obesity is thought to increase cardiovascular disease (CVD) risk partly through dyslipidemia. Yet, obesity's effects on dyslipidemia are not uniform. Understanding the shared genetic basis between obesity and lipid traits can provide insight into this heterogeneity and its implications for CVD risk.
METHODS: We examined local genetic correlations between three lipid measures [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)] and body mass index (BMI) using genome-wide association study summary statistics from European ancestry UK Biobank participants. We identified genomic loci with opposing genetic effects on obesity and dyslipidemia risk (protective BMI-lipid loci) and those with concordant directions for both obesity and dyslipidemia risk (adverse BMI-lipid loci). Gene-based association analyses were used to prioritize potential causal genes. We then constructed polygenic risk scores for BMI (PRSBMI) based on protective and adverse loci and assessed their associations with BMI, lipid levels, CVD, and related traits in the diverse Population Architecture using Genomics and Epidemiology (PAGE) study. PheWAS was performed in the All of Us cohort. Mendelian randomization (MR) was conducted to assess the causal impact of protective/adverse loci on cardiometabolic outcomes. Finally, we investigated the associations with fat distribution traits using MRI-based fat measures in the UK Biobank.
RESULTS: Among 2495 regions, we identified 789 HDL, 26 LDL, and 494 TG loci with significant local genetic correlation with BMI (including overlapping loci). Of these, 3 HDL, 10 LDL, and 8 TG loci showed protective correlations. Gene-based analyses prioritized 18 candidate causal genes. The protective PRSBMI(+)HDL(+) was associated with higher BMI but favorable lipid profiles and reduced CVD risk in PAGE. PheWAS revealed protective associations with hyperlipidemia, atrial fibrillation, and Alzheimer's disease. MR supported the favorable causal effects of these protective loci on several cardiometabolic outcomes. Notably, protective PRSBMI(+)TG(-) was uniquely associated with decreased visceral-to-abdominal subcutaneous adipose tissue ratio.
CONCLUSIONS: Identifying and validating genomic loci with shared genetic signals between BMI and lipid levels further supports the importance of genetics in defining the heterogeneous impact of obesity on dyslipidemia and CVD.}, }
@article {pmid41053438, year = {2025}, author = {Zainal, NH and Bossarte, RM and Gildea, SM and Hwang, I and Kennedy, CJ and Liu, H and Leung, LB and Luedtke, A and Marx, BP and Petukhova, MV and Post, EP and Ross, EL and Sampson, NA and Sverdrup, E and Turner, B and Wager, S and Kessler, RC}, title = {Correction: Developing an individualized treatment rule for Veterans with major depressive disorder using electronic health records.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-025-03299-0}, pmid = {41053438}, issn = {1476-5578}, }
@article {pmid41053396, year = {2025}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Gruell, H and Kreer, C and Ercanoglu, MS and Gristick, HB and Schommers, P and Ahmadov, E and Radford, C and Mazzolini, A and Zhang, L and West, AP and Worczinski, J and Momot, A and Reichwein, ML and Knüfer, J and Stumpf, R and Mkhize, NN and Kaldine, H and Bhebhe, S and Deshpande, S and Giovannoni, F and Stefanutti, E and Benigni, F and Havenar-Daughton, C and Corti, D and Kroidl, A and Adhikari, A and Nanfack, AJ and Ambada, GE and Duerr, R and Maganga, L and William, W and Ntinginya, NE and Wolf, T and Geldmacher, C and Hoelscher, M and Lehmann, C and Moore, PL and Mora, T and Walczak, AM and Gilbert, PB and Doria-Rose, NA and Huang, Y and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, pmid = {41053396}, issn = {1529-2916}, support = {1032144//Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)/ ; INV-002143/GATES/Gates Foundation/United States ; ANR-19-CE45-0018//Agence Nationale de la Recherche (French National Research Agency)/ ; R01AI140891//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01AI169385//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; P01AI100148//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 1U54AI170856//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, abstract = {Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a VH1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml[-1], breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml[-1], breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.}, }
@article {pmid41053137, year = {2025}, author = {Mkhize, NN and Zhang, B and Brackett, C and Elyanu, PJ and Tapley, A and Dadabhai, S and Hu, J and Do, BTN and Schuster, DJ and Heptinstall, J and Sawant, S and Seaton, K and Sarzotti-Kelsoe, M and Hudson, A and Jin, Y and Bhebhe, S and Kaldine, H and Kgagudi, P and Modise, T and Mgodi, NM and Andriesen, J and Randhawa, AK and Fisher, LH and Kee, JJ and Magaret, CA and Peng, J and Kenny, A and Carpp, LN and Chen, Z and Heng, S and Villaran, M and Takalani, A and Le Roux, B and Wilkinson, E and Odhiambo, J and Shah, P and Polakowski, L and Yacovone, M and Samandari, T and Chirenje, Z and Makhema, J and Kamuti, E and Njekwa, K and Nuwagaba-Biribonwoha, H and Baguma, A and Badal-Faesen, S and Brumskine, W and Coetzer, S and Dawson, R and Delany-Moretlwe, S and Diacon, AH and Fry, S and Gill, K and Madikida, A and Hoosain, ZAE and Hosseinipour, MC and Inambao, M and Innes, C and Innes, S and Kalonji, D and Mwape, H and Kassim, P and Kamanga, MC and Kilembe, W and Laher, F and Malahleha, M and Maluleke, VL and Mboya, G and Madiega, PA and McHarry, K and Mitha, E and Duki, Y and Mda, P and Moerane, M and Moloantoa, T and Nuwamanya, S and Mahomed, S and Naicker, V and Nana, A and Nanvubya, A and Kawoozo, B and Nchabeleng, M and Otieno, W and Potgieter, EL and Potloane, D and Punt, Z and Said, J and Singh, Y and Kassim, S and van der Vendt, D and Tayob, MS and Vahed, Y and Wabwire, DO and Kublin, JG and Bekker, LG and Corey, L and Gray, GE and Huang, Y and Kotze, P and Garrett, N and Hural, J and Ferrari, G and Andersen-Nissen, E and Montefiori, D and Moore, PL and McElrath, MJ and Tomaras, GD and Gilbert, PB and , }, title = {Neutralizing and binding antibodies are a correlate of risk of COVID-19 in the CoVPN 3008 study in people with HIV.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8876}, pmid = {41053137}, issn = {2041-1723}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; R37AI054165//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; T32AI007044-45//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068614-14//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068614-14//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068635/AI/NIAID NIH HHS/United States ; 3UM1AI068618-15S1//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068614-14//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; *COVID-19/immunology/prevention & control/epidemiology/virology ; *Antibodies, Neutralizing/immunology/blood ; *HIV Infections/immunology/complications/virology ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; Male ; Female ; Adult ; Middle Aged ; *COVID-19 Vaccines/immunology/administration & dosage ; 2019-nCoV Vaccine mRNA-1273/immunology ; }, abstract = {People with HIV (PWH) are understudied in COVID-19 vaccine trials, leaving knowledge gaps on whether the identified immune correlates of protection also hold in PWH. CoVPN 3008 (NCT05168813) enrolled predominantly PWH and reported lower COVID-19 incidence for a Hybrid vs. Vaccine Group (baseline SARS-CoV-2-positive and one mRNA-1273 dose vs. negative and two doses). Using case-cohort sampling, antibody markers at enrolment (M0) and four weeks post-final vaccination (Peak) are assessed as immune correlates of COVID-19. For the Hybrid Group [n = 287 (195 PWH)], all M0 markers inversely correlate with COVID-19 through 230 days post-Peak, with 50% inhibitory dilution BA.4/5 neutralizing antibody titer (nAb-ID50 BA.4/5) the strongest and only independent correlate (HR per 10-fold increase=0.46, 95% CI 0.28, 0.75; P = 0.002). For the Vaccine Group [n = 115 (86 PWH)], Peak nAb-ID50 BA.4/5 correlates with reduced COVID-19 risk (1.9%, 1.1%, and 0.3% at titers 10, 100, and 1000 AU/ml) through 92, but not 165, days post-Peak. Using multivariable Cox analysis of binding and nAb, nAb titers predict COVID-19 in PWH. Two doses of a 100-µg Ancestral strain mRNA vaccine in baseline-SARS-CoV-2-negative individuals elicit sufficient cross-reacting Omicron antibodies to reduce COVID-19 incidence for 90 days post-Peak, but viral evolution and waning antibodies abrogate this protection thereafter.}, }
@article {pmid39896535, year = {2025}, author = {Verwimp, S and Wagoner, J and Arenas, EG and De Coninck, L and Abdelnabi, R and Hyde, JL and Schiffer, JT and White, JM and Matthijnssens, J and Neyts, J and Polyak, SJ and Delang, L}, title = {Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39896535}, issn = {2692-8205}, support = {R01 AI121129/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable.
METHODS: We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis.
FINDINGS: In human skin fibroblasts, synergistic antiviral effects were observed for combinations of MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver cells, FAV + MPV conferred additive to synergistic activity against VEEV and SINV, while SOF synergized with FAV against SINV. In mice, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titres. Combination treatment with MPV and SOF significantly reduced swelling and infectious virus titres compared to monotherapies of each drug. Sequencing of CHIKV RNA from joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to monotherapy with several higher doses of MPV.
INTERPRETATION: Combining these approved oral nucleoside analogues confers potent suppression of multiple alphaviruses in vitro and in vivo with enhanced control of viral genetic evolution in face of antiviral pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.
FUNDING: This work was supported by a PhD fellowship granted to S.V. by the Research Foundation - Flanders (FWO) (11D5923N). L.D.C. was also supported by Research Foundation - Flanders (FWO) PhD fellowship (11L1325N). Dr. Polyak and Schiffer are partially supported by R01AI121129.}, }
@article {pmid41053004, year = {2025}, author = {Foster, L and Anderson, LD and Chung, A and Chaulagain, CP and Pettijohn, E and Cowan, AJ and Costello, C and Larson, S and Sborov, DW and Shain, KH and Silbermann, R and Voorhees, P and Krevvata, M and Pei, H and Patel, S and Khare, V and Cortoos, A and Carson, R and Lin, TS and Badros, A}, title = {Daratumumab plus lenalidomide maintenance in newly diagnosed multiple myeloma after transplant: AURIGA subgroup analyses.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {154}, pmid = {41053004}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/therapy/mortality/drug therapy/diagnosis ; *Lenalidomide/administration & dosage/therapeutic use ; Female ; Male ; Middle Aged ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Antibodies, Monoclonal/administration & dosage/therapeutic use ; Adult ; *Hematopoietic Stem Cell Transplantation ; Maintenance Chemotherapy ; }, abstract = {In the primary analysis (32.3-month median follow-up) of the randomized, phase 3 AURIGA study (NCT03901963), daratumumab-lenalidomide (D-R) maintenance significantly improved MRD-negative conversion rates and reduced the risk of disease progression or death by 47% versus R maintenance in anti-CD38 monoclonal antibody-naïve and post-transplant MRD-positive patients with newly diagnosed MM. Here, we present a post hoc analysis across relevant subgroups, including high-risk cytogenetic abnormalities (HRCAs) per original, revised, and modified International Myeloma Society (IMS) 2024 criteria. MRD-negative (10[-5]) conversion rates by 12 months of maintenance were higher for D-R versus R across cytogenetically high-risk subgroups per original (31.8% vs 6.7%), revised (43.8% vs 13.3%), and modified IMS 2024 (41.2% vs 0%) criteria and cytogenetically ultra-high-risk disease (≥2 revised HRCAs; 54.5% vs 0%). Similar trends in overall MRD-negative conversion rates were observed across subgroups. D-R demonstrated a trend towards improved PFS versus R (HR [95% CI]) in cytogenetically high-risk subgroups per original (0.60 [0.21-1.70]), revised (0.53 [0.21-1.31]), and modified IMS 2024 (0.45 [0.13-1.53]) criteria and cytogenetically ultra-high-risk disease (0.61 [0.17-2.25]). Similar outcomes were observed regardless of age or race, with no additional safety concerns among older (≥65 years) or Black patients. These data support the benefit of D-R maintenance regardless of age, race, and risk status.}, }
@article {pmid41052457, year = {2025}, author = {Balogh, EP and Levit, LA and Unger, JM and Accordino, MK and Chism, DD and Kirkwood, MK and Parsons, HM and Patel, MI and Peppercorn, JM and Polite, BN and Sedrak, MS and Sharma, P and Subbiah, IM and Temel, JS and Yabroff, KR and Osarogiagbon, RU}, title = {ASCO State of Cancer Care in America Special Report 2025: Access to Cancer Clinical Trials in the United States.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500233}, doi = {10.1200/OP-25-00233}, pmid = {41052457}, issn = {2688-1535}, abstract = {Improving patient access to cancer clinical trials is a fundamental ASCO priority because clinical cancer research is the essential link transforming biomedical discoveries into meaningful progress in cancer care and patient outcomes. Today's standard of care emerged from yesterday's clinical trials. However, numerous barriers continue to threaten patient access to cancer clinical trials. This Special Report describes the essential role clinical trials play in improving cancer care and patient outcomes, current challenges in the design and conduct of clinical trials, and steps taken by ASCO to make clinical trials more accessible, patient-centered, and embedded within the communities where people live.}, }
@article {pmid41052403, year = {2025}, author = {Modi, D and Aljawai, YM and DeFor, TE and Bupp, C and Al Malki, MM and Bolaños-Meade, J and Gooptu, M and Jimenez Jimenez, AM and Liu, H and Mensah, F and Mielcarek, M and Shaffer, BC and Shaw, BE and Spellman, SR and Stefanski, HE and Auletta, JJ and Devine, SM and Khimani, F and Abboud, R}, title = {Matched Unrelated vs Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017194}, pmid = {41052403}, issn = {2473-9537}, abstract = {Post-transplant cyclophosphamide (PTCy)-based graft-vs-host disease (GVHD) prophylaxis is the new standard for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT). Prior studies comparing MUD and haploidentical donor HCT using PTCy were limited by size and short follow-up. We therefore performed a registry-based analysis examining the impact of donor type on HCT with PTCy. Adult patients (n=5,873) who received MUD (n=1,973) or haploidentical (n=3900) HCT with PTCy for acute leukemia (74.2%) or myelodysplastic syndrome (25.8%) reported to the CIBMTR between 2017- 2021 were included. Primary endpoints were three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS). Cox regression and sensitivity analyses were performed through adjustment of propensity scores. Haploidentical HCT had worse OS (Hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.04-1.27, p=0.005) and GRFS (HR 1.19, 95% CI 1.10-1.29, p<0.001) compared to MUD HCT. Donor age was the only other consistent donor-related factor associated with survival. Results were confirmed in a sensitivity analysis adjusted for propensity scores. When the cohort was restricted to reduced intensity conditioning only or donors <30 years-old, OS did not differ between groups. Haploidentical HCT was associated with higher primary graft failure (HR 1.67; p=0.002), increased grade III-IV acute GVHD (HR 1.28; p=0.039), higher moderate/severe chronic GVHD (HR 1.47; p<0.001) and non-relapse mortality (HR 1.34; p<0.001). Grade II-IV aGVHD and relapse risk did not differ between the donor types. This large analysis showed that in adults with acute leukemia or MDS, MUD HCT was associated with improved outcomes compared to haplo HCT with PTCy-based GVHD prophylaxis.}, }
@article {pmid41052219, year = {2025}, author = {Brokaw, A and Wallen, G and Orvis, A and Kwon, HJ and Seepersaud, R and Nguyen, S and Sharma, K and Coleman, M and Quach, P and Twentyman, J and Vornhagen, J and Jones, LA and Lin, C and Gafken, PR and Rajagopal, L}, title = {The serine protease HtrA regulates Group B Streptococcus virulence and affects the host response to infection.}, journal = {PLoS pathogens}, volume = {21}, number = {10}, pages = {e1013562}, doi = {10.1371/journal.ppat.1013562}, pmid = {41052219}, issn = {1553-7374}, abstract = {Group B Streptococcus (GBS) rectovaginally colonizes up to 20% of women worldwide and is a leading cause of invasive infections during pregnancy, contributing annually to a significant proportion of preterm births, neonatal infections, and stillbirths. Despite its reputation as a perinatal pathogen, GBS infection rates in non-pregnant adults are also increasing. While much progress has been made to understand transcriptional regulation of virulence by two-component systems, many aspects of GBS virulence regulation remain understudied. Although many bacterial pathogens utilize high temperature response A (HtrA) family serine proteases to regulate virulence and stress responses through varied mechanisms, the function of HtrA in GBS was unknown. Here, we demonstrate that HtrA is localized to the GBS membrane and regulates the abundance of endogenous surface and secreted proteins, including a subset of virulence factors. Although deletion of htrA (ΔhtrA) increased dissemination to placentas and fetuses, this strain caused significantly fewer adverse pregnancy outcomes compared to isogenic wild-type (WT). Placentas from ΔhtrA-infected dams contained more chemokines, pro-inflammatory IL-1β, and neutrophil myeloperoxidase than isogenic WT-infected placentas, suggesting that ΔhtrA GBS induces potent neutrophil chemotaxis. However, immunosuppressive IL-10 was present at increased concentration, which may in part explain the attenuation of adverse pregnancy outcomes during ΔhtrA infection. Finally, we note that recombinant GBS HtrA directly cleaves human fibronectin in vitro, highlighting that this protease may also target host substrates during infection. Together, these findings support a role for HtrA as a post-translational regulator of GBS virulence and suggest that inhibiting HtrA activity may hold therapeutic promise against GBS induced adverse pregnancy outcomes.}, }
@article {pmid41051932, year = {2025}, author = {Jones, SMW and Aoki, RF and Alexeeff, SE and Carrell, D and Cronkite, D and Kushi, LH and Mosen, D and Strayhorn, S and Tuzzio, L and Mogk, J and Mammini, L and Kroenke, CH}, title = {Evaluation of the Electronic Health Record-Support Social Support Score in Breast Cancer: Comparison of Count and Item Response Theory Scores.}, journal = {Population health management}, volume = {}, number = {}, pages = {}, doi = {10.1177/19427891251383539}, pmid = {41051932}, issn = {1942-7905}, abstract = {In breast cancer, clinicians add data on social support to patient electronic health records (EHRs) often in free text notes, but those data may be challenging to use for population health initiatives or research purposes. We evaluated the EHR-Support score designed to summarize need for social support using data from the EHR. This study included 996 women from the Pathways study, a Kaiser Permanente Northern California cohort of women diagnosed in 2005-2013 with breast cancer. This unique data resource included both EHR data and questionnaire data on patient-reported social support. Using unstructured EHR data and natural language processing, we developed 11 concept groups (items) characterizing social support. We also used structured data to create two additional concept groups. EHR-Support scores reflecting the lack of social support were generated three ways: counting the number of negative concept groups (count score), using item response theory (IRT), and converting counts to the IRT metric (converted count scores). The count scores were only associated with two of six patient-reported measures (r's: -0.004 to -0.073). The IRT score (r's: -0.038 to -0.179) and converted count score (r's: -0.032 to -0.195) were associated with five of six patient-reported measures, indicating more need for support was associated with less patient-reported social support. The EHR-Support score is a valid and feasible measure of social support that can be used for health services research and managing population health. The converted count score may provide the best balance of validity, precision from IRT and feasibility.}, }
@article {pmid41047833, year = {2025}, author = {Bower, JE and Radin, A and Ganz, PA and Irwin, MR and Cole, SW and Petersen, L and Asher, A and Hurvitz, SA and Crespi, CM}, title = {Inflammation and dimensions of fatigue in women with early stage breast cancer: A longitudinal examination.}, journal = {Cancer}, volume = {131}, number = {20}, pages = {e70038}, pmid = {41047833}, issn = {1097-0142}, support = {//Breast Cancer Research Foundation/ ; P30 CA016042/CA/NCI NIH HHS/United States ; R01 CA160427/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/complications/pathology/blood ; *Fatigue/etiology/blood ; Middle Aged ; *Inflammation/blood ; Longitudinal Studies ; C-Reactive Protein/metabolism/analysis ; Adult ; Interleukin-6/blood ; Receptors, Tumor Necrosis Factor, Type II/blood ; Tumor Necrosis Factor-alpha/blood ; Aged ; Neoplasm Staging ; }, abstract = {BACKGROUND: Fatigue is a common and long-lasting side effect of cancer. Although fatigue is a multidimensional symptom, biologic mechanisms of fatigue dimensions have not been identified.
METHODS: Women recently diagnosed with early stage breast cancer (n = 192) completed assessments before and after adjuvant therapy and at 6-month, 12-month, and 18-month posttreatment follow-up visits. At each assessment, women completed the Multidimensional Fatigue Symptom Inventory and provided blood for protein markers of inflammation (tumor necrosis factor [TNF] alpha [TNF-α], soluble tumor necrosis factor receptor type II [sTNF-RII], interleukin 6 [IL-6], and C-reactive protein [CRP]). Mixed-effect linear models examined within-person and between-person associations between inflammatory markers and dimensions of fatigue.
RESULTS: Analyses demonstrated a positive within-person association between general fatigue and TNF-α (b = 1.67; p = .037), sTNF-RII (b = 2.77; p = .002), and IL-6 (b = 0.86; p = .010) when controlling for age, race, education, body mass index, and cancer stage. Similarly, there was a positive within-person association between physical fatigue and TNF-α (b = 1.58; p = .007), sTNF-RII (b = 2.38; p < .001), and CRP (b = 0.43; p = .007). Conversely, there were negative within-person associations between emotional fatigue and TNF-α (b = -1.92; p = .004) and sTNF-RII (b = -2.10; p = .006). General and physical fatigue were positively associated with CRP at the between-person level (b = 0.82, p = .024 for general; b = 0.71; p = .012 for physical). No significant associations between mental fatigue and inflammatory makers were found.
CONCLUSIONS: The current findings identified distinct dimensions of fatigue associated with inflammatory activity in women with breast cancer and highlighted individual variability in inflammatory markers as a key predictor of fatigue symptoms.}, }
@article {pmid41047130, year = {2025}, author = {Johnson, JJ and Ghosh, S and Shaw, PA and Neuhouser, ML and Lampe, JW and Tinker, LF and Prentice, RL and Tasevska, N and Freedman, LS and Boyer, BB and Hopkins, SE and Nash, SH and Votruba, SB and Krakoff, J and O'Brien, DM}, title = {The carbon isotope ratio of alanine is a biomarker of added sugar and sugar-sweetened beverage intakes: a pooled analysis of four studies.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.09.049}, pmid = {41047130}, issn = {1938-3207}, abstract = {BACKGROUND: The alanine carbon isotope ratio (Ala CIR) biomarker was positively associated with added sugar (AS) and sugar-sweetened beverage (SSB) intake in multiple studies from the USA. Association strengths varied, and Ala CIR was also correlated with protein source in certain studies.
OBJECTIVE: To examine Ala CIR associations with AS and SSB intake and animal protein ratio (animal protein/total protein, APR), and adjustment for APR, by pooling data from 4 previous studies.
METHODS: We pooled diet and biomarker data from 4 studies (n=346). These included a cross-sectional study of Yup'ik Alaska Native adults (n=62), a 12-wk randomized controlled feeding study in men (n=32), a 2-wk habitual intake controlled feeding study in postmenopausal women (n=153), and a 15-d habitual intake controlled feeding study of adults (n=99). We estimated correlations between amino acid CIRs and diet, and performed multivariable regression of Ala CIR on standardized intake variables to determine simultaneous associations with AS (g/d) or SSBs (servings/d) and APR. We included study by intake interactions to allow for heterogeneity among studies. We then ran models where leucine (Leu) CIR was included to adjust for APR.
RESULTS: There were positive correlations (95% CIs) between Ala CIR and AS intake [r=0.54 (0.46, 0.61)], log-SSB intake [r=0.63 (0.56, 0.69)], and APR [r=0.32 (0.22, 0.41)]. Study-specific slopes for the relationship between Ala CIR and AS or SSB intake were similar in models with and without adjustment for APR. Across studies, slopes ranged from 0.34 (0.08, 0.61) to 1.75 (1.29, 2.20) for AS intake in models with APR and from 0.35 (0.01, 0.68) to 1.11 (0.81, 1.40) for SSB intake in models with APR. Replacing APR with Leu CIR resulted in similar slopes between Ala CIR and AS/SSB intake.
CONCLUSIONS: The Ala CIR is a robust biomarker of AS/SSB intake. Potential associations with APR can be adjusted for using a simultaneously-measured biomarker.
(DBD study) clinicaltrials.gov/NCT01237093; (NPAAS) clinicaltrials.gov/NCT00000611.}, }
@article {pmid41046201, year = {2025}, author = {Robesti, D and Micheli, F and Rai, SN and Fallara, G and Gallina, A and Montorsi, F and Briganti, A and Fossati, N and Grivas, P and van der Heijden, AG and Ploussard, G and Malavaud, B and Martini, A}, title = {Addressing Uneven Treatment Discontinuation Rate in the Chemotherapy Arm of the EV-302 Phase 3 Randomized Clinical Trial: Implications for Outcome Interpretation.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {102423}, doi = {10.1016/j.clgc.2025.102423}, pmid = {41046201}, issn = {1938-0682}, abstract = {INTRODUCTION: The EV-302 trial demonstrated a very significant overall survival (OS) benefit for Enfortumab Vedotin plus Pembrolizumab (EVP) relative to standard chemotherapy (CHT) for patients with metastatic urothelial carcinoma. However, questions have been raised regarding the high rate of treatment discontinuation in the CHT arm for reasons unrelated to adverse events or progression (33% vs. 10% with EVP, P < .01), potentially resulting in loss of unaccounted information, or informative censoring, and affecting survival results interpretation.
MATERIALS AND METHODS: We performed a multistep analysis to assess the impact of differential dropout on trial outcomes. First, Kaplan-Meier (KM) curves were reconstructed from published data to estimate time-to-event outcomes. Second, a reverse KM analysis was conducted to evaluate censoring patterns in the overall population and key subgroups (PD-L1 expression; cisplatin eligibility). Third, simulation models were employed to test whether informative censoring could negatively impact survival benefit by EVP. Finally, we compared the CHT arm of EV-302 to those of other contemporary RCTs through reconstructed survival analyses and risk-of-bias assessments.
RESULTS: Overall, no significant imbalance in censoring between the treatment arms of EV-302 was found on reverse KM analysis when assessing OS (P = .73); however, a significant difference was noted for progression-free survival (PFS) (P = .002). Simulation analysis revealed that even under extreme assumptions of informative censoring, the OS benefit of EVP remained statistically significant. Comparison with historical RCTs confirmed that the CHT outcomes in EV-302 were not anomalously poor. Risk of bias was low overall, although deviations from intervention and outcome measurement were flagged for EV-302.
CONCLUSIONS: Despite the high discontinuation rate in the CHT arm, OS benefit with EVP remains robust. These findings support the reliability of EV-302 results and mitigate concerns about informative censoring, thus encouraging the use of EVP in clinical practice.}, }
@article {pmid41046057, year = {2025}, author = {Arnold, DE and Leiding, JW and Logan, B and Marsh, RA and Griffith, LM and Grunebaum, E and Murguía-Favela, L and Mallhi, K and Chellapandian, D and Deal, CL and Lim, SS and Prasad, V and Heimall, J and Chandrakasan, S and Chen, K and Yu, LC and Seroogy, CM and Gillio, A and Bednarski, JJ and Kapoor, N and Moore, TB and Cuvelier, GDE and Touzot, F and Rayes, A and Ebens, CL and Schaefer, E and Bauchat, A and Chopek, A and Burroughs, L and Cowan, MJ and Dvorak, CC and Haddad, E and Kohn, DB and Notarangelo, LD and Pai, SY and Puck, JM and Pulsipher, MA and Torgerson, T and Malech, HL and Kang, EM and Parikh, S}, title = {Umbilical Cord Blood Transplantation Provides an Alternative for Patients with Chronic Granulomatous Disease Lacking HLA-Matched Donors: a PIDTC Report.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.020}, pmid = {41046057}, issn = {2666-6367}, abstract = {BACKGROUND: Allogeneic hematopoietic cell transplantation corrects the phagocytic defect in patients with chronic granulomatous disease (CGD) and resolve infection risk and immune dysregulation. Umbilical cord blood transplantation (UCBT) is an option for patients lacking suitable HLA-matched bone marrow or peripheral blood stem cell donors. However, information related to UCBT for CGD is limited to a few small case series and limited subsets of larger cohorts where detailed information is lacking.
OBJECTIVES: To describe UCBT procedures and outcomes in patients with CGD.
STUDY DESIGN: Thirty-nine patients with CGD who underwent UCBT at Primary Immune Deficiency Treatment Consortium (PIDTC) centers between 2001 and 2019 were included.
RESULTS: All patients were male, and most (97%) had X-linked CGD due to pathogenic variants in CYBB. High infection burden (1.72/person years) and inflammatory disease (38%) were common in the year pre-UCBT. Median age at receipt of UCBT was 2.1 (range 0.3-14.0) years. Most (87%) patients received UCB from unrelated donors, and most (72%) patients received busulfan and cyclophosphamide-based conditioning. All but two (95%) patients received serotherapy with anti-thymocyte globulin or alemtuzumab. Neutrophil and platelet recovery occurred at a median of 18 (range 12-46) and 38 (range 21-186) days, respectively. Nine patients experienced early graft failure [donor myeloid chimerism <10% or receipt of second hematopoietic cell transplantation (HCT) within 100 days] for a cumulative incidence of 23.1% (95% CI 11.3-37.3). There were no cases of late graft failure (after 100 days), and median whole blood and myeloid donor chimerism of engrafted patients were >95% at all time points. One of the nine patients with early graft failure had autologous reconstitution. The remaining 8 patients underwent repeat HCT; six of the patients survived and achieved durable myeloid engraftment on long-term follow-up. Twenty-eight patients were alive at a median follow-up of 4.28 (IQR 2.66-6.08) years. Estimated 3-year overall and event-free survival were 73.7% (95% CI 56.5-84.9) and 56.2% (95% CI 39.3-70.1), respectively. No identifiable factors, including history of infection or inflammatory disease in the year prior to UCBT, year of UCBT, age at UCBT, conditioning regimen, cell dose, and recipient and donor HLA match, were associated with graft failure or survival. Infections decreased with time post-UCBT and pre-existing inflammatory disease resolved in all surviving patients CONCLUSIONS: UCBT for CGD is associated with high rates of early graft failure. Nevertheless, UCBT can provide an effective alternative for CGD patients when HLA-matched donors are not available with resolution of disease. Strategies to overcome high rates of early graft failure while optimizing conditioning regimens to minimize toxicity are needed.}, }
@article {pmid41045509, year = {2025}, author = {Kim, D and Ding, W and Shaw, AN and Torkel, M and Turtle, CJ and Yang, P and Yang, J}, title = {Multi-view gene panel characterization for spatially resolved omics.}, journal = {Briefings in bioinformatics}, volume = {26}, number = {5}, pages = {}, pmid = {41045509}, issn = {1477-4054}, support = {//AIR@innoHK program of the Innovation and Technology Commission of Hong Kong/ ; DI2-0000000197//Chan Zuckerberg Initiative Single Cell Biology Data Insights/ ; APP2017023//National Health and Medical Research Council (NHMRC) Investigator/ ; 1173469//NHMRC Investigator/ ; //Metcalf Prize from National Stem Cell Foundation of Australia/ ; //CLEARbridge Foundation/ ; //Anthony Rothe Memorial Trust/ ; 2033771//NHMRC/ ; //Australian Commonwealth Government Research Training Program Stipend Scholarship/ ; //Children's Medical Research Institute Top up Award/ ; }, mesh = {Humans ; Algorithms ; *Gene Expression Profiling/methods ; *Transcriptome ; *Genomics/methods ; *Computational Biology/methods ; }, abstract = {Spatially resolved transcriptomics has revolutionized the study of complex tissues by enabling cellular and subcellular resolution. However, targeted spatial technologies depend on pre-selected gene panels, which are typically curated based on prior biological knowledge or specific research hypotheses. While existing methods often focus on optimizing for cell type identification, we argue that effective panel design should also account for transcriptional variation, pathway-level coverage, and minimal gene redundancy. To meet these broader criteria, we developed a two-part framework: (i) panelScope, a gene panel characterization platform that characterizes panels from multiple perspectives, allowing for holistic comparisons of gene panels for custom panel design; and (ii) panelScope-OA, a genetic algorithm that integrates these characterization metrics into a multi-loss function to automate panel optimization. We applied panelScope and panelScope-OA to characterize nine panels across four datasets. Notably, computationally constructed gene panels performed competitively in capturing major cell types when compared to our in-house manually curated panel. However, refined manual curation offered distinct advantages, particularly in capturing minor cell types. Our results demonstrate the utility of panelScope and panelScope-OA by offering quantitative and multi-dimensional insights to support the design of panels tailored to diverse research needs.}, }
@article {pmid41001449, year = {2025}, author = {Ssemambo, PK and Burton, M and Mirembe, BG and Nakabiito, C and Donnell, D and Beauchamp, G and Delany-Moretlwe, S and Celum, C and Velloza, J}, title = {Correlates of long-acting reversible contraceptive (LARC) use among young women in Southern Africa: a secondary analysis from HPTN 082.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001449}, abstract = {BACKGROUND: Long-acting reversible contraception (LARCs), including intrauterine devices (IUDs), injectables, and implants, are highly effective in preventing unintended pregnancies but LARC use rates are low among African adolescents and young women (AGYW). Understanding factors associated with LARC uptake and continuation among African AGYW may provide insights into strategies to promote LARC use.
METHODS: We conducted a secondary data analysis from the HIV Prevention Trials Network (HPTN 082) pre-exposure prophylaxis (PrEP) study, which enrolled 451 AGYW in Zimbabwe and South Africa ages 16-25 years, who reported vaginal or anal sex in the prior month, and reported PrEP interest (ClinicalTrials.gov, NCT02732730). Contraception and contraceptive counseling were offered at enrollment and visits at 4, 8, 13, 26, and 39 weeks post enrollment, with follow-up through 52 weeks. The outcome variable was any LARC use, defined as copper or hormonal IUDs, injectable contraceptives, and implants. We performed descriptive analyses and regression models to assess contraceptive use patterns and characteristics associated with LARC use and condomless sex.
RESULTS: Overall, 60% (299/499) of AGYW adopted a LARC method at enrollment and 78% (234/299) persisted on a LARC method during follow up. Among the 449 women who used contraception at enrollment and/or during follow-up, 38 (8.4%) switched between non-LARC to LARC and 34 (7.5%) discontinued contraception at some point during the study. AGYW not using a LARC at enrollment were more likely to switch contraceptive method through week 39 compared to those already using a LARC (32.7% vs. 14.7%, respectively; p-value<0.001). Factors significantly associated with choosing a LARC method were prior pregnancy [adjusted odds ratio [aOR]:2.46; 95% confidence interval [CI]: 1.59-3.79; p<0.01], and comfort talking to close friends about sexual relationships [aOR:1.82; 95% CI:1.02-3.23; p=0.04]. Consistent condom users were less likely to choose a LARC method [aOR:0.27; 95% CI:0.19-0.39; p<0.01].
CONCLUSION: Contraceptive counseling and offering LARC methods with HIV PrEP was associated with a majority of African AGYW selecting a LARC method. Peer support is important in facilitating LARC use and the high contraceptive efficacy of LARC should be discussed with AGYW using condoms for contraception. Contraceptive counseling and promotion of LARCs should be integrated with PrEP delivery for African AGYW.}, }
@article {pmid40291683, year = {2025}, author = {Cimino, PJ and Keiser, DJ and Parrish, AG and Holland, EC and Szulzewsky, F}, title = {C-terminal fusion partner activity contributes to the oncogenic functions of YAP1::TFE3.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40291683}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, abstract = {YAP1 gene fusions are found in a multitude of human tumors, are potent oncogenic drivers, and are the likely initiating tumorigenic events in these tumors. We and others have previously shown that a YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity that is resistant to inhibitory Hippo pathway signaling. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we used the RCAS/tv-a system to express eight different YAP1 gene fusions in vivo and observed significant differences in the latencies of tumors induced by the various YAP1 fusions. We observed that tumors induced by YAP1::TFE3 displayed a significantly different histomorphology compared to tumors induced by other YAP1 fusions or activated non-fusion YAP1. To assess the extent to which the functional TFE3 domains (DNA binding: leucine zipper (LZ) and basic-helix-loop-helix (bHLH); activation domain (AD)) contribute to the oncogenic functions of YAP1::TFE3, we generated several mutant variants and performed functional in vitro and in vivo assays. In vitro, mutation or deletion of the TFE3 DNA binding domains (LZ, bHLH) resulted in reduced TFE3 activity but increased YAP1 activity of YAP1::TFE3. In vivo, deletion of the LZ and bHLH domains did not result in a decrease in tumor incidence but induced the formation of more YAP1-like tumors that lacked prominent features of YAP1::TFE3-driven tumors. By contrast, loss of the TFE3 AD almost completely abrogated tumor formation. Our results suggest that the TFE3 domains significantly contribute to the oncogenic activity of YAP1::TFE3.}, }
@article {pmid41045472, year = {2025}, author = {Ko, B and Rojanasopondist, P and Grady, WM}, title = {Top advances of the year: Noninvasive colorectal cancer screening tests.}, journal = {Cancer}, volume = {131}, number = {20}, pages = {e70115}, doi = {10.1002/cncr.70115}, pmid = {41045472}, issn = {1097-0142}, support = {//RACE Charities/ ; U2CCA271902//Division of Cancer Prevention, National Cancer Institute/ ; //Cottrell Family Fund/ ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/blood ; *Early Detection of Cancer/methods ; Feces/chemistry ; Occult Blood ; Biomarkers, Tumor/blood ; Sensitivity and Specificity ; Mass Screening/methods ; }, abstract = {Colorectal cancer (CRC) screening has been shown to be more effective in preventing deaths from this common cancer, but current methods are suboptimal. Because of limitations and barriers, interval cancers occur, and many people (25%-40%) are not compliant with colorectal cancer screening. Advances over the past year, which have led to a blood-based screening test and more accurate stool tests, address the limitations of current tests. Three clinical trials published in the past year have led to a novel blood-based test, a multitarget stool eRNA test, and an improved multitarget stool DNA test for colorectal cancer screening. The multitarget eRNA stool-based test and multitarget stool DNA test are 94.4% sensitive (87.9% specificity) and 93.5% sensitive (90.6% specificity) for CRC and 45.9% sensitive and 43.4% sensitive for advanced polyps, respectively. The blood test uses cell free DNA to detect CRC and is 83% sensitive for CRC (89.6% specificity) and 13% sensitive for advanced adenomas. These advances provide a novel effective blood-based test for CRC screening, which promises to increase compliance, and more accurate stool-based tests, which promise to lead to fewer interval CRCs.}, }
@article {pmid41045294, year = {2025}, author = {Fernández-Penny, FE and Mozingo, K and Bhurgri, A and Perez, HA and Samorodnitsky, S and Lehmann, AE and Humphreys, IM and Abuzeid, WM and Jafari, A}, title = {Patient and Procedural Predictors of Early Recovery Quality After Endoscopic Endonasal Surgery.}, journal = {International forum of allergy & rhinology}, volume = {}, number = {}, pages = {}, doi = {10.1002/alr.70037}, pmid = {41045294}, issn = {2042-6984}, }
@article {pmid41043776, year = {2025}, author = {McCurdy, SR and Solomon, SR and Shaffer, BC and He, M and Bolon, YT and Blouin, AG and Keyzner, A and Socola, FA and Ibrahim, U and Zou, J and Safah, H and Saba, N and Gadalla, S and Perales, MA and Paczesny, S and Marsh, SGE and Petersdorf, EW and Wang, T and Lee, SJ and Fuchs, EJ}, title = {Post-Transplant Cyclophosphamide Improves Survival in HLA-DPB1 Mismatched Unrelated Donor Allogeneic Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.048}, pmid = {41043776}, issn = {2666-6367}, abstract = {BACKGROUND: HLA-DPB1 mismatching is common in unrelated donor (URD) hematopoietic cell transplantation (HCT) and increases graft-versus-host disease (GVHD) when using methotrexate and tacrolimus (MTX/Tac)-based GVHD prophylaxis. Historically, national and international guidelines recommended prioritizing HLA-DPB1 matching in URD selection. The impact of HLA-DPB1 matching in URD HCT when using post-transplantation cyclophosphamide (PTCy) has been understudied.
OBJECTIVES: Our primary endpoint was the association of GVHD-prophylaxis strategy with overall survival (OS) after T cell-replete 12/12 HLA-matched or permissive or non-permissive (NP) mismatch (MM) at HLA-DPB1 (defined by the T-cell-epitope groups model) URD HCT.GVHD-free, relapse-free survival (GRFS) was our key secondary endpoint.
STUDY DESIGN: This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Recipients underwent a first HCT from 2015-2020 for acute leukemia or myelodysplastic syndrome using either HLA-DPB1 NP MM (n=329), permissive MM (n=992), or 12/12 HLA-matched (n=300) URD with PTCy ± mycophenolate mofetil and/or a calcineurin inhibitor, or HLA-DPB1 NP MM (n=709), permissive MM (n=2,395), or 12/12 HLA-matched (n=911) URD with MTX/Tac.
RESULTS: HLA-DPB1 NP MM with MTX/Tac was associated with higher treatment-related mortality (TRM) (hazard ratio [HR]: 1.64, 1.08-2.49, p=0.019), lower relapse (HR: 0.73, 0.59-0.92, p=0.0073), inferior OS (HR: 1.27, 1.03 -1.57, p=0.023), and worse GRFS (HR: 1.61, 1.34-1.94, p<0.0001) when compared with PTCy. Adjusted 1-yr estimates for GRFS were 54% (95% confidence interval [CI]: 49-60%) for PTCy and 40% (CI: 37-44%) for MTX/Tac. For permissive MM URD HCT, MTX/Tac was associated with inferior GRFS (HR 1.54, CI: 1.36-1.76, p<0.0001) when compared with PTCy. When using PTCy, there were no significant differences in these outcomes for HLA-DPB1 NP MM, HLA-DPB1 permissive MM, or 12/12 HLA-matched URD HCT.
CONCLUSIONS: PTCy should be the preferred GVHD prophylaxis strategy for HLA-DPB1 MM URD HCT. Furthermore, within PTCy platforms, survival is comparable across HLA-DPB1 match and thus NP mismatching at HLA-DPB1 should not be a determinant in URD selection.}, }
@article {pmid41043723, year = {2025}, author = {El-Serag, HB and Lopez, C and Luster, M and Reddy, KR and Parikh, N and Singal, AG and Marrero, JA and Thrift, AP and Chhatwal, J and Feng, Z and Page-Lester, S and Jin, Q and Tayob, N and Kanwal, F}, title = {HES V2.0 validation and performance compared to GALAD and ASAP in the HEDS cohort.}, journal = {Journal of hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jhep.2025.09.023}, pmid = {41043723}, issn = {1600-0641}, abstract = {BACKGROUND: We previously developed Hepatocellular Carcinoma Early Detection Screening (HES) V2.0, biomarker panel (age, ALT, platelets, etiology, AFP, AFP L3, DCP and their gradient over the past one year) for early detection of HCC among patients with cirrhosis. We externally validated HES V2.0 and compared its performance to HES V1.0, GALAD, and ASAP.
METHODS: We conducted a prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) cohort study in the HEDS (Hepatocellular Carcinoma Early Detection Strategy) 1,485 cirrhosis cohort (119 developed HCC). Patient- and test-level true positive rate (TPR) for HCC were calculated at 6, 12, 24 months before HCC diagnosis based on a threshold at a fixed false positive rate (FPR) of 10% and 18.1% - the latter corresponded to GALAD cut-off of -1.36.
RESULTS: HES V2.0 and GALAD had same AUROC (0.79) but different TPR/FPRs. At the FPR of 10%, HES V2.0 had 2.0%, 6.7%, and 6.0% higher TPR (sensitivity) than GALAD within 6, 12, and 24 months before HCC diagnosis (one-sided p-values 0.24, 0.025, 0.078, respectively). At 18.1% FPR, GALAD had 6% and 2% higher sensitivity than HES V2.0 within 6 and 12 months before HCC and similar sensitivity within 24 months before HCC diagnosis (all p-values >0.05).The sensitivity for HES V2.0 was 11.9% higher than HES V1.0 at 12 months (p=0.007). The sensitivity for HES V2.0 was considerably (10.9-16.3%) higher than ASAP. For patients with available labs to calculate gradients over time, the sensitivity of HES V2.0 was 3.5-8.7% higher than GALAD at all time points of testing before HCC (8.7% to 24.0% relative increase) with p<0.05 for several comparisons.
CONCLUSIONS: In a phase 3 biomarker validation study, HES V2.0 had higher sensitivity than ASAP for HCC detection, and a similar or higher sensitivity than GALAD only at 12 months before HCC diagnosis at 10% FPR and when over time gradients in AFP, AFP L3, and DCP are available.
IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with early detection being critical for improving survival outcomes. This study provides a rigorous phase 3 validation of the HES V2.0 biomarker panel, demonstrating its superior or comparable sensitivity to established models like GALAD and ASAP in a large, diverse U.S. cirrhosis cohort. The findings are particularly impactful for clinicians and researchers focused on liver cancer surveillance, as HES V2.0 offers enhanced detection performance, especially when longitudinal biomarker data are available. These results support the integration of HES V2.0 into clinical workflows and future trials, potentially improving early HCC detection and enabling timely curative interventions for at-risk patients.}, }
@article {pmid41043413, year = {2025}, author = {Zhang, P and Haeseleer, F and Waltner, OG and Gartlan, KH and Bhise, SS and Minnie, SA and Adams, RC and Yeh, AC and Ensbey, KS and Legg, SRW and Sekiguchi, T and Atilla, E and Nemychenkov, NS and Nelson, EL and Joshi, T and Liang, EC and Hirayama, AV and Abe, K and Koyama, M and Clouston, AD and Gauthier, J and Furlan, SN and Hill, GR}, title = {Eomesodermin[+] CD4[+] T cells are critical for curative immunotherapy outcomes.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.09.004}, pmid = {41043413}, issn = {1097-4180}, abstract = {Interleukin 10 (IL-10)-producing CD4[+] type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory in vivo from Eomes[+]IL-10[-] to Eomes[+]IL-10[+] subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes[+]CD4[+] fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4[+] Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes[+] Tr1 cells represented a stable population comprising 40%-80% of the CD4[+] CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4[+] T cells, essential for curative immunotherapy outcomes.}, }
@article {pmid41043390, year = {2025}, author = {Keogh, MC and Almouzni, G and Andrews, AJ and Armache, KJ and Arrowsmith, CH and Baek, SH and Bedford, MT and Bernstein, E and Côté, J and David, Y and Denu, JM and Fierz, B and Garcia, BA and Glass, KC and Gozani, O and Helin, K and Henikoff, S and Jensen, ON and Josefowicz, SZ and Kelleher, NL and Kutateladze, TG and Lindner, HH and Lu, C and Luger, K and Mallick, P and Musselman, CA and Muir, TW and Paša-Tolić, L and Schneider, R and Shi, X and Shi, Y and Sidoli, S and Smith, LM and Tyler, JK and Wolberger, C and Workman, JL and Strahl, BD and Young, NL}, title = {A needed nomenclature for nucleosomes.}, journal = {Molecular cell}, volume = {85}, number = {19}, pages = {3554-3561}, doi = {10.1016/j.molcel.2025.08.029}, pmid = {41043390}, issn = {1097-4164}, mesh = {*Nucleosomes/metabolism/genetics/classification ; *Protein Processing, Post-Translational ; *Histones/metabolism/genetics/classification ; Humans ; *Terminology as Topic ; Animals ; Chromatin/metabolism/genetics ; Chromatin Assembly and Disassembly ; }, abstract = {Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform to describe the particular gathering of histones within an individual nucleosome. There is now a need to define specific forms of these entities in prose while providing space for experimental nuance. To this end, we introduce a nomenclature that can express discrete PTMs, proteoforms, nucleoforms, or situations where defined PTMs exist in an uncertain context. Though specifically designed for the chromatin field, adaptions of the framework could be used to describe-and thus dissect-how proteoforms are configured in functionally distinct complexes across biology.}, }
@article {pmid41043162, year = {2025}, author = {Chung, K and Sotak, N}, title = {Use of Trigger Point Injections in the Management of Myofascial Pain in Patients With Temporomandibular Disorders.}, journal = {Compendium of continuing education in dentistry (Jamesburg, N.J. : 1995)}, volume = {46}, number = {8}, pages = {376-379}, pmid = {41043162}, issn = {2158-1797}, mesh = {Humans ; Aged ; *Trigger Points ; *Temporomandibular Joint Disorders/complications/drug therapy ; *Myofascial Pain Syndromes/drug therapy ; Male ; Anesthetics, Local/administration & dosage ; Injections ; }, abstract = {Myofascial pain, a prevalent condition that often involves trigger points in the craniofacial region, can significantly impair function and quality of life. This article reports on the case of a 69-year-old patient with chronic head and neck myofascial pain and limited mouth opening, which hindered dental care and obstructive sleep apnea management. Following a series of trigger point injections (TPIs), combined with pharmacologic and physical therapy, the patient experienced substantial symptom relief and improved jaw function, and was subsequently able to receive successful dental and sleep apnea treatment. The case underscores the importance of accurate diagnosis and multidisciplinary management of myofascial pain, highlighting TPI therapy as an effective, minimally invasive treatment within a multimodal care approach.}, }
@article {pmid41043099, year = {2025}, author = {Ueda Oshima, M and Vo, PT and Boeckh, M and Bouvier, ME and Carpenter, PA and Mielcarek, M and Petersdorf, EW and Storb, R and Gooley, T and Sandmaier, BM}, title = {Sirolimus and Cyclosporine With Post-Transplant Cyclophosphamide or Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis in Unrelated Donor Hematopoietic Cell Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501238}, doi = {10.1200/JCO-25-01238}, pmid = {41043099}, issn = {1527-7755}, abstract = {PURPOSE: To determine whether sirolimus (SIR) and cyclosporine (CSP) combined with post-transplantation cyclophosphamide (PTCy), after nonmyeloablative or reduced-intensity conditioning unrelated donor hematopoietic cell transplantation (HCT), would be more effective than SIR, CSP, and mycophenolate mofetil (MMF) in reducing the risk of chronic graft-versus-host disease (cGVHD) without increasing risk of recurrent malignancy.
METHODS: In a Phase II trial of HLA-matched or mismatched unrelated donor mobilized blood HCT (ClinicalTrials.gov identifier: NCT03246906), adults with hematologic malignancies ineligible for myeloablative HCT were randomly assigned 1:1 to GVHD prophylaxis with SIR/CSP/PTCy (50 mg/kg once daily on days +3, +4) or SIR/CSP/MMF. The primary end point was 1-year chronic GVHD-free relapse-free survival (CRFS).
RESULTS: One hundred forty-five patients were randomly assigned and transplanted. Median follow-up among survivors was 3.0 (range, 0.6-7.0) years. Comparing PTCy-based with non-PTCy-based immunosuppression, estimated 1-year CRFS was 73% (95% CI, 61% to 82%) versus 48% (95% CI, 36% to 59%), translating into a hazard ratio (HR) for CRFS failure of 0.46 (95% CI, 0.26 to 0.79; P = .005) for PTCy. Probabilities of acute GVHD (aGVHD) grades II-IV and III-IV, respectively, were 40% versus 42% and 6% versus 10%. One-year estimates for secondary end points were as follows: moderate-to-severe cGVHD, 3% (95% CI, 1% to 9%) versus 33% (95% CI, 22% to 44%); relapse, 15% versus 15%; progression-free survival, 75% versus 78%; survival, 86% versus 86%; and nonrelapse mortality, 10% versus 7%. The HR of ≥grade 3 infections with PTCy versus non-PTCy was 2.65 (95% CI, 1.41 to 4.97; P = .003).
CONCLUSION: After HLA-matched or mismatched unrelated donor mobilized blood HCT, replacing MMF with PTCy, when used in combination with SIR and CSP, significantly reduced risk of cGVHD, without increasing risks of aGVHD or relapse. Thus, the combination of PTCy and SIR/CSP may have synergistic cGVHD-protective effects warranting further study.}, }
@article {pmid41042747, year = {2025}, author = {Feldacker, C and Fabens, I and Dong, TQ and Moyo, K and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Pienaar, J and Sardini, M and Ndebele, F and Tweya, H and Holec, M and Waweru, E and Setswe, G}, title = {Strengthening evidence for text-based telehealth in post-operative care: A pragmatic study of the reach and effectiveness of two-way, text-based follow-up after voluntary medical male circumcision in South Africa.}, journal = {PloS one}, volume = {20}, number = {10}, pages = {e0314436}, pmid = {41042747}, issn = {1932-6203}, mesh = {Humans ; Male ; *Circumcision, Male/adverse effects ; South Africa ; *Telemedicine ; *Text Messaging ; Adult ; Adolescent ; *Postoperative Care/methods ; Young Adult ; Follow-Up Studies ; Middle Aged ; }, abstract = {Building upon evidence of safety and efficiency gains from a randomized control trial (RCT) in South Africa, we further scaled implementation of two-way, short message service (SMS), text-based (2wT) follow-up after voluntary medical male circumcision (VMMC). We aimed to determine if gains in adverse event (AE) identification and reduced follow-up visits could be maintained when 2wT was implemented in routine VMMC settings. A pragmatic, stepped wedge design (SWD) study was implemented across three districts in South Africa. Men ages 15 and older could opt into the 2wT telehealth follow-up approach when their facility was in the intervention period. Men in routine periods were offered the standard of care (SoC): in-person post-operative visits on days 2 and 7 as per national VMMC guidelines. 2wT participants were not required to attend any postoperative visits but could return for care if desired or referred. Two quality of care markers, safety (AE ascertainment rate) and efficiency (# in-person follow-up visits), were compared between groups. We aimed for at least 200 men per step to have 80% power to detect a change in AE rate from before to after 2wT was implemented. Secondary analysis explored response rates; client and site uptake; and AE details. Among 6842 clients in the intervention period, 2856 opted into 2wT (37.8%) across three intervention waves and two platforms (SMS or WhatsApp). Among those with post-operative follow-up, the AE ascertainment rate was higher among 2wT (0.60%) than SoC (0.13%) clients (p = 0.0018), demonstrating safety gains. On average, 2wT participants had 2.1 fewer visits compared to SoC clients (p < 0.001), demonstrating gains in follow-up efficiency. Among 2wT men, 2069/2586 (80%) responded via 2wT over 14 days, demonstrating engagement in post-operative care. Of all intervention clients, 93 2wT (3.6%) and 342 (8.0%) SoC were considered lost to follow-up. In this expansion trial, we provided additional evidence that the 2wT approach maintains the quality of post-operative care for adult VMMC clients. 2wT should be scaled to augment in-person, post-operative visits after VMMC for eligible, interested males ages 15 and older. To achieve potential impact, effort is needed to improve access and uptake to 2wT among providers and sites, expanding the 2wT approach for other acute follow-up care especially among men.}, }
@article {pmid41001472, year = {2025}, author = {Kerrebijn, I and Bjornsdottir, G and Arbabi, K and Urpa, L and Haapaniemi, H and Thorleifsson, G and Stefansdottir, L and Frangakis, S and Valliere, J and Kunorozva, L and Abner, E and Ji, C and Aagaard, B and Bliddal, H and Brunak, S and Bruun, MT and Didriksen, M and Erikstrup, C and Geirsson, AJ and Gudbjartsson, DF and Hansen, TF and Jonsdottir, I and Knight, S and Knowlton, KU and Mikkelsen, C and Nadauld, LD and Olafsdottir, TA and Ostrowski, SR and Pedersen, OB and Saevarsdottir, S and Skuladottir, AT and Sørensen, E and Stefansson, H and Sulem, P and Sveinsson, OA and Thorlacius, GE and Thorsteinsdottir, U and Ullum, H and Vikingsson, A and Werge, TM and , and , and , and , and , and Saxena, R and Stefansson, K and Brummett, CM and Glintborg, B and Clauw, DJ and Thorgeirsson, TE and Williams, FM and Sinnott-Armstrong, N and Ollila, HM and Wainberg, M}, title = {The genetic architecture of fibromyalgia across 2.5 million individuals.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001472}, support = {K08 AR082454/AR/NIAMS NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; }, abstract = {Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including CAMKV, DCC, DRD2/NCAM1, MDGA2, and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric, and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.}, }
@article {pmid41000947, year = {2025}, author = {Kanaan, SB and Underwood, JG and Gladden, RG and Fan, E and Bhise, SS and Thakar, MS and Jaeger-Ruckstuhl, CA and Stevens, J and Gray, AN and Riddell, SR and Bleakley, M and Meshinchi, S and Furlan, SN}, title = {Quantifying HLA transcripts by genotype in chimeric mixtures at single-cell resolution.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000947}, issn = {2692-8205}, abstract = {Gene products from the highly variable major histocompatibility locus, including HLA, are essential for self-recognition and immune surveillance of malignancy. Following allogeneic hematopoietic cell transplantation (alloHCT), genetic and epigenetic alterations in HLA can drive disease recurrence, making precise HLA assessment critical for determining future therapy. However, current methods lack the sensitivity to quantify HLA transcripts at the single-cell level, limiting their clinical utility. We introduce scrHLA-typing, a novel technique that accurately identifies and quantifies HLA transcripts in single cells using long-read sequencing. When applied to samples from patients with post-transplant relapse, scrHLA-typing successfully detected HLA allele-specific expression, across a range of levels of donor-recipient chimerism, at clinically actionable levels. By characterizing allele expression in residual leukemia cells, our assay identified differences in expression patterns among patients. This capability highlights scrHLA-typing's potential to improve risk stratification and guide the selection of appropriate salvage therapies, enhancing personalized treatment strategies after relapse.}, }
@article {pmid41000687, year = {2025}, author = {Wick, BJ and Kluesner, MG and Slipek, NJ and Skeate, JG and Niemeyer, EM and Webber, BR and Moriarity, BS}, title = {Installation of Dominant-Negative Mutations in FAS and TGFβR2 via Base Editing in Primary T Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000687}, issn = {2692-8205}, abstract = {Adoptive cell transfer (ACT) of engineered T cells is effective against B-cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FASL and TGFβ are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach which directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGFβ signaling. CAR-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our novel approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.}, }
@article {pmid40291684, year = {2025}, author = {Vick, SC and Domenjo-Vila, E and Frutoso, M and Glabman, RA and Warrier, LS and Hughes, SM and Kirby, AC and Fialkow, MF and Hladik, F and Prlic, M and Lund, JM}, title = {Mucosal tissue NK cells tune their function between optimal anti-pathogen activity and tissue protection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40291684}, issn = {2692-8205}, support = {K99 AI180649/AI/NIAID NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; }, abstract = {Preserving barrier integrity is of great importance in mucosal tissues while simultaneously defending against inflammatory threats and exposures to pathogens. NK cells at barrier sites are essential for viral control during infections such as herpes simplex virus 2 (HSV-2) but must also balance pathogen response with tissue protection. We have characterized human tissue NK cells in the vaginal tissue (VT) as having distinct effector and tissue protective functions. Using scRNA-seq and high-parameter flow cytometry, we uncovered a unique signature for VT NK cells, indicating a reduced effector phenotype with increased factors related to tissue residency and immunoregulation at steady state. Despite their functionally quiescent nature, these cells were able to respond robustly to inflammatory signals, suggesting they are poised for pathogen response. We found that the gene signatures between mouse and human NK cells were remarkably similar, demonstrating the feasibility of using a mouse model to probe distinct NK cell functions during mucosal infection. In mice, VT NK cells responded robustly to acute HSV-2 infection and retained an enhanced recall potential after viral clearance. They also secreted tissue repair factors and played a role in restricting tissue damage following viral infection. Our data, using both human tissues and a mouse model, reveal an unexpected role of mucosal tissue NK cells in the VT in balancing host protection with tissue repair in the context of localized mucosal tissue infection.}, }
@article {pmid41042680, year = {2025}, author = {Srinivasan, S and Strenk, SM and Beamer, MA and Fiedler, TL and Proll, S and Acevedo-Oquendo, GR and Bonura, GM and Nagana Gowda, GA and Raftery, D and Hillier, SL and Fredricks, DN}, title = {Umbribacter vaginalis gen. nov., sp. nov.: novel bacterium isolated from the human vagina.}, journal = {International journal of systematic and evolutionary microbiology}, volume = {75}, number = {10}, pages = {}, pmid = {41042680}, issn = {1466-5034}, mesh = {*Phylogeny ; Female ; RNA, Ribosomal, 16S/genetics ; Humans ; *Vagina/microbiology ; Fatty Acids/analysis/chemistry ; DNA, Bacterial/genetics ; Bacterial Typing Techniques ; Base Composition ; *Vaginosis, Bacterial/microbiology ; Sequence Analysis, DNA ; Adult ; }, abstract = {Gram-variable obligately anaerobic novel bacteria DNF00809 and PR-HUZ-602407-17 were isolated from vaginal fluid samples from women with bacterial vaginosis (BV) in two independent studies conducted in different laboratories. They each displayed ≥99.9% 16S rRNA gene sequence identity to the uncultured bacterial clone sequence AY738656 designated as Eggerthella-like vaginal bacterium (ELVB) and shared 100% 16S rRNA gene sequence identity with each other. Studies using molecular bacterial identification have associated ELVB sequences with BV, higher risk for human immunodeficiency virus acquisition and development of pelvic inflammatory disease in women. Given the clinical significance of this bacterium, we characterized the novel bacterium designated DNF00809[T] using biochemical, genotypic and phylogenetic analyses. DNF00809[T] was a coccobacillus that was non-motile, non-spore forming, asaccharolytic, proteolytic and indole negative. Fatty acid methyl ester analysis for DNF00809[T] indicated C14 : 0, C16 : 0, C16 : 0 dimethyl acetal and C18 : 1 cis9 to be the major fatty acids. Whole genomic DNA G+C content was 46.1 mol%. Phylogenetic and phylogenomic analyses indicate that DNF00809[T] represents a novel genus and novel species within the Eggerthellaceae family. We propose the name Umbribacter vaginalis gen. nov., sp. nov. with DNF00809[T] representing the type strain of this species (=DSM 118866[T]=CCUG77988[T]).}, }
@article {pmid41042528, year = {2025}, author = {Boiko, JR and Cooke, KR}, title = {Moving the needle on chronic GVHD of the lung.}, journal = {Blood advances}, volume = {9}, number = {19}, pages = {5038-5039}, doi = {10.1182/bloodadvances.2025017297}, pmid = {41042528}, issn = {2473-9537}, }
@article {pmid41042026, year = {2025}, author = {Rafati, M and Wang, Y and Koppayi, AL and Savage, SA and Godley, LA and Williams, KM and Porter, C and Jones, K and Hicks, B and Spellman, SR and He, M and Atshan, R and Iwuagwu, C and Bolon, YT and Arrieta-Bolaños, E and Saultz, JN and Benjamin, CL and Lee, SJ and Saber, W and Gadalla, SM}, title = {Germline Pathogenic Variants in MUTYH Are Associated With Inferior Survival After Hematopoietic Cell Transplantation in Patients With Hematologic Malignancies or Disorders.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70093}, pmid = {41042026}, issn = {1096-8652}, support = {W81XWH-19-1-0241/CP/NCI NIH HHS/United States ; 75N910D00024/CA/NCI NIH HHS/United States ; U24CA076518//U.S. Public Health Service/ ; //Congressionally Directed Medical Research Programs/ ; }, }
@article {pmid41039543, year = {2025}, author = {Bouras, E and Papagiannopoulos, CK and Mustafa, R and Sobieski, D and Schmit, SL and Wu, AH and Brenner, H and Li, CI and Chan, AT and Pellatt, AJ and Zheng, W and Keku, TO and Moreno, V and Um, CY and Van Guelpen, B and Phipps, AI and Pai, RK and Lewis, SJ and Martin, RM and Gunter, MJ and Peters, U and Dehghan, A and Tsilidis, KK}, title = {Investigating the relationship of plasma microRNAs and colorectal cancer risk using genetic evidence.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {532}, pmid = {41039543}, issn = {1741-7015}, support = {C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/blood ; *MicroRNAs/blood/genetics ; Mendelian Randomization Analysis ; Male ; Genetic Predisposition to Disease ; Risk Factors ; Female ; Case-Control Studies ; Middle Aged ; }, abstract = {BACKGROUND: MicroRNAs (miRNAs) are short, single-stranded RNAs that function as post-transcriptional regulators of gene expression. Although circulating miRNAs have been linked to carcinogenesis, they have not yet been systematically investigated in relation to risk of colorectal cancer (CRC).
METHODS: We used Mendelian randomization (MR) and colocalization analyses to investigate the association of genetically predicted plasma miRNA concentrations (2083 miRNAs in 710 individuals) with risk of CRC (58,221 cases and 67,694 controls). For miRNAs associated with CRC risk, we also investigated their association with circulating plasma proteins (4907 proteins in 35,559 participants), bidirectionally, using MR. We performed pathway enrichment analysis (PEA) to explore downstream molecular pathways.
RESULTS: Associations of five miRNAs with CRC were found in MR and supported in colocalization analyses. Specifically, miR-146a-5p, miR-21-5p, and miR-4707-3p were positively, and miR-1908-5p and miR-6810-3p were inversely associated with CRC risk. Several protein associations were found for these miRNAs (range of proteins with P < 0.05: 78-796; 211 with FDR < 5%), and 11 pathways were identified in PEA, including regulation of Erb-B2 receptor tyrosine kinase 4 (miR-6810-3p) and insulin-like growth factor pathways (miR-1908-5p).
CONCLUSIONS: Our results support a potential implication of miR-146a-5p, miR-21-5p, miR-4707-3p, miR-1908-5p, and miR-6810-3p to CRC risk. However, their downstream effects should be elucidated before they can be utilized as preventive targets.}, }
@article {pmid41038991, year = {2025}, author = {Termini, CM}, title = {SLAM passes the haematopoietic stem cell identity test.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, pmid = {41038991}, issn = {1471-0080}, }
@article {pmid41037133, year = {2025}, author = {Garzia, NA and Fest, S and Cushing-Haugen, K and Kensler, TW and Chavarro, JE and Tamimi, RM and Harris, HR}, title = {Childhood and adolescent dietary patterns and incidence of benign breast disease.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {41037133}, issn = {1573-7225}, support = {T32 CA094880/NH/NIH HHS/United States ; U01 HL145386/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Childhood and adolescence may represent critical time windows for shaping future breast cancer risk. The association between early-life diet and breast cancer risk has been investigated, but few studies have examined the relation between adolescent diet and benign breast disease (BBD), an established breast cancer risk factor.
METHODS: Among 11,422 female Growing Up Today Study participants followed from 1996 to 2016 who completed food frequency questionnaires, we investigated the associations between adherence to three dietary patterns (Alternative Healthy Eating Index [AHEI], the Empirical Dietary Inflammatory Pattern [EDIP], and the Empirical Dietary Index for Hyperinsulinemia [EDIH]) at ages 10 and 14 years and self-reported BBD diagnosis. Cox proportional hazards models were used to estimates hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: Over 20 years of follow-up, 554 BBD cases were ascertained, with 259 biopsy-confirmed cases. Non-significant inverse associations were observed between greater adherence to the AHEI at age 10 and BBD risk (HR for fourth vs. first quartile = 0.74; 95% CI = 0.50-1.10; ptrend = 0.09), and between AHEI at age 14 and biopsy-confirmed BBD (HR for fourth vs. first quartile = 0.70; 95% CI = 0.48-1.03; ptrend = 0.10). Non-significant positive associations were observed between adherence to the EDIH at age 10 and (HR for fourth vs. first quartile = 1.49; 95% CI = 0.91-2.43; ptrend = 0.09) age 14 (HR for fourth vs. first quartile = 1.33; 95% CI = 0.97-1.82; ptrend = 0.09) and BBD risk. No associations were observed for EDIP. In secondary analyses, the association between EDIH at age 10 and BBD became statistically significant after accounting for change in dietary pattern quartile from age 10 to 14 (HR for fourth vs. first quartile = 2.14; 95% CI = 1.04-4.41). Adjustment for adult diet also strengthened associations between EDIH at age 10 and BBD risk (HR = 1.94; 95% CI = 1.12-3.37; ptrend = 0.007), and showed a significant inverse trend for AHEI (ptrend = 0.04).
CONCLUSION: These findings may suggest that greater early-life adherence to a healthier dietary pattern (AHEI) is associated with lower BBD risk, while consuming a more insulinemic dietary pattern (EDIH) may be associated with increased risk. Associations for EDIH at age 10 were statistically significant in secondary analyses accounting for dietary change and adult diet. Further research is needed to confirm these findings and clarify potential mechanisms.}, }
@article {pmid41036248, year = {2025}, author = {Wallace, B and Dimitrov, D and Hébert-Dufresne, L and Berdahl, AM}, title = {Hotspot model shows how location-based superspreading accelerates and reshapes epidemics.}, journal = {PNAS nexus}, volume = {4}, number = {9}, pages = {pgaf299}, pmid = {41036248}, issn = {2752-6542}, abstract = {During outbreaks of many diseases, a small number of infected individuals are responsible for a disproportionately large number of new infections in what are called superspreading events (SSEs). SSEs broadly fall into four categories: (i) a single individual is more infectious due to biological differences in their infection or (ii) their greater degree of social connection; or (iii) the disease spreads more readily in certain high-risk facilities or (iv) "opportunistic" situations such as large gatherings. Existing modeling approaches work well to understand the first two of these but are not well suited to describe the dynamics in the latter two. Here, we introduce a simple agent-based model which captures the essential features of disease spreading more readily at high-risk locations or gatherings, which we call "hotspots." In our model, disease spreads and people recover as in a standard Susceptible, Infected, Recovered model, but agents are also characterized by individual probability of visiting the hotspot where disease spreads much more readily, providing an additional risk structure to the population. We use this model to investigate how an outbreak's probability, peak, and final size all vary under different risk heterogeneity assumptions. We show how some particular distributions of risk-taking behavior across the population heighten these effects. We complement our simulations with analytic results that provide theoretical bases for all of our numerical results and allow for robust interpretation and prediction.}, }
@article {pmid41035891, year = {2025}, author = {Lawore, DC and Jena, S and Berard, AR and Birse, K and Lamont, A and Mackelprang, RD and Noel-Romas, L and Perner, M and Hou, X and Irungu, E and Mugo, N and Knodel, S and Muwonge, TR and Katabira, E and Hughes, SM and Levy, C and Calienes, FL and Hladik, F and Lingappa, JR and Burgener, AD and Green, LN and Brubaker, DK}, title = {Computational microbiome pharmacology analysis elucidates the anti-cancer potential of vaginal microbes and metabolites.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1602217}, pmid = {41035891}, issn = {1664-302X}, abstract = {The vaginal microbiome's role in risk, progression, and treatment of female cancers has been widely explored. Yet, there remains a need to develop methods to understand the interaction of microbiome factors with host cells and to characterize their potential therapeutic functions. To address this challenge, we developed a systems biology framework we term the Pharmacobiome for microbiome pharmacology analysis. The Pharmacobiome framework evaluates similarities between microbes, microbial byproducts, and known drugs based on their impact on host transcriptomic cellular signatures. Here, we apply our framework to characterization of the Anti-Gynecologic Cancer Vaginal Pharmacobiome. Using published vaginal microbiome multi-omics data from the Partners PrEP clinical trial, we constructed vaginal epithelial gene signatures associated with each profiled vaginal microbe and metabolite. We compared these microbiome-associated host gene signatures to post-drug perturbation host gene signatures related to 35 FDA-approved anti-cancer drugs from the Library of Integrated Network-based Cellular Signatures database to identify vaginal microbes and metabolites with high statistical and functional similarity to these drugs. We found that select lactobacilli particularly L. crispatus and their metabolites, such as taurine, can regulate host gene expression in ways similar to certain anti-cancer drugs. Additionally, we experimentally tested our model prediction that taurine, a metabolite produced by L. crispatus, kills cancerous breast and endometrial cancer cells. Our study shows that the Pharmacobiome is a robust framework for characterizing the anti-cancer therapeutic potential of vaginal microbiome factors with generalizability to other cancers, microbiomes, and diseases.}, }
@article {pmid41034423, year = {2025}, author = {Setiawan, T and Muhammad, JA and Marcellina, N and Wirawan, LM and Jun, N and Sari, IN and Oehler, VG and Kim, DW and Kwon, HY}, title = {Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {41034423}, issn = {1476-5551}, support = {2023R1A2C1003952//National Research Foundation of Korea (NRF)/ ; RS-2024-00437643//Korea Health Industry Development Institute (KHIDI)/ ; }, abstract = {Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.}, }
@article {pmid41034193, year = {2025}, author = {Guo, B and Cai, Y and Kim, D and Smit, RAJ and Wang, Z and Iyer, KR and Hilliard, AT and Haessler, J and Tao, R and Broadaway, KA and Wang, Y and Pozdeyev, N and Stæger, FF and Yang, C and Vanderwerff, B and Patki, AD and Stalbow, L and Lin, M and Rafaels, N and Shortt, J and Wiley, L and Stanislawski, M and Pattee, J and Davis, L and Straub, PS and Shuey, MM and Cox, NJ and Lee, NR and Jørgensen, ME and Bjerregaard, P and Larsen, C and Hansen, T and Moltke, I and Meigs, JB and Stram, DO and Yin, X and Zhou, X and Chang, KM and Clarke, SL and Guarischi-Sousa, R and Lankester, J and Tsao, PS and Buyske, S and Graff, M and Raffield, LM and Sun, Q and Wilkens, LR and Carlson, CS and Easton, CB and Liu, S and Manson, JE and Marchand, LL and Haiman, CA and Mohlke, KL and Gordon-Larsen, P and Albrechtsen, A and Boehnke, M and Rich, SS and Manichaikul, A and Rotter, JI and Yousri, NA and Irvin, RM and , and , and Gignoux, C and North, KE and Loos, RJF and Assimes, TL and Peters, U and Kooperberg, C and Raghavan, S and Highland, HM and Darst, BF}, title = {Polygenic risk score for type 2 diabetes shows context-dependent effects across populations.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8632}, pmid = {41034193}, issn = {2041-1723}, support = {R01HL143885//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HD30880//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL151152//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK139598//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL142302//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL143885//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL163262//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK122503//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL151152//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL156991//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK123019//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UM1DK078616//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R00CA246063//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R03CA287235//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01CA261339//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL174378//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U54HG013243//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; PPM2-0226-170020//Qatar National Research Fund (QNRF)/ ; NPRP11S-0114-180299//Qatar National Research Fund (QNRF)/ ; NNF20OC0059313//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; NNF18CC0034900//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; P50CA097186//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/epidemiology ; *Multifactorial Inheritance/genetics ; Male ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Genome-Wide Association Study ; Risk Factors ; Aged ; Adult ; Polymorphism, Single Nucleotide ; Case-Control Studies ; Genetic Risk Score ; }, abstract = {Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.}, }
@article {pmid41033921, year = {2025}, author = {Kishan, AU and Juarez Casillas, JE and Sargos, P and Kalbasi, TR and Chabaud, S and Brihoum, M and Sachdeva, A and Nikitas, JN and Ma, TM and Karasik, D and Ballas, LK and Lock, D and Valle, L and Taparra, K and Reiter, RE and Saigal, C and Chamie, K and Donin, N and Chin, AI and Rettig, M and Nickols, NG and Sun, Y and Spratt, D and Lamb, JM and Cao, M and Pommier, P and Steinberg, ML}, title = {Stereotactic Intensity-modulated Radiotherapy After Radical Prostatectomy (SCIMITAR): 4-Year Outcomes of a Phase 2 Clinical Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.09.4149}, pmid = {41033921}, issn = {1873-7560}, abstract = {In the phase 2 SCIMITAR trial, stereotactic body radiotherapy (SBRT; 30-34 Gy in 5 fractions) was delivered to the prostatic fossa after radical prostatectomy in 100 patients requiring postoperative RT, with or without nodal RT and androgen deprivation therapy (ADT). The primary endpoint was 4-yr biochemical recurrence (BCR)-free survival (BCR-FS), with events defined as BCR (prostate-specific antigen ≥0.2 ng/ml above nadir), salvage ADT, or death. Outcomes were compared to individual patient data (IPD) from a phase 3 trial of conventionally fractionated RT (CFRT) using inverse probability of treatment weighting and Fine-Gray models. At median follow-up of 53 mo, the 4-yr BCR-FS rate was 60% (95% confidence interval [CI] 50-70%). The IPD analysis revealed that for men not receiving ADT, the risk of BCR was lower with SBRT than with CFRT (subdistribution hazard ratio [sHR] 0.49, 95% CI 0.29-0.84; p = 0.008). For men receiving ADT, there was no significant difference in BCR risk between SBRT and CFRT (sHR 1.58, 95% CI 0.81-3.11; p = 0.18), although the asymmetrically broad 95%CI and directionality of the point estimate suggest that a higher BCR risk with SBRT cannot be ruled out. The 4-yr cumulative incidence rates for late grade ≥2 gastrointestinal and genitourinary toxicities were 6.6% and 32%, respectively. At 48 mo, the proportion of patients reporting a decline of more than two times the minimal clinically important difference in urinary incontinence, urinary irritative/obstructive, bowel, and sexual domains was 23%, 6.7%, 13%, and 9.7%, respectively. SBRT to the prostatic fossa appears to be safe and effective through 4 yr.}, }
@article {pmid41032739, year = {2025}, author = {Owens, CA and Ludmir, EB and Liu, Q and Qiu, W and Gupta, AC and Smith, SA and Rigaud, B and Brock, KK and Bates, JE and Meyers, TG and Paulino, AC and Peterson, CB and Kry, SF and Teepen, JC and Ronckers, CM and Neglia, JP and Leisenring, WM and Oeffinger, KC and Nathan, PC and Turcotte, LM and Hodgson, DC and Hudson, MM and Robison, LL and Moskowitz, CS and Armstrong, GT and Henderson, TO and Yasui, Y and Howell, RM}, title = {Colorectal-Specific Radiation Dose and Chemotherapy Risk for Subsequent Colorectal Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study (CCSS) Report.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500531}, doi = {10.1200/JCO-25-00531}, pmid = {41032739}, issn = {1527-7755}, abstract = {PURPOSE: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations.
METHODS: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (VX Gy) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models and excess rate ratio (ERR) models evaluated dose-response relationships for the incidence of colorectal SMNs. Reference groups were those not receiving the assessed treatment(s).
RESULTS: Among 25,723 survivors (median follow-up = 28.5 years; range = 5.0-48.9), 104 colorectal SMNs were identified. A dose-response relationship was observed between MCD and colorectal SMN rates; incidence rate ratios (IRRs) for 10 to <20 Gy and ≥20 Gy were 3.6 (95% CI, 1.9 to 6.9) and 8.3 (95% CI, 3.9 to 17.8), respectively. When ≥20% of the colorectum volume was irradiated, IRRs increased with increasing volume. The V20 Gy IRRs were 3.8 (95% CI, 1.9 to 7.6), 4.9 (95% CI, 2.0 to 12.0), and 8.7 (95% CI, 3.5 to 21.6) for irradiated volumes of 20% to <40%, 40% to <80%, and ≥80%, respectively. The IRR was 1.8 (95% CI, 1.0 to 3.0) for doxorubicin-equivalent dose ≥250 mg/m[2], 3.7 (95% CI, 2.2 to 6.4) for cyclophosphamide-equivalent dose ≥6,000 mg/m[2], and 4.5 (95% CI, 2.0 to 10.1) for platinum dose ≥450 mg/m[2]. For procarbazine dose, the IRR was 6.3 (95% CI, 3.0 to 13.2) for 4,200 to <7,036 mg/m[2] and 9.0 (95% CI, 4.3 to 18.9) for ≥7,036 mg/m[2]. In the absence of RT, colorectal SMN rates increased with exposure to any platinum-based agent (IRR, 3.8 [95% CI, 1.1 to 12.7]), alkylator (IRR, 4.8 [95% CI, 1.6 to 14.4]), or procarbazine (IRR, 16.9 [95% CI, 5.9 to 48.8]). Colorectal SMN rates increased linearly with procarbazine dose (ERR per 1,000 mg/m[2] = 73.0 [95% CI, 26.4% to 119.6%]) and MCD (ERR per 1 Gy = 20.8 [95% CI, 9.0% to 32.5%]). Quadratic ERR models did not improve data fit compared with linear ERR models.
CONCLUSION: These RT and chemotherapy dose-response relationships can better inform contemporary RT planning for pediatric patients and surveillance guidelines for high-risk survivors.}, }
@article {pmid41032722, year = {2025}, author = {Curtis, DJ and Reynolds, J and Hill, GR}, title = {Cyclophosphamide and Cyclosporin for GVHD Prevention. Reply.}, journal = {The New England journal of medicine}, volume = {393}, number = {13}, pages = {1350-1351}, doi = {10.1056/NEJMc2511563}, pmid = {41032722}, issn = {1533-4406}, }
@article {pmid41032518, year = {2025}, author = {Corey, L}, title = {Operation Warp Speed offers a roadmap for improving the efficiency of bench to bedside medical advances.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {40}, pages = {e2502975122}, doi = {10.1073/pnas.2502975122}, pmid = {41032518}, issn = {1091-6490}, support = {UM1 AI068614-14//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, }
@article {pmid41032288, year = {2025}, author = {Blechter, B and Wang, X and Dai, J and Karsonaki, C and Shi, J and Shiraishi, K and Choi, J and Matsuo, K and Chen, TY and Hung, RJ and Chen, K and Shu, XO and Kim, YT and Choudhury, PP and Williams, J and Landi, MT and Lin, D and Zheng, W and Yin, Z and Zhou, B and Wang, J and Seow, WJ and Song, L and Chang, IS and Hu, W and Chien, LH and Cai, Q and Hong, YC and Kim, HN and Wu, YL and Wong, MP and Richardson, BD and Li, S and Zhang, T and Breeze, C and Wang, Z and Bassig, BA and Kim, JH and Albanes, D and Wong Sm, JY and Shin, MH and Chung, LP and Yang, Y and Zheng, H and Dai, H and Yatabe, Y and Zhang, XC and Kim, YC and Caporaso, NE and Chang, J and Ho, JCM and Daigo, Y and Momozawa, Y and Kamatani, Y and Kobayashi, M and Okubo, K and Honda, T and Hosgood, HD and Kunitoh, H and Watanabe, SI and Miyagi, Y and Matsumoto, S and Horinouchi, H and Tsuboi, M and Hamamoto, R and Goto, K and Takahashi, A and Goto, A and Minamiya, Y and Hara, M and Nishida, Y and Takeuchi, K and Wakai, K and Matsuda, K and Murakami, Y and Shimizu, K and Suzuki, H and Saito, M and Ohtaki, Y and Tanaka, K and Wu, T and Wei, F and Machiela, MJ and Kim, YH and Oh, IJ and Lee, VHF and Chang, GC and Chen, KY and Su, WC and Chen, YM and Seow, A and Park, JY and Kweon, SS and Gao, YT and Liu, J and Schwartz, AG and Houlston, R and Gorlov, IP and Wu, X and Yang, P and Lam, S and Tardon, A and Chen, C and Bojesen, SE and Johansson, M and Risch, A and Bickeböller, H and Ji, BT and Wichmann, HE and Christiani, DC and Rennert, G and Arnold, SM and Brennan, P and McKay, J and Field, JK and Davies, MPA and Shete, SS and Le Marchand, L and Liu, G and Andrew, AS and Kiemeney, LA and Zienolddiny-Narui, S and Grankvist, K and Cox, A and Taylor, F and Yuan, JM and Lazarus, P and Schabath, MB and Aldrich, MC and Jeon, HS and Jiang, SS and Chen, CH and Hsiao, CF and Hu, Z and Burdett, L and Yeager, M and Hutchinson, A and Hicks, B and Liu, J and Berndt, SI and Wu, W and Wang, J and Li, Y and Choi, JE and Park, KH and Sung, SW and Kang, CH and Wang, WC and Xu, J and Guan, P and Tan, W and Yu, CJ and Yang, G and Sihoe, ADL and Choi, YY and Park, IK and Hung, HH and Vermeulen, RCH and Cheng, I and Wu, J and Tsai, FY and Chan, JKC and Li, J and Lin, HC and Liu, J and Song, B and Sawada, N and Yamaji, T and Wyatt, K and Ma, H and Zhu, M and Wang, Y and Qi, T and Li, X and Ren, Y and Chao, A and Iwasaki, M and Zhu, J and Wu, G and Chen, CY and ScD, CC and Yang, PC and Stevens, VL and Fraumeni, JF and Lin, K and Walters, RG and Chen, Z and Chatterjee, N and Gorlova, OY and Amos, CI and Shen, H and Hsiung, CA and Chanock, SJ and Rothman, N and Kohno, T and Lan, Q and Zhang, H}, title = {Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf272}, pmid = {41032288}, issn = {1460-2105}, abstract = {BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction.
METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates.
RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier.
CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.}, }
@article {pmid41031719, year = {2025}, author = {Nizam, A and Nguyen, CB and Li, J and Zabor, EC and Msaouel, P and Jiang, CY and Alhalabi, O and Oh, E and Davidsohn, MP and Epstein, IB and Bakaloudi, DR and Talukder, R and Jindal, T and Taylor, AK and Glover, MJ and Khaki, AR and Lemke, E and Mabey, H and Abuqayas, B and Jang, A and Brown, JR and Evans, ST and Pywell, C and Basu, A and Bilen, MA and Barata, PC and Zakharia, Y and Milowsky, MI and Kilari, D and Hoimes, CJ and Shah, SA and Emamekhoo, H and Davis, NB and Gupta, S and Grivas, P and Bellmunt, J and Campbell, MT and Alva, AS and Koshkin, VS}, title = {Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study.}, journal = {Cancer medicine}, volume = {14}, number = {19}, pages = {e71284}, pmid = {41031719}, issn = {2045-7634}, mesh = {Humans ; Male ; Female ; Aged ; Retrospective Studies ; Middle Aged ; *Antibodies, Monoclonal/adverse effects ; Aged, 80 and over ; *Immunoconjugates/adverse effects/therapeutic use/administration & dosage ; *Urologic Neoplasms/drug therapy/mortality/pathology ; *Carcinoma, Transitional Cell/drug therapy/mortality/pathology ; Treatment Outcome ; *Antineoplastic Agents, Immunological/adverse effects ; *Urinary Bladder Neoplasms/drug therapy/mortality/pathology ; }, abstract = {INTRODUCTION: Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data and no validated predictive biomarkers. Retrospective studies suggest higher objective response rates (ORR) among patients developing EV-related dermatologic toxicities, but survival implications remain unclear. This analysis assessed the safety of EV monotherapy and the impact of dermatologic and neurologic toxicities on efficacy outcomes in a multi-institutional cohort.
MATERIALS AND METHODS: UNITE is a multicenter, retrospective study across 16 US sites of patients with aUC treated with targeted agents, including EV. Primary endpoints were the incidence of EV treatment-related adverse events (TRAEs, any grade) and TRAE-related treatment modifications. Secondary endpoints included a comparison of ORR, progression-free survival (PFS), and overall survival (OS) between patients with and without dermatologic toxicities and neuropathy. To reduce immortal time bias, Cox regression models incorporated TRAEs as time-dependent covariates to adjust for EV treatment duration as well as Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, and liver metastases.
RESULTS: Between 2018 and 2023, 485 patients with aUC received > 1 dose of EV monotherapy. Most (67%) received > 2 prior therapy lines. Any grade TRAEs occurred in 77%, most frequently neuropathy (36%) and dermatologic toxicities (27%); 57% required treatment modification and 21% discontinued EV, primarily due to neuropathy (9%) and fatigue (3%). Patients with dermatologic toxicities and neuropathy had higher ORR (56% vs. 42%; p = 0.007 and 64% vs. 35%; p < 0.0001, respectively). Neuropathy was independently associated with improved OS (HR 0.66; 95% CI 0.50-0.87; p = 0.002); dermatologic TRAEs were not associated with PFS or OS benefit.
CONCLUSIONS: EV safety outside clinical trials was consistent with prior reports, with no new signals. Treatment modifications were most often due to neuropathy, dermatologic toxicities, and fatigue. Both dermatologic toxicities and neuropathy correlated with higher ORR, but only neuropathy was independently associated with improved OS.}, }
@article {pmid41031512, year = {2025}, author = {Chalitsios, CV and Markozannes, G and Aglago, EK and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Dimou, N and Drew, DA and French, AJ and Georgeson, P and Giannakis, M and Gruber, SB and Gunter, MJ and Harrison, TA and Hoffmeister, M and Hsu, L and Huang, WY and Hullar, MA and Huyghe, JR and Lynch, BM and Moreno, V and Murphy, N and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Qu, C and Schmit, SL and Steinfelder, RS and Sun, W and Thomas, CE and Toland, AE and Trinh, QM and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Schoen, RE and Woods, MO and Brenner, H and Andreson, L and Pellatt, AJ and Peters, U and Phipps, AI and Tsilidis, KK}, title = {Physical activity and molecular subtypes of colorectal cancer: a pooled observational analysis and mendelian randomisation study.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf095}, pmid = {41031512}, issn = {2515-5091}, abstract = {BACKGROUND: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.
METHODS: Pooled observational (ncases=5,386, ncontrols=6,798; nstudies=5) and genome-wide association data (ncases=8,178, ncontrols=10,472; nstudies=5) were utilised. We used multivariable logistic regression models and Mendelian randomisation (MR) to assess the association between physical activity and the risk of CRC subtypes defined by individual tumour markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests.
RESULTS: In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (ORObs-per 1SD=0.94, 95%CI 0.90-0.97), with an association that was stronger in males (ORObs-per 1SD=0.91, 95%CI 0.87-0.96) than in females (ORObs-per 1SD=0.97, 95%CI 0.91-1.03) (Pinteraction=0.04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or MR analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC.
CONCLUSIONS: Our findings suggest that physical activity is not differentially associated with the four major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.}, }
@article {pmid41028200, year = {2025}, author = {Cheung, KJ and Horne-Badovinac, S}, title = {Publisher Correction: Collective cell migration modes in development, tissue repair and cancer.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41580-025-00911-7}, pmid = {41028200}, issn = {1471-0080}, }
@article {pmid41028170, year = {2025}, author = {Bot, A and Scharenberg, A and Friedman, K and Guey, L and Hofmeister, R and Andorko, JI and Klichinsky, M and Neumann, F and Shah, JV and Swayer, AJ and Trudeau, K and Weissman, D and Stephan, MT and Buchholz, CJ and June, CH}, title = {In vivo chimeric antigen receptor (CAR)-T cell therapy.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, pmid = {41028170}, issn = {1474-1784}, abstract = {Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient's body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies - including RNA delivered by lipid nanoparticles and engineered viral vectors - and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus.}, }
@article {pmid41027579, year = {2025}, author = {Cheng, GS and Campbell, AP and Xie, H and Ogimi, C and Waghmare, A and Kuypers, J and Nichols, WG and Carpenter, P and Corey, L and Callais, C and Sandmaier, BM and Stevens-Ayers, T and Jerome, KR and Chien, JW and Leisenring, WM and Englund, JA and Boeckh, M}, title = {Respiratory Virus Infections and Pulmonary Impairment after Allogeneic Hematopoietic Cell Transplantation.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf503}, pmid = {41027579}, issn = {1537-6613}, abstract = {BACKGROUND: Respiratory virus infections (RVI) are common after hematopoietic cell transplantation (HCT), but their effect on pulmonary outcomes, including bronchiolitis obliterans syndrome (BOS), and mortality is poorly defined.
METHODS: Prospective cohort study of 471 allogeneic HCT recipients transplanted in the pre-COVID-19 pandemic era in an academic cancer center. Participants were prospectively followed for one year with serial handheld spirometry, symptom questionnaires, and multiplex 11-virus PCR. Pulmonary function testing occurred at recommended intervals. Cox proportional hazard and generalized estimating equation models were used to estimate associations between RVI and weekly spirometry with late airflow obstruction (AFO), BOS, and overall mortality.
RESULTS: The one-year cumulative incidence of at least one RVI was 62%; lower respiratory tract disease (LRTD) occurred in 7.6% of patients. Late AFO developed in 15.6% of patients and BOS in 3.9% of patients. Any symptomatic viral upper respiratory tract infections (URTI) were associated with AFO (adjusted HR [aHR] 1.87, 95% CI 1.11-3.16) and BOS (aHR 2.65, 95% CI 1.02-6.91). Individually, PIV-3 URTI were associated with AFO (aHR 2.83, 95% CI 1.01-7.97) and RSV URTI were associated with BOS (aHR 6.32, 95% CI 2.04-19.6). Short-term airflow decline was associated with AFO. Any LRTD (aHR 3.49, 95% CI 2.18-5.57), as well as symptomatic influenza URTI (aHR 2.68, 95% CI 1.52-4.72), were associated with mortality.
CONCLUSIONS: RVI after HCT, particularly those caused by RSV, PIV-3 and influenza, increase the risk of pulmonary impairment and mortality. These infections should be targeted for specific anti-viral approaches and intensified monitoring for late onset pulmonary disease.}, }
@article {pmid41027557, year = {2025}, author = {Spellman, SR and Xu, K and Oloyede, T and Ahn, KW and Akhtar, OS and Bolon, YT and Broglie, L and Bloomquist, J and Bupp, C and Chen, M and Devine, SM and Jurdi, NE and Hamadani, M and Hengen, M and Huppler, AH and Jaglowski, S and Kuxhausen, M and Lee, SJ and Moskop, A and Page, KM and Pasquini, MC and Pérez, WS and Phelan, R and Rizzo, D and Saber, W and Stefanski, HE and Steinert, P and Tuschl, E and Visotcky, A and Vogel, R and Auletta, JJ and Shaw, BE and Allbee-Johnson, M}, title = {Corrigendum to: Current Activity Trends and Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy - A Report from the CIBMTR, Transplantation and Cellular Therapy, 31:8, August 2025, 505-532; Article Number: JTCT-S-25-00377.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.001}, pmid = {41027557}, issn = {2666-6367}, }
@article {pmid40924543, year = {2025}, author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A}, title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.}, journal = {Bioinformatics (Oxford, England)}, volume = {41}, number = {10}, pages = {}, doi = {10.1093/bioinformatics/btaf488}, pmid = {40924543}, issn = {1367-4811}, support = {//Research Foundation-Flanders/ ; }, mesh = {*Software ; *Phylogeny ; *SARS-CoV-2/genetics/classification ; Bayes Theorem ; *Ebolavirus/genetics/classification ; Algorithms ; Humans ; *Computational Biology/methods ; COVID-19/virology ; }, abstract = {SUMMARY: In Bayesian phylogenetic and phylodynamic studies, it is common to summarize the posterior distribution of trees with a time-calibrated summary phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel summary tree method-the highest independent posterior subtree reconstruction, or (HIPSTR)-contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both summary trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the summary tree.
RESULTS: HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 datasets show that HIPSTR yields summary trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥0.95) as well as a large number of clades with moderate to high posterior probability (≥50%), whereas HIPSTR-in particular its majority-rule extension MrHIPSTR-achieves near-perfect performance in this respect. HIPSTR and MrHIPSTR also exhibit favourable computational performance over MCC in TreeAnnotator X. Comparison to the recent CCD0-MAP algorithm yielded mixed results and requires a more in-depth investigation in follow-up studies.
TreeAnnotator X is available as part of the BEAST X (v10.5.0) software package, available at https://github.com/beast-dev/beast-mcmc/releases, and on Zenodo (DOI: https://doi.org/10.5281/zenodo.4895234).}, }
@article {pmid41027157, year = {2025}, author = {Dominguez Islas, CP and Magaret, CA and Molitor, C and Serebryannyy, L and Narpala, S and Castro, M and Posavad, CM and Roberts, PC and Lyke, KE and Atmar, RL and Janes, H and Deming, ME}, title = {SARS-CoV-2 spike sequence-based distance as a marker of binding antibody response to COVID-19 vaccines.}, journal = {Vaccine}, volume = {65}, number = {}, pages = {127738}, doi = {10.1016/j.vaccine.2025.127738}, pmid = {41027157}, issn = {1873-2518}, abstract = {COVID-19 vaccines based on ancestral SARS-CoV-2 have proven highly effective at reducing the risk of illness, especially severe disease. Both binding and neutralizing antibodies have been demonstrated to be strong predictors of the level of vaccine efficacy (VE). Both VE and vaccine-induced antibody responses have been shown to be lower against emergent SARS-CoV-2 viruses; therefore, predicting COVID-19 VE against emergent viruses is critical for decision-making regarding the composition of new vaccines. The data needed to enable such prediction are unclear. We report on 728 individuals without prior SARS-CoV-2 infection who received primary vaccination with ancestral-virus-based mRNA and vector-based COVID-19 vaccines and who were boosted in a homologous or heterologous fashion with mRNA, vector, or protein-based COVID-19 vaccines including a bivalent B.1.351 mRNA vaccine. Post-prime and post-boost binding antibody responses were used to evaluate the extent and drivers of variability in these responses to 22 SARS-CoV-2 Spike antigens from viruses that emerged between 2020 and 2021. We evaluated how well proteomic distance between the vaccine and assay Spike antigen predicted the vaccine-induced antibody response. Following primary vaccination, antibody responses varied across Spike antigens and were, on average, 36 % lower per 10-amino acid (AA) difference between the vaccine and assay Spike antigen (95 % CI: 30 % to 43 %). The geometric mean antibody response to a given antigen was nearly perfectly predicted by the sequence-based distance of the antigen to the vaccine. Post-boost responses were less variable across antigens and weakly associated with Spike distance (17 % lower per 10-AA difference; 95 % CI: 14 % to 20 %). The high variability in binding antibodies across individuals was only partially explained by participant characteristics. Given that populations now have experienced multiple rounds of prior vaccination and infection, measurement of vaccine-induced antibody responses from representative populations will likely be needed to predict the efficacy of COVID-19 vaccines against future strains.}, }
@article {pmid41025350, year = {2025}, author = {Jakubek, YA and Smith, AP and Leng, XI and Hall, ME and Ezzat, D and Pershad, Y and Collins, JM and Uddin, MM and Fardo, DW and Natarajan, P and Bick, AG and Kitzman, JO and Honigberg, MC and Hayden, KM and Manson, JE and Jaiswal, S and Whitsel, EA and Reiner, AP}, title = {Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women's Health Initiative Memory Study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70737}, pmid = {41025350}, issn = {1552-5279}, support = {//WHI/ ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Cognitive Dysfunction/genetics/epidemiology ; Aged ; *Clonal Hematopoiesis/genetics ; Risk Factors ; Women's Health ; *Dementia/genetics/epidemiology ; Aged, 80 and over ; Middle Aged ; Proportional Hazards Models ; Incidence ; }, abstract = {INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) confers an increased risk of several chronic aging-related diseases. Paradoxically, CHIP was associated with lower risk of dementia in recent studies.
METHODS: We examined associations between baseline CHIP and incident mild cognitive impairment (MCI) and/or probable dementia in the Women's Health Initiative Memory Study. CHIP was detected using blood-based targeted sequencing. Cox proportional hazards models examined time to onset of cognitive impairment, adjusting for traditional risk factors.
RESULTS: Using a conventional variant allele fraction (VAF) threshold of 2%, CHIP was not associated with incident cognitive impairment. The presence of larger CHIP clone (VAF ≥ 8%) was associated with a lower incidence of adjudicated probable dementia (hazard ratio = 0.62 [95% confidence interval = 0.41 to 0.94], p = 0.025), while the association with the composite outcome MCI/probable dementia was weaker and overlapped 1.0.
DISCUSSION: The association of CHIP with lower risk of cognitive impairment in postmenopausal women may be dependent on VAF and impairment severity.
HIGHLIGHTS: The WHIMS comprises ∼5000 postmenopausal women, followed for up to 25 years. CHIP was associated with reduced risk of adjudicated probable dementia in WHIMS. Large CHIP clones (> 8% VAF), but not small clones (<8% VAF), showed an association. CHIP was not associated with MCI in the WHIMS cohort.}, }
@article {pmid41024277, year = {2025}, author = {Gafken, PR and Paczesny, S}, title = {Blood proteomics for quantitative biomarkers of cellular therapies.}, journal = {Biomarker research}, volume = {13}, number = {1}, pages = {120}, pmid = {41024277}, issn = {2050-7771}, support = {P30CA015704/CA/NCI NIH HHS/United States ; R01CA168814/CA/NCI NIH HHS/United States ; R21AI178981//National Institute of Allergy and Infectious Diseases/ ; R01HL158096/HL/NHLBI NIH HHS/United States ; }, abstract = {Cellular therapies for several blood cancers particularly of lymphoid origin have made remarkable leaps forward. In parallel, blood proteomics, specifically quantitative proteomics, has been a powerful tool for identifying and quantifying protein biomarkers associated with cellular therapies, providing insights into treatment efficacy and toxicity. Both mass spectrometry (MS)-based proteomics and large-scale affinity-based platforms such as Olink and SomaScan have been increasingly implemented in research and clinical laboratories to identify and quantify candidate biomarkers in the blood. Biomarkers are used for risk stratification, early diagnosis, prognosis, and for treatment response prediction and monitoring in context of treatment efficacy and toxicity. These biomarkers might facilitate timely and selective therapeutic intervention and understand pathogenesis mechanisms of responses and adverse events. They are anticipated to undergo faster transition from bench to bedside soon. This review article summarizes recent technical progresses in clinical proteomics. The review also provides current information on validated biomarkers in the field of cellular therapies.}, }
@article {pmid41022768, year = {2025}, author = {Liu, P and Li, JJ}, title = {mcRigor: a statistical method to enhance the rigor of metacell partitioning in single-cell data analysis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8602}, pmid = {41022768}, issn = {2041-1723}, support = {R35GM140888//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1846216//NSF | BIO | Division of Biological Infrastructure (DBI)/ ; 2113754//NSF | Directorate for Mathematical & Physical Sciences | Division of Mathematical Sciences (DMS)/ ; 2022-249355//Silicon Valley Community Foundation (SVCF)/ ; }, mesh = {*Single-Cell Analysis/methods ; Algorithms ; Humans ; RNA-Seq ; Reproducibility of Results ; Gene Expression Profiling/methods ; *Computational Biology/methods ; Software ; }, abstract = {In single-cell data analysis, addressing sparsity often involves aggregating the profiles of homogeneous single cells into metacells. However, existing metacell partitioning methods lack checks on the homogeneity assumption and may aggregate heterogeneous single cells, potentially biasing downstream analysis and leading to spurious discoveries. To fill this gap, we introduce mcRigor, a statistical method to detect dubious metacells, which are composed of heterogeneous single cells, and optimize the hyperparameter(s) of a metacell partitioning method. The core of mcRigor is a feature-correlation-based statistic that measures the heterogeneity of a metacell, with its null distribution derived from a double permutation scheme. As an optimizer for existing metacell partitioning methods, mcRigor has been shown to improve the reliability of discoveries in single-cell RNA-seq and multiome (RNA + ATAC) data analyses, such as uncovering differential gene co-expression modules, enhancer-gene associations, and gene temporal expression. Moreover, mcRigor enables benchmarking and selection of the most suitable metacell partitioning method with optimized hyperparameter(s) tailored to a specific dataset, ensuring reliable downstream analysis. Our results indicate that among existing metacell partitioning methods, MetaCell and SEACells consistently outperform MetaCell2 and SuperCell, albeit with the trade-off of longer runtimes.}, }
@article {pmid41021636, year = {2025}, author = {Giersch, RM and Sevigny, JK and Weinandt, SA and Mayo, C and Garrett, FES and Tindbaek, K and Yonemitsu, MA and Hart, SFM and Metzger, MJ}, title = {Variation in natural infection outcomes and cancer cell release from soft-shell clams (Mya arenaria) with bivalve transmissible neoplasia.}, journal = {PLoS pathogens}, volume = {21}, number = {9}, pages = {e1013537}, doi = {10.1371/journal.ppat.1013537}, pmid = {41021636}, issn = {1553-7374}, support = {R01 CA255712/CA/NCI NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; }, abstract = {Bivalve transmissible neoplasias (BTNs) are leukemia-like cancers found in at least 10 bivalve species, in which the cancer cells themselves transfer from one individual to another, spreading as an unusual form of infectious disease. Before the infectious etiology was known, there were reports of lethality and outbreaks of cancer in the soft-shell clam (Mya arenaria) on the east coast of North America. Using sensitive and specific qPCR assays, we followed the outcomes of BTN in naturally-infected soft-shell clams from Maine, USA. We observed variable outcomes, with about half of clams (9/21) progressing to high levels of cancer and death, about half exhibiting long-term non-progression (11/21), and a single animal showing regression of cancer. We also observe a significant decrease in survival in animals that progress to >10% cancer in their hemolymph, while we see no effect on survival in clams with BTN that are long-term non-progressors. As most bivalves do not physically contact each other, and BTN cells can survive in seawater, it has been proposed that BTN is spread through release of cancer cells into the water. We used qPCR to detect BTN-specific sequences in environmental DNA (eDNA) in the tanks of animals throughout this experiment. We show that BTN-specific eDNA (likely from released cancer cells) can be detected in tank water of most clams with >24% cancer in their hemolymph, but not below this level. This detection of BTN eDNA is variable and occurs in bursts, but in clams with >24% cancer, the detection of BTN eDNA correlates with progression of the cancer in the hemolymph. This study demonstrates the lethality of BTN, but the observation that about half of clams with BTN do not progress to death provides evidence suggesting that there may be a block to the progression of BTN in a large portion of clams in a population with this enzootic disease. This study also further supports the hypothesis that BTN cells transmit through seawater and provides insights into the mechanisms of the transmission dynamics.}, }
@article {pmid41021323, year = {2025}, author = {Etzioni, R and Owens, L}, title = {Learning from prostate cancer statistics.}, journal = {CA: a cancer journal for clinicians}, volume = {}, number = {}, pages = {}, doi = {10.3322/caac.70037}, pmid = {41021323}, issn = {1542-4863}, }
@article {pmid41019149, year = {2025}, author = {Mohty, M and Banerjee, R}, title = {Networking for a successful career in clinical hematology: a strategic approach.}, journal = {Clinical hematology international}, volume = {7}, number = {3}, pages = {20-23}, pmid = {41019149}, issn = {2590-0048}, abstract = {Networking is fundamental to career development in clinical hematology, providing avenues for knowledge exchange, collaborations, and professional growth. This manuscript examines specific strategies for networking within this specialized field, detailing effective platforms, strategies, overcoming challenges, and illustrating real-world success stories. References to key studies and expert opinions underscore the importance of building a robust professional network through in-person and online activities. An extensive review of literature highlights how networking contributes to scientific collaboration, mentorship, career opportunities, and the dissemination of cutting-edge hematological research.}, }
@article {pmid41018806, year = {2025}, author = {Li, S and Gilbert, PB and Duan, R and Luedtke, A}, title = {Data fusion using weakly aligned sources.}, journal = {Journal of the American Statistical Association}, volume = {}, number = {}, pages = {}, pmid = {41018806}, issn = {0162-1459}, support = {DP2 LM013340/LM/NLM NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {We introduce a new data fusion method that utilizes multiple data sources to estimate a smooth, finite-dimensional parameter. Most existing methods only make use of fully aligned data sources that share common conditional distributions of one or more variables of interest. However, in many settings, the scarcity of fully aligned sources can make existing methods require unduly large sample sizes to be useful. Our approach enables the incorporation of weakly aligned data sources that are not perfectly aligned, provided their degree of misalignment is known up to finite-dimensional parameters. We quantify the additional efficiency gains achieved through the integration of these weakly aligned sources. We characterize the semiparametric efficiency bound and provide a general means to construct estimators achieving these efficiency gains. We illustrate our results by fusing data from two harmonized HIV monoclonal antibody prevention efficacy trials to study how a neutralizing antibody biomarker associates with HIV genotype.}, }
@article {pmid41018563, year = {2025}, author = {Williamson, BD and King, D and Huang, Y}, title = {Practical Considerations for Variable Screening in the Super Learner.}, journal = {The New England Journal of Statistics in Data Science}, volume = {}, number = {}, pages = {}, pmid = {41018563}, issn = {2693-7166}, support = {S10 OD028685/OD/NIH HHS/United States ; R01 GM106177/GM/NIGMS NIH HHS/United States ; R01 CA277133/CA/NCI NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {Estimating a prediction function is a fundamental component of many data analyses. The super learner ensemble, a particular implementation of stacking, has desirable theoretical properties and has been used successfully in many applications. Dimension reduction can be accomplished by using variable screening algorithms (screeners), including the lasso, within the ensemble prior to fitting other prediction algorithms. However, the performance of a super learner using the lasso for dimension reduction has not been fully explored in cases where the lasso is known to perform poorly. We provide empirical results that suggest that a diverse set of candidate screeners should be used to protect against poor performance of any one screener, similar to the guidance for choosing a library of prediction algorithms for the super learner. These results are further illustrated through the analysis of HIV-1 antibody data.}, }
@article {pmid40711480, year = {2025}, author = {Wesolowski, R and Rugo, HS and Specht, JM and Han, HS and Kabos, P and Vaishampayan, U and Wander, SA and Gogineni, K and Spira, A and Schott, AF and Abu-Khalaf, M and Mutka, SC and Suzuki, S and Sullivan, B and Gorbatchevsky, I and Layman, RM}, title = {Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {19}, pages = {4040-4048}, doi = {10.1158/1078-0432.CCR-25-0992}, pmid = {40711480}, issn = {1557-3265}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/genetics/metabolism/mortality ; Letrozole/administration & dosage ; Pyridines/administration & dosage/adverse effects ; Piperazines/administration & dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration & dosage ; Receptor, ErbB-2/metabolism/genetics ; Middle Aged ; Receptors, Estrogen/metabolism ; Aged ; Receptors, Progesterone/metabolism ; Adult ; Aged, 80 and over ; Class I Phosphatidylinositol 3-Kinases/genetics ; }, abstract = {PURPOSE: Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor-positive (HR+)/HER2- breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2- advanced breast cancer. Simultaneous blockade of the estrogen receptor, CDK4/6, and PAM pathways may optimize antitumor control in the treatment-naïve advanced breast cancer setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2- advanced breast cancer.
PATIENTS AND METHODS: Treatment-naïve patients from a phase Ib study with HR+/HER2- advanced breast cancer treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival.
RESULTS: Of 41 patients, all had stage IV disease, 93% had measurable disease, 78% had visceral metastases, and 22% had detectable PIK3CA mutations. The objective response rate was 79% in patients with evaluable disease (N = 33). The median duration of response was 48 months for confirmed responders. The median PFS was 48.4 months, and the median overall survival was 77.3 months. The overall response rate and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).
CONCLUSIONS: Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for advanced breast cancer. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2- advanced breast cancer.}, }
@article {pmid41017661, year = {2025}, author = {Lasowski, P and Tollefson, D and Menacho, L and DePierro, J and Duerr, A}, title = {High prevalence of pain and mental health conditions amongst people well-established in HIV care: results of a cross-sectional survey in Lima, Peru.}, journal = {AIDS care}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/09540121.2025.2562242}, pmid = {41017661}, issn = {1360-0451}, abstract = {People living with HIV (PLWH) are at risk for mental health (MH) disorders and pain, but this burden is largely unknown in low/middle-income countries. From February-October 2023, we conducted a cross-sectional survey at a large HIV clinic in Lima, Peru to quantify the prevalence of MH disorders and pain amongst PLWH established in care and to explore relationships between MH and well-managed HIV. At clinic visits, PLWH were invited to complete validated measures for depression, post-traumatic stress disorder (PTSD), alcohol use disorder (AUD), and pain (PHQ-8, PCL5, AUDIT-C, and BPISF). We abstracted data on treatment and viral suppression from medical charts. We calculated the prevalence of depression (PHQ8 ≥ 10), PTSD (PCL-5 ≥ 30), AUD (AUDIT-C ≥ 4 for men, ≥ 3 for women), and pain severity/interference (none, mild, moderate, or severe). We conducted logistic regression analyses to determine associations between MH/pain and viral suppression. Among 397 participants, 32% (95% CI: 27-37%) reported AUD, 21% (17-26%) reported depression, and 13% (9.5-16%) reported PTSD; 14% (11-18%) and 12% (9.3-16%) reported moderate/severe pain intensity and interference, respectively. There were no associations between MH/pain and viral suppression. High levels of MH disorders and pain among PLWH established in care suggest screening is needed for all PLWH, even those with well-controlled HIV.}, }
@article {pmid41017648, year = {2025}, author = {Hyde, ET and Bandoli, GE and Zou, J and Crespo, NC and Parada, H and Evenson, KR and Howard, AG and LaMonte, MJ and Stefanick, ML and Tinker, LF and Haring, B and Manson, JE and Lee, IM and LaCroix, AZ}, title = {Prospective associations between accelerometer-measured physical activity, sedentary behavior, and healthy longevity: the Women's Health Accelerometry Collaboration.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glaf206}, pmid = {41017648}, issn = {1758-535X}, abstract = {BACKGROUND: The influence of physical activity (PA) and sedentary behavior (SB) on survival to late age with intact mobility is unclear. This study investigated associations between accelerometer-measured daily PA, SB, and survival to age 90 birthyear with and without intact mobility in the Women's Health Accelerometry Collaboration (WHAC).
METHODS: Postmenopausal U.S. women aged 78-89 years without mobility disability were followed for an average of 6.1 years. At age 90 birthyear, participants were categorized as: (1) surviving with intact mobility, (2) surviving with mobility disability, or (3) deceased. Participants wore an accelerometer on the hip for up to 7 days at baseline from 2011-2015. Covariate-adjusted multinomial logistic regression models estimated odds ratios (ORs) of PA (light, moderate-to-vigorous [MVPA], total, steps) and SB (sitting time, mean sitting bout duration) with survival outcomes relative to dying.
RESULTS: Among 2,656 women (mean baseline age 83.1 years), 62.8% survived with intact mobility, 22.3% with mobility disability, and 15.0% died. Compared to dying before age 90, the OR (95% confidence intervals [CI]) for every 1-SD increment in accelerometer variables and survival with intact mobility were 1.36 (1.20, 1.54) for light PA, 1.69 (1.47, 1.96) for MVPA, 1.51 (1.33, 1.71) for total PA, 1.75 (1.51, 2.03) for steps, 0.70 (0.61, 0.80) for sitting time, and 0.79 (0.70, 0.89) for sitting bouts. Similar, weaker trends were present for mobility disability.
CONCLUSIONS: These findings corroborate the potential role of increasing physical activity in preserving physical functioning as an important element of healthy longevity.}, }
@article {pmid41017259, year = {2025}, author = {Sharma, P and George, N and Srivastava, D and Chow, EJ and Alderfer, MA and Leisenring, W and Long, KA and Lown, AE and Oeffinger, KC and Zeltzer, LK and Armstrong, GT and Krull, KR and Brinkman, TM and Buchbinder, D}, title = {Psychosocial Health and Chronic Health Conditions Among Bereaved Siblings: A Report From the Childhood Cancer Survivorship Study (CCSS).}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e32076}, doi = {10.1002/pbc.32076}, pmid = {41017259}, issn = {1545-5017}, support = {CA55727/CA/NCI NIH HHS/United States ; //to St. Jude Children's Research Hospital/ ; CA21765//Cancer Center Support/ ; //American Lebanese-Syrian Associated Charities/ ; }, abstract = {OBJECTIVE: To compare psychosocial health and chronic health conditions (CHCs) in bereaved and non-bereaved adult siblings impacted by childhood cancer and to identify predictors of emotional distress and health-related quality of life among bereaved siblings.
METHODS: A total of 4558 adult siblings (733 bereaved; 3825 non-bereaved) of 5-year survivors of childhood cancer completed measures of emotional distress (Brief Symptom Inventory [BSI]-18) and health-related quality of life (Medical Outcomes Survey Short Form [SF]-36) and reported their social attainment milestones (i.e., educational attainment, employment, and marital status). CHCs' burden was classified as none/low versus medium/high/very severe. Cancer-associated complications prior to the patient's death, sibling age at bereavement, and social attainment variables were examined as predictors of emotional distress and health-related quality of life among bereaved siblings using multivariable modified Poisson regression.
RESULTS: Bereaved siblings in this sample reported excellent psychosocial health long term (e.g., depressive symptoms 6.5%, somatization 4.4%, anxiety 3.5%). Bereaved siblings had an elevated risk of depression (relative risk [RR] 1.53; 1.10-2.13, p = 0.01), reduced social quality of life (RR 1.35; 1.00-1.82, p = 0.05), diminished educational attainment, and greater CHC burden than non-bereaved siblings. No differences were observed for other subscales or social attainment outcomes. Among bereaved siblings, risk factors for depression included male sex (RR 0.42; 0.19-0.93, p = 0.05), never being married (RR 3.02; 1.45-6.28, p = 0.05), and greater CHC burden (RR 2.42; 1.18-4.99, p = 0.05). Risk factors for poor social functioning included unemployment (RR 2.24; 1.12-4.45, p = 0.05) and never being married (RR 2.16; 1.22-3.82, p = 0.05).
CONCLUSION: Bereaved siblings report excellent psychosocial health long-term and demonstrate only a marginally elevated risk of experiencing symptoms of depression and poor social quality of life compared to non-bereaved siblings.}, }
@article {pmid41016483, year = {2025}, author = {K, R and Ac, H and K, B and Je, G and A, A and G, O and D, M and S, K and Z, N and M, F and M, S and F, F and Mh, A and P, S and Y, B and F, L and C, P and K, M and I, M and J, G and A, B and M, S and A, D and K, K and A, L and B, N and Ks, B and K, R and S, C}, title = {Late Effects After Haematopoietic Stem Cell Transplantation in patients with HLH: A Histiocyte Society, PDWP, IEWP and TCWP EBMT Study.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2025.09.014}, pmid = {41016483}, issn = {1097-6825}, abstract = {BACKGROUND: Hematopoietic stem cell transplantation is the only curative treatment in primary hemophagocytic lymphohistiocytosis. However, hematopoietic stem cell transplantation is associated with a wide range of late effects.
OBJECTIVE: Characterization of the long-term outcome and late effects following hematopoietic stem cell transplantation in primary hemophagocytic lymphohistiocytosis.
METHODS: 274 children with pHLH from the EBMT registry who underwent allogeneic hematopoietic stem cell transplantation between 2004 and 2015 were included. Multivariable logistic regression models were performed to evaluate the adjusted impact of baseline variables on CNS and hormonal late effects, respectively.
RESULTS: A broad spectrum of late effects was identified, with neurological (31%) and hormonal (34.8%) complications being the most prevalent. Chemotherapy (HLH-94/HLH04) before hematopoietic stem cell transplantation was identified as a significant risk factor for endocrinological late effects (p=0.03), highlighting a novel aspect not previously reported. The presence of neurological abnormality at diagnosis was an independent risk factor for neurological late effects (p<0.001) as was incomplete remission status at time of HCT (p=0.04).
CONCLUSION: Hematopoietic stem cell transplantation has significantly improved survival in primary hemophagocytic lymphohistiocytosis patients, however survivors still face significant risks of late effects.}, }
@article {pmid41015745, year = {2025}, author = {Samady, H and Drangsholt, M and Sebastian, G and Dean, D}, title = {Osteonecrosis of the jaw as a possible adverse effect of tocilizumab.}, journal = {Oral surgery, oral medicine, oral pathology and oral radiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.oooo.2025.08.011}, pmid = {41015745}, issn = {2212-4411}, abstract = {We report the case of a 79-year-old female with a complex medical history, presenting with recurrent gingival swelling, progressive gingival hyperplasia, and osteonecrosis of the jaw potentially associated with tocilizumab. Oral complications developed in close proximity to diagnosis of chronic myelomonocytic leukemia, complicating diagnosis and management.}, }
@article {pmid41015336, year = {2025}, author = {Shoenbill, KA and Ostroff, JS and Taylor, KL and Jafarinia, A and Minion, M and Chichester, LA and Omernik, B and McCall, M and Yeung, S and Wiseman, K and Chen, LS and Salloum, RG and Warren, G}, title = {Recommendations for Standardization of Tobacco Use Treatment Data.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2025.09.1756}, pmid = {41015336}, issn = {1556-1380}, abstract = {INTRODUCTION: Although there is widespread acceptance of the importance of assessing and treating tobacco use in cancer care settings, there is much variation in the documentation and reporting of metrics relevant to tobacco treatment. The Cancer Center Cessation Initiative (C3I), as part of NCI's Cancer Moonshot, convened a Metrics Standardization Workgroup to develop a data dictionary and make recommendations for standardized quality measurement, program evaluation, and tobacco treatment program development.
METHODS: A multidisciplinary workgroup of 12 subject matter experts was convened to deliberate and standardize definitions for tobacco assessment and treatment utilization metrics. Decisions on which data elements to include were informed by clinical guidelines, literature reviews, and workgroup members' expertise. Consensus was reached when all members agreed that the proposed metric was clear, clinically relevant, and could be abstracted and reported.
RESULTS: The group considered metrics in the following categories: (1) patient identification, screening, and referral, (2) tobacco treatment process metrics, and (3) treatment outcomes. We developed a tobacco screening, referral and engagement workflow, and a data library for the following terms: patient population, screening rate, tobacco use prevalence, referral rate, reach, unsuccessful reach attempts, enrollment, treatment engagement, and counseling dose. Outcome metrics (i.e., varied "quit rate" terms) were collated and defined.
DISCUSSION: The proposed standardized data definitions can be used to improve communication and measure effectiveness for tobacco use treatment, research, operational performance, policy, quality improvement, and guideline development.}, }
@article {pmid41014345, year = {2025}, author = {Zhao, LP and Papadopoulos, GK and McFarland, BJ and Skyler, JS and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, Å}, title = {Correction: Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.}, journal = {Diabetologia}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00125-025-06557-6}, pmid = {41014345}, issn = {1432-0428}, }
@article {pmid41014159, year = {2025}, author = {Fernandez Turizo, MJ and Velez, MA and Glenn, B and Cummings, AL and Segarra-Vazquez, B and Gorbatov, S and Park, SJ and Shen, C and Lind-Lebuffe, JP and Unger, JM and Garon, EB}, title = {Characteristics of clinical trials associated with appeal and return on investment to participants, A Review and Framework.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyaf313}, pmid = {41014159}, issn = {1549-490X}, abstract = {Despite decades of investment in clinical research infrastructure, patient participation in clinical trials remains strikingly low. In the United States, fewer than 1 in 10 adults report ever being invited to participate in a clinical trial, and among those, less than half ultimately enroll. In oncology, across all adult cancer patients, only about 8% enroll in a clinical trial, regardless of eligibility or trial availability. Active engagement of patients in cancer clinical trials substantially enhances scientific knowledge, and patient participation is required to obtain approval for novel therapeutics. Analyses focusing on evaluating if clinical trial participation improves survival for participants have yielded conflicting results. Yet, there is limited data or metrics to assess the specific attributes of oncology trials that hold greater appeal or return on investment to participants, limiting researchers' ability to determine if these factors vary across different populations. Our group demonstrated that patients with limited English proficiency were unlikely to participate in studies not sponsored by industry as compared to industry-sponsored studies. If trial participation for specific populations can differ by sponsor type, it could also differ by the trial's appeal or return on investment. While the underrepresentation of racial and ethnic minority groups in trials is attributed to multiple factors, it is possible that patients from these groups are less likely to be offered participation in studies with higher appeal or return on investment, due to systemic biases, disparities in recruitment practices and/or lack of access. In this manuscript, we propose a systematic framework for evaluating attributes of interventional oncology clinical trials, with an emphasis on the study's purpose, experimental design and investigational agent. This framework aims to pinpoint characteristics that may enhance trials' appeal or return on investment to participants and could lay a foundation for future research. This will allow investigators to assess the return on investment of appeal of studies offered across different patient populations.}, }
@article {pmid41012183, year = {2025}, author = {Pallerla, S and Kallur Siddaramaiah, L and Mundsperger, P and Katinger, D and Fauland, K and Kreismayr, G and Weik, R and Arslan, O and Shen, M and Ozorowski, G and Lee, WH and Ward, AB and Baboo, S and Diedrich, JK and Yates, JR and Paulson, JC and Blumen, T and Craig, D and Swoyer, R and Yuan, M and Stamatatos, L}, title = {GMP Manufacturing and Characterization of the HIV Booster Immunogen HxB2.WT.Core-C4b for Germline Targeting Vaccine Strategies.}, journal = {Vaccines}, volume = {13}, number = {9}, pages = {}, pmid = {41012183}, issn = {2076-393X}, support = {7E11AI093022-02/NH/NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVES: Despite progress in antiretroviral therapy, HIV remains a major global health challenge with over one million new infections annually. An effective vaccine is urgently needed. Germline-targeting immunogens show promise in initiating broadly neutralizing antibody (bNAb) precursors. This study developed a scalable, cGMP-compliant process to manufacture the HIV vaccine booster immunogen HxB2.WT.Core-C4b, a nanoparticle designed to direct bNAb precursor maturation after priming.
METHODS: A CHO cell platform was established through single-cell cloning from a high-producing stable pool. Upstream and downstream processes were optimized for scalability and yield. Three scales were tested 10 L, 40 L, and 400 L. Key parameters (pH, temperature, feeding, metabolite profiles) were systematically refined. Analytical characterization included glycosylation profiling, electron microscopy, and antigenicity testing. Viral clearance was evaluated per ICH Q5A guidelines.
RESULTS: Optimization ensured consistent yields above 130 mg/L, with titers up to 250 mg/L. The selected clone (4E22) demonstrated strong growth, viability, and reproducibility. Glycan occupancy at 18 N-linked sites, including bNAb epitopes (N276, N332), was stable across scales. Over 70% of self-assembling nanoparticle were fully assembled at the GMP level. Antigenicity and purity met cGMP release criteria. Viral clearance achieved >13-log reduction for enveloped and >7-log for non-enveloped viruses.
CONCLUSIONS: This work establishes a robust, scalable platform for HIV nanoparticle immunogens. Consistent quality and yield across scales support clinical development of HxB2.WT.Core-C4b and provide a model for other glycosylated nanoparticle vaccines. The immunogen is being evaluated in clinical study HVTN 320 (NCT06796686), enabling early testing of next-generation vaccines designed to elicit broadly neutralizing antibodies.}, }
@article {pmid41006096, year = {2025}, author = {Button, E and Zhang, ARY and Thamm, C and Chan, RJ and Charalambous, A and Ee, C and Merlo, G and McErlean, G and Anderson, BO and Kitson, AL}, title = {The Australian Cancer Plan through a Caring Life Course Lens: Moving from Cancer to Care by Placing the Person at the Center of Care.}, journal = {Seminars in oncology nursing}, volume = {}, number = {}, pages = {152020}, doi = {10.1016/j.soncn.2025.152020}, pmid = {41006096}, issn = {1878-3449}, abstract = {OBJECTIVE: We propose the Caring Life Course Theory (CLCT) as a lens that can inform and enrich national cancer policy and clinical practice. The purpose of this discussion paper is to highlight how a CLCT lens can inform the implementation of a national cancer control plan, using sections of the Australian Cancer Plan as examples-Optimal Care Pathways and the Australian Comprehensive Cancer Network.
METHODS: This discussion paper presents novel suggestions by drawing on CLCT concepts-care biographies, care networks, and self-care. Contrasting "current state" and "future state" vignettes are described to demonstrate how CLCT can help cancer policy move from cancer to care. Based on a robust theoretical lens, recommendations for policy and practice have been made at the micro, meso, and macro levels, with reflection on the nurses' role, and application to other national cancer control plans.
RESULTS: Optimal care pathways should include holistic assessments that incorporate broader histories at key clinical time points. The Australian Comprehensive Care Network should consider the holistic needs of people affected by cancer, and harness innovative approaches for how these needs can be met in a networked approach. In addition to clinical considerations, understanding of an individual's care biography, care network, and self-care can inform the delivery of high-quality cancer care. Implementation of these aspects of care will be led by nurses, supported by a multidisciplinary team.
CONCLUSIONS: A CLCT lens can help support implementation of the aspirational person-centered objectives described in the ACP. The potential exists for application of the CLCT approach to other national cancer control plans, including those in low-resource settings.
Nurses play a vital role in leading the implementation of person-centered dimensions of cancer control plans and core aspects of the CLCT approach.}, }
@article {pmid41005288, year = {2025}, author = {Symonds, LK and Davidson, NE}, title = {RecOVARY? Using anti-Müllerian hormone to predict ovarian function after anti-HER2 therapy for early breast cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf247}, pmid = {41005288}, issn = {1460-2105}, support = {//Breast Cancer Research Foundation/ ; }, }
@article {pmid41004543, year = {2025}, author = {Müller, NF and Bouckaert, RR and Wu, CH and Bedford, T}, title = {MASCOT-Skyline integrates population and migration dynamics to enhance phylogeographic reconstructions.}, journal = {PLoS computational biology}, volume = {21}, number = {9}, pages = {e1013421}, doi = {10.1371/journal.pcbi.1013421}, pmid = {41004543}, issn = {1553-7358}, abstract = {The spread of infectious diseases is shaped by spatial and temporal aspects, such as host population structure or changes in the transmission rate or number of infected individuals over time. These spatiotemporal dynamics are imprinted in the genomes of pathogens and can be recovered from those genomes using phylodynamics methods. However, phylodynamic methods typically quantify either the temporal or spatial transmission dynamics, which leads to unclear biases, as one can potentially not be inferred without the other. Here, we address this challenge by introducing a structured coalescent skyline approach, MASCOT-Skyline, that allows us to jointly infer spatial and temporal transmission dynamics of infectious diseases using Markov chain Monte Carlo inference. To do so, we model the effective population size dynamics in different locations using a non-parametric function, allowing us to approximate a range of population size dynamics. We show, using a range of different viral outbreak datasets, potential issues with phylogeographic methods. We then use these viral datasets to motivate simulations of outbreaks that illuminate the nature of biases present in the different phylogeographic methods. We show that spatial and temporal dynamics should be modeled jointly, even if one seeks to recover just one of the two. Further, we showcase conditions under which we can expect phylogeographic analyses to be biased, particularly different subsampling approaches, as well as provide recommendations on when we can expect them to perform well. We implemented MASCOT-Skyline as part of the open-source software package MASCOT for the Bayesian phylodynamics platform BEAST2.}, }
@article {pmid41004338, year = {2025}, author = {Rominger, MC and O'Brien, S and Gupta, S and Moorthi, S and McSharry, M and Kamlapurkar, S and Lowe, AR and Waldum, A and Lo, A and Duke, F and Wu, F and Headley, MB and Cromwell, E and Glabman, R and Koehne, A and Berger, AH}, title = {Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.}, journal = {Cell reports}, volume = {44}, number = {10}, pages = {116185}, doi = {10.1016/j.celrep.2025.116185}, pmid = {41004338}, issn = {2211-1247}, abstract = {Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1[M90I] variant. We show that autochthonous expression of RIT1[M90I] and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1[M90I] and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.}, }
@article {pmid41003951, year = {2025}, author = {Iyer, HS and Karasaki, S and Yi, L and Hswen, Y and James, P and VoPham, T}, title = {Harnessing Geospatial Artificial Intelligence (GeoAI) for Environmental Epidemiology: A Narrative Review.}, journal = {Current environmental health reports}, volume = {12}, number = {1}, pages = {34}, pmid = {41003951}, issn = {2196-5412}, support = {K01ES035734, P30ES005022/ES/NIEHS NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; UG3OD035533//NIH Office of the Director/ ; P01AG082653/AG/NIA NIH HHS/United States ; R01 HL150119/HL/NHLBI NIH HHS/United States ; K01 DK125612/DK/NIDDK NIH HHS/United States ; }, mesh = {*Artificial Intelligence ; Humans ; *Environmental Exposure ; Geographic Information Systems ; *Environmental Health/methods ; }, abstract = {PURPOSE OF REVIEW: Geospatial analysis is an essential tool for research on the role of environmental exposures and health, and critical for understanding impacts of environmental risk factors on diseases with long latency (e.g. cardiovascular disease, dementia, cancers) as well as upstream behaviors including sleep, physical activity, and cognition. There is emerging interest in leveraging machine learning and artificial intelligence (AI) for environmental epidemiology research. In this review, we provide an accessible overview of recent advances.
RECENT FINDINGS: There have been two major recent shifts in geospatial data types and analytic methods. First, novel methods for statistical prediction, combining geospatial analysis with machine learning and artificial intelligence (GeoAI), allow for scalable geospatial exposure assessment within large population health databases (e.g. cohorts, administrative claims). Second, the widespread adoption of smartphones and wearables with global positioning systems and other sensors has allowed for passive data collection from people, and when combined with geographic information systems, enables exposure assessment at finer spatial scales and temporal resolution than ever before. Illustrative examples include refining models for predicting outdoor air pollution exposure, characterizing populations susceptible to water pollution, and use of deep learning to classify Street View image-derived measures of greenspace. While these tools and approaches may facilitate more rapid, higher quality objective exposure measures, they pose challenges with respect to participant privacy, representativeness of collected data, and curation of high quality validation sets for training of GeoAI algorithms. GeoAI approaches are beginning to be used for environmental exposure assessment and behavioral outcome ascertainment with higher spatial and temporal precision than before. Epidemiologists should continue to apply critical assessment of measurement accuracy and design validity when incorporating these new tools into their work.}, }
@article {pmid40999576, year = {2025}, author = {Dela Cruz, FS and Stewart, EA and Surdez, D and Daley, JD and Soragni, A and Tomazou, EM and Alvarez-Perez, J and Feinberg, TY and Amatruda, JF and Ganapathi, SS and Ohm, JE and Heske, CM and Cohen-Gogo, S and Pesic, D and Nash, JO and Shlien, A and Roundhill, EA and Burchill, SA and Crompton, BD and Lawlor, ER and Loeb, DM and Delattre, O and Mora, J and Scotlandi, K and Reed, DR and Grohar, PJ and Grünewald, TGP and Kovar, H and Bailey, KM}, title = {Advancing Preclinical Biology for Ewing Sarcoma: An International Effort.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {OF1-OF23}, doi = {10.1158/1535-7163.MCT-25-0428}, pmid = {40999576}, issn = {1538-8514}, abstract = {Ewing sarcoma is an aggressive bone and soft-tissue cancer affecting adolescents and young adults. In vitro and in vivo models of Ewing sarcoma have been instrumental in advancing our understanding of Ewing sarcoma biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease for which effective treatment options remain limited. Through an international collaborative effort between the Children's Oncology Group Bone Tumor Committee and the Euro Ewing Consortium, we review the current landscape of preclinical modeling used in Ewing sarcoma research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and nonmammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in Ewing sarcoma modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically relevant Ewing sarcoma models to enable translation of preclinical findings into effective therapeutic strategies for patients with Ewing sarcoma.}, }
@article {pmid40666860, year = {2025}, author = {Harris, ED and McGovern, M and Pernikoff, S and Ikeda, R and Kipnis, L and Hannon, W and Sobolik, EB and Gray, M and Greninger, AL and He, S and Chin, CN and Fu, TM and Pancera, M and Boonyaratanakornkit, J}, title = {DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666860}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI171186/AI/NIAID NIH HHS/United States ; }, abstract = {Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.}, }
@article {pmid40661569, year = {2025}, author = {Risse-Adams, OS and Liquori, JL and Sinnott-Armstrong, N and Musharoff, SA}, title = {Examining the Effect of Social Determinants of Health on Human Trait Heritability.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661569}, issn = {2692-8205}, support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; U54 CA267738/CA/NCI NIH HHS/United States ; }, abstract = {Social determinants of health (SDOH) data are often excluded from genetic models of human traits. We use individual-level data from the All of Us Research Program to assess whether SDOH survey variables alter heritability estimates. Incorporating SDOH summaries decreases heritability significantly for 4 of 18 anthropometric and metabolic traits in individuals whose self-reported race is "White" (n=67,545). There are no such significant changes in individuals whose self-reported race is "Black or African American" (n=6,538), likely reflecting reduced statistical power. Incorporating genetic principal components consistently lowers heritability estimates in both groups, whether or not SDOH summaries are included. These findings demonstrate that survey-derived SDOH summaries can change heritability estimates and should be considered along with genetic summaries.}, }
@article {pmid39484476, year = {2025}, author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Gujral, T and Holland, EC}, title = {Integrated transcriptomic landscape of medulloblastoma and ependymoma reveals novel tumor subtype-specific biology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484476}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, abstract = {Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. This landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients' bulk RNA-seq data onto the reference framework to predict biology and outcome from nearest neighbor analysis facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application.}, }
@article {pmid39464160, year = {2025}, author = {Hsieh, YP and O'Keefe, IP and Wang, Z and Sun, W and Yang, H and Vu, LM and Ernst, RK and Dandekar, AA and Malik, HS}, title = {Magnesium depletion unleashes two unusual modes of colistin resistance with different fitness costs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464160}, issn = {2692-8205}, support = {R01 AI104895/AI/NIAID NIH HHS/United States ; R35 GM152107/GM/NIGMS NIH HHS/United States ; }, abstract = {Increasing bacterial resistance to colistin, a vital last-resort antibiotic, is an urgent challenge. We previously reported that magnesium sequestration by Candida albicans enables Pseudomonas aeruginosa to become colistin-resistant. Here, we show that Mg[2+] depletion drives P. aeruginosa to evolve greater colistin resistance through genetic changes in lipid A biosynthesis-modification pathways and a putative magnesium transporter. These mutations synergize with the Mg[2+]-sensing PhoPQ two-component signaling system to remodel lipid A structures of the bacterial outer membrane in previously uncharacterized ways. One predominant mutational pathway relies on early mutations in htrB2, a non-essential gene involved in lipid A biosynthesis, which enhances resistance but compromises outer membrane integrity, resulting in fitness costs and increased susceptibility to other antibiotics. A second pathway achieves increased colistin resistance independently of htrB2 mutations without compromising membrane integrity. In both cases, reduced binding of colistin to the bacterial membrane underlies resistance. Our findings reveal that Mg[2+] scarcity unleashes two novel trajectories of colistin resistance evolution in P. aeruginosa. (160).}, }
@article {pmid41000465, year = {2018}, author = {Mitov, KV and Yanev, NM and Hyrien, O}, title = {MULTITYPE BRANCHING PROCESSES WITH INHOMOGENEOUS POISSON IMMIGRATION.}, journal = {Advances in applied probability}, volume = {50}, number = {A}, pages = {211-228}, pmid = {41000465}, issn = {0001-8678}, support = {R01 AI069351/AI/NIAID NIH HHS/United States ; R01 AI129518/AI/NIAID NIH HHS/United States ; R01 CA134839/CA/NCI NIH HHS/United States ; R01 NS039511/NS/NINDS NIH HHS/United States ; }, abstract = {In this paper we introduce multitype branching processes with inhomogeneous Poisson immigration, and consider in detail the critical Markov case when the local intensity r(t) of the Poisson random measure is a regularly varying function. Various multitype limit distributions (conditional and unconditional) are obtained depending on the rate at which r(t) changes with time. The asymptotic behaviour of the first and second moments, and the probability of nonextinction are investigated.}, }
@article {pmid40998424, year = {2025}, author = {White, AJ and Hart, JE and Quraishi, SM and Bookwalter, DB and Sweeney, MR and Spalt, EW and Hendryx, MS and Irvin, VL and Lane, DS and Shadyab, AH and Sealy-Jefferson, S and Neuhouser, ML and Whitsel, EA and Kaufman, JD and Laden, F and Sandler, DP}, title = {Air Pollutants and Breast Cancer Risk: A Parallel Analysis of Five Large US Prospective Cohorts.}, journal = {American journal of public health}, volume = {}, number = {}, pages = {e1-e14}, doi = {10.2105/AJPH.2025.308247}, pmid = {40998424}, issn = {1541-0048}, abstract = {Objectives. To determine whether outdoor air pollution exposure is associated with breast cancer incidence. Methods. Residential-level concentrations of nitrogen dioxide (NO2, parts per billion [ppb]), fine particulate matter (PM2.5; ≤ 2.5 μ/m[3]) and ozone (ppb) in the United States were estimated for participants of the Nurses' Health Studies, Women's Health Initiative Clinical Trials and Observational Study Cohort, and Sister Study using high-resolution spatiotemporal models. Cox proportional hazards regression estimated cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), and a random effects model determined summary HRs, overall and by estrogen receptor (ER)/progesterone receptor (PR) subtype and census region. Results. NO2 was positively associated with overall breast cancer incidence (n = 28 811 cases; HR = 1.03; 95% CI = 1.00, 1.05), with little variation by subgroups. PM2.5 was associated with higher incidence of ER-/PR- tumors (n = 2367 cases; HR = 1.14; 95% CI = 1.04, 1.24; P-heterogeneity < .001) and with higher overall incidence in the Midwest (HR = 1.15; 95% CI = 1.01, 1.32; P-heterogeneity = .01). Ozone was not associated with overall incidence, but was associated with ER-/PR- tumors (n = 3406 cases; HR = 1.10; 95% CI = 1.00, 1.21; P-heterogeneity = .03). Conclusions. In this largest US study to date, we confirmed an association between NO2 and breast cancer, and we present novel associations of PM2.5 and ozone with ER-/PR- tumors. (Am J Public Health. Published online ahead of print September 25, 2025:e1-e14. https://doi.org/10.2105/AJPH.2025.308247).}, }
@article {pmid40998267, year = {2025}, author = {Ardila, V and Onstad, L and Carpenter, P and Pidala, J and Kitko, C and Jurdi, NE and Lee, SJ and Hamilton, BK}, title = {Obesity Associations with Chronic Graft-Versus-Host Disease.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.030}, pmid = {40998267}, issn = {2666-6367}, abstract = {BACKGROUND: Obesity is increasing in prevalence and has been linked to inflammation, leading to worse outcomes in various disease states. Pre-clinical studies have demonstrated deleterious effects of obesity on graft-versus-host disease (GVHD). Several retrospective clinical studies have investigated the impact of obesity on allogeneic hematopoietic cell transplantation (HCT); however, with varying results and more limited data on the impact on chronic GVHD.
OBJECTIVES: We aimed to investigate the association of obesity on organ involvement, severity, and response to chronic GVHD therapy in a multicenter cohort of patients with chronic GVHD, as well as its impact on overall survival (OS), non-relapse mortality (NRM), failure-free survival (FFS), and quality of life (QOL).
STUDY DESIGN: We conducted a retrospective study of patients enrolled from 2007 to 2019 in two prospective longitudinal observational studies from the Chronic GVHD Consortium. Obesity was defined as a body mass index (BMI) ≥30, as calculated based on height and weight at the time of enrollment. Grade, organ involvement, and response to chronic GVHD therapy were compared between obese (BMI ≥30) and non-obese (BMI <30) patients. Secondary outcomes included OS, NRM, FFS, and QOL measurement with the Lee symptom scale (LSS), Functional Assessment of Cancer Therapy (FACT), and Medical Outcomes Study Short Form 36 (SF-36).
RESULTS: Among 487 patients identified with newly diagnosed chronic GVHD within 3 months of study enrollment, 114 (23.4%) had BMI ≥ 30. The only significant difference between obese and non-obese patients was the presence of diabetes as a comorbidity. There were no significant differences in affected organs, grade, overall response to treatment, or organ-specific response to treatment between obese and non-obese patients. Chronic lung GVHD was more common in obese compared to non-obese patients (24.6% vs 13.9% for mild, 5.3% vs 4.8% for moderate, and 0.9% vs 0.8% for severe lung GVHD, p=0.047) however small case numbers and the lack of between group differences in OS, NRM or FFS limit this interpretation. QOL analyses revealed greater patient-reported symptom burden and worse QOL in obese patients at enrollment and after 6 months.
CONCLUSION: We found obesity is associated with worse QOL but not with chronic GVHD phenotypes, responsiveness to treatment, or survival outcomes in a multicenter cohort of allogeneic HCT recipients. Given the increasing evidence of a multi-factorial role for obesity as a modulator of immune processes, additional studies investigating more accurate measures of obesity and body composition are needed to further understand their role in chronic GVHD.}, }
@article {pmid40998264, year = {2025}, author = {Kogler, V and Pagano, MB and Fontaine, MJ and Azimi, V and Brancamp, R and Cataife, G and Covington, M and Delaney, M and Eichbaum, Q and Jacquot, C and Kutner, JM and Lu, W and Saifee, NH and Shan, H and Thibodeaux, SR and Wali, JA and Yeh, A and Yokoyama, APH and Yunce, M and Ziman, A and , }, title = {Serologic Characteristics and Clinical Significance of Non-ABO Red Blood Cell Antibodies in Hematopoietic Stem Cell Transplant. The BEST Collaborative Study.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.040}, pmid = {40998264}, issn = {2666-6367}, abstract = {BACKGROUND: ABO-incompatible hematopoietic stem cell transplant (HSCT) has a number of well-established complications including hemolysis, delayed RBC engraftment, pure red cell aplasia (PRCA), and transfusion dependence. However, the clinical significance of non-ABO RBC antibodies in allogeneic HSCT remains insufficiently explored.
OBJECTIVE: The aim of this study is to characterize the prevalence, incidence, and clinical implications of non-ABO RBC auto- and alloantibodies in the HSCT population.
STUDY DESIGN: This international, multicenter, retrospective study analyzed HSCT 2010-2021 across nine U.S. and one Brazilian academic centers. This study focused on immunohematologic findings in recipients of allogeneic HSCTs, excluding hemoglobinopathies. RBC antibodies were evaluated pre-HSCT and 100 days post-HSCT. Hemolysis was assessed by labs and confirmed by a two-physician review of the medical records. Descriptive statistics and regression analysis were performed. IRB approval and data use agreements were obtained at each center.
RESULT: Study analysis included a total of 8896 transplants. The majority of transplants utilized apheresis collections (78.0%), were matched unrelated (41.6%), involved a non-myeloablative conditioning regimen (51.2%), and were ABO-compatible (56.7%). The prevalence of non-ABO antibodies pre-HSCT, including auto-, alloantibodies, and passive transfer of anti-D, was 4.0% (n=355). The majority of these were alloantibodies (77.5%), followed by warm autoantibodies (7.3%) and both alloantibodies and warm-reactive autoantibodies (6.5%). De-novo antibody formation post-HSCT occurred in 1.5% (n=135). The most frequent pre-HSCT alloantibody specificities were in the Rh blood group system (46%), followed by Kell (17%) and Kidd (13%). The incidence of anti-D in RhD-mismatched transplant was 1% (n=8) for RhD-positive recipients with RhD-negative donors, and 0.2% (n=2) for RhD-negative recipients with RhD-positive donors. Myeloproliferative neoplasms and myelodysplastic syndromes had the highest rate of antibodies pre- and post-HSCT. Hemolysis was observed in 24 cases (antibodies present pre-HSCT) and 15 de-novo cases post-HSCT. Pure red cell aplasia was not observed in any of these cases. The presence of non-ABO RBC antibodies was associated with higher RBC transfusions, but not platelet transfusions; engraftment of neutrophils and platelets were not affected by the presence of RBC antibodies.
CONCLUSION: The current study reports on a low prevalence of RBC antibodies, including allo- and autoantibodies, in HSCT patients during the peri-transplant period, with a rate of 4% for those with pre-existing antibodies prior to transplant and 1% for the de-novo antibody formation post-transplant. They are associated with a low risk of mild to moderate hemolysis, but increased RBC transfusions. Comprehensive immunohematology data should be incorporated into HSCT databases for improved risk assessment, monitoring, and management.}, }
@article {pmid40998194, year = {2025}, author = {Hammouda, K and Tokuyama, N and Corredor, G and Pathak, T and Dakarapu, R and Genega, E and Mian, OY and Pavicic, PG and Diaz-Montero, CM and Mirtti, T and Farré, X and Gupta, S and Madabhushi, A}, title = {AI-informed computational pathology classifier predicts outcomes across treatment modalities in muscle-invasive urothelial carcinoma.}, journal = {Cancer letters}, volume = {634}, number = {}, pages = {218059}, doi = {10.1016/j.canlet.2025.218059}, pmid = {40998194}, issn = {1872-7980}, abstract = {Urothelial carcinoma (UC) is one of the leading causes of cancer-related mortality, and effective, scalable biomarkers for treatment planning remain limited. We present UC-TIL, an artificial intelligence (AI)-based model that quantifies spatial patterns of tumor-infiltrating lymphocytes (TILs) from routine H&E-stained slides to predict survival and immunotherapy response. We analyzed 558 whole-slide images across three cohorts: TCGA (D0&1, N = 292), Emory (D2, N = 161), and TRRC2819 (D3, N = 105), spanning chemotherapy and immune checkpoint inhibitor (ICI) treatments. UC-TIL classification was associated with OS (HR = 2.11, 95 %CI:1.01-4.41, p = 0.011) and PFS (HR = 3.68, 95 %CI:1.07-12.65, p = 0.0012) in locally advanced disease (D1 and D2), with consistent results in metastatic disease (D3) (HR = 1.73, 95 %CI:1.08-2.77, p = 0.043; PFS HR = 1.73, 95 %CI:1.07-2.81, p = 0.047). In the ICI-treated D3 cohort, UC-TIL achieved AUC = 0.757 and identified non-responders with 91 % specificity. UC-TIL enables reliable risk stratification and treatment response prediction in both locally advanced and metastatic urothelial carcinoma by analyzing spatial TIL patterns from standard pathology slides. These findings position UC-TIL as a readily deployable tool to guide personalized therapy across multiple clinical settings.}, }
@article {pmid40998019, year = {2025}, author = {Glenny, EM and Lin, T and Bandera, VM and Mirminachi, B and Khumukcham, SS and Gigic, B and Warby, CA and Aksonova, O and Coleman, MF and Carpanese, A and Busch, C and Himbert, C and Ose, J and Nix, DA and Boucher, K and Schirmacher, P and Strehli, I and Hardikar, S and Cohan, JN and Jedrzkiewicz, J and Brobeil, A and Schneider, MA and Kahlert, C and Siegel, EM and Byrd, DA and Toriola, AT and Shibata, D and Li, CI and Figueiredo, JC and Tan, AC and Roper, J and Ulrich, CM and Hursting, SD}, title = {Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: Evidence from mouse models and the ColoCare Study patient cohort.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.09.031}, pmid = {40998019}, issn = {1938-3207}, abstract = {BACKGROUND: The global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed.
OBJECTIVE: This study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the two species.
METHODS: We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato colon tumor organoids. Epithelial cell adhesion molecule (EpCAM)-positive cells from murine tumors, and 193 human colon tumors and 188 human mesenteric adipose tissue samples from the prospective ColoCare Study cohort underwent transcriptomic analyses.
RESULTS: Diet-induced obesity reduced survival in the mouse model of colon cancer. Integrated transcriptomic analyses of EpCAM-positive murine tumor cells and bulk human tumors revealed obesity-driven enrichment of inflammation and metabolic pathways, including upregulation of genes involved in innate immune sensing (TLR2, MYD88, IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the study patients (63±13 years old, 48% female, BMI: 28.9±6.0 kg/m[2]) indicated that obesity was associated with enriched inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions.
CONCLUSIONS: These results establish obesity-associated adipose tissue dysregulation as a key inter-tissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.}, }
@article {pmid40997296, year = {2025}, author = {Wang, ES and Montesinos, P and Foran, J and Erba, H and Rodríguez-Arbolí, E and Fedorov, K and Heiblig, M and Heidel, FH and Altman, JK and Baer, MR and Ades, L and Pettit, K and Peterlin, P and Papayannidis, C and Berthon, C and Walter, RB and Shah, MV and Balasubramanian, S and Khawandanah, M and Salamero Garcia, O and Bergeron, J and Madanat, YF and Roboz, GJ and Ulrickson, M and Redner, RL and McCloskey, J and Pigneux, A and de la Fuente Burguera, A and Mitra, A and Soifer, HS and Tabachri, M and Zhang, Z and Riches, M and Corum, D and Leoni, M and Issa, GC and Fathi, AT and , }, title = {Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501694}, doi = {10.1200/JCO-25-01694}, pmid = {40997296}, issn = {1527-7755}, abstract = {PURPOSE: Ziftomenib-a potent, highly selective, oral menin inhibitor-was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial.
METHODS: In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh).
RESULTS: From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events.
CONCLUSION: Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.}, }
@article {pmid40996773, year = {2025}, author = {Fasching, PA and Stroyakovskiy, D and Yardley, DA and Huang, CS and Crown, J and Bardia, A and Chia, S and Im, SA and Martin, M and Xu, B and Loi, S and Barrios, C and Untch, M and Moroose, R and Visco, F and Hortobagyi, GN and Slamon, DJ and Fresco, R and Zarate, JP and Li, Z and Waters, S and Hurvitz, SA}, title = {Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.3700}, pmid = {40996773}, issn = {2374-2445}, abstract = {IMPORTANCE: Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.
OBJECTIVE: To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.
This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.
INTERVENTIONS: Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).
MAIN OUTCOMES AND MEASURES: The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.
RESULTS: Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.
CONCLUSIONS AND RELEVANCE: This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03701334.}, }
@article {pmid40996743, year = {2025}, author = {Barber, B and Harris, H}, title = {Acid-Resistant Oral Microbiome on Oral Cancer Development-Reply.}, journal = {JAMA otolaryngology-- head & neck surgery}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoto.2025.3047}, pmid = {40996743}, issn = {2168-619X}, }
@article {pmid40996319, year = {2025}, author = {Janitz, AE and Qiu, W and Schraw, JM and Mostoufi-Moab, S and Mirabello, L and Stewart, DR and Neglia, JP and Turcotte, LM and Bhatia, S and Yasui, Y and Chow, EJ and Armstrong, GT and Lupo, PJ}, title = {Health Outcomes in Childhood Cancer Survivors with Congenital Anomalies in the Childhood Cancer Survivor Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0611}, pmid = {40996319}, issn = {1538-7755}, abstract = {BACKGROUND: Congenital anomalies are associated with increased risk of childhood cancer. However, there is a knowledge gap regarding health outcomes for childhood cancer survivors with congenital anomalies.
METHODS: We included childhood cancer survivors from the Childhood Cancer Survivor Study (n=22,247) comparing survivors with and without self-reported anomalies. Using Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) of chronic health conditions (CHC) classified per the Common Terminology Criteria for Adverse Events (CTCAE) from 1 (mild) to 5 (fatal) and subsequent malignant neoplasms (SMN) comparing survivors by anomaly status. We calculated age-sex-calendar year-specific mortality rates and standardized mortality ratios (SMR) for survivors compared to the US population.
RESULTS: Among survivors, 16.9% (n=3,880) reported a congenital anomaly. Survivors with anomalies had a higher rate of any CHC (grades 1-5 HR: 1.24, 95% CI: 1.18-1.31), severe CHCs (grades 3-5 HR: 1.29, 95% CI 1.19-1.40), and multiple CHCs of any grade (≥2 CHCs HR: 1.31, 95% CI 1.24-1.39; ≥3 HR: 1.42, 95% CI 1.33-1.52). Survivors with anomalies had an increased rate of soft-tissue sarcomas (HR: 1.96, 95% CI 1.12-3.44). For deaths related to the original cancer diagnosis, survivors with anomalies (compared to no anomalies) had a lower mortality rate (0.64 vs. 0.90 per 1000 person-years).
CONCLUSIONS: We identified an increased rate of CHCs and SMNs among childhood cancer survivors with anomalies and lower mortality directly related to the cancer diagnosis.
IMPACT: Future work will focus on evaluation of genetic pathways that increase the risk of CHCs and SMNs.}, }
@article {pmid40995047, year = {2025}, author = {Moore, M and Anderson, L and Bracis, C and Swan, DA and Painter, I and Everson, E and Janes, H and Schiffer, JT and Matrajt, L and Dimitrov, D}, title = {Estimating Population Immunity and Impact of COVID-19 Vaccination in Washington State and Oregon.}, journal = {Open forum infectious diseases}, volume = {12}, number = {9}, pages = {ofaf531}, pmid = {40995047}, issn = {2328-8957}, abstract = {BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine showed high clinical efficacy against the ancestral variant, but immunological waning, emergence of new variants, and the durability of infection-induced immunity complicate the estimation of population-level effectiveness. We used mathematical modeling to calculate the proportion of hospitalizations averted by vaccination in Washington and Oregon.
METHODS: We used an age- and region-structured compartmental model of vaccine-induced and infection-induced immunity from January 2020 until December 2022. We parameterized the strength and durability of immunity via a meta-regression of vaccine efficacy. We calibrated a time-varying contact matrix to weekly hospitalizations reported by the Washington Department of Health and Oregon Health Authority. We validated our model with Centers for Disease Control and Prevention serosurveillance data. To estimate vaccine effectiveness, we created counterfactual scenarios with no vaccination either in the entire population or in select age groups.
RESULTS: We found that total hospitalizations were reduced 74% (95% credible interval [CrI], 69%-78%) and 15% (95% CrI, 9%-19%) by primary vaccination and boosters, respectively. Vaccination effectiveness was highest during the Alpha wave, averting 90% (95% CrI, 88%-93%) of hospitalizations and in people aged 65+, averting 78% (95% CrI, 73%-81%). Relative to only vaccinating individuals aged 50+, vaccination of individuals aged 18-49 averted 52% (95% CrI, 44%-58%) of hospitalizations overall and 42% (95% CrI, 35%-48%) of hospitalizations among individuals 65+.
CONCLUSIONS: The SARS-CoV-2 vaccination program in Washington and Oregon averted the majority of hospitalizations. Vaccinating individuals aged 18-49 significantly reduced hospitalization among individuals aged 65+.}, }
@article {pmid40993182, year = {2025}, author = {Sarnowski, C and Zhang, Y and Ammous, F and Shade, LMP and DiCorpo, D and Jian, X and Arnett, DK and Austin, TR and Beiser, A and Bis, JC and Blangero, J and Boerwinkle, E and Bressler, J and Curran, JE and DeCarli, CS and Doddapaneni, H and Dupuis, J and Fardo, DW and Florez, JC and Gabriel, S and Gibbs, RA and Glahn, DC and Gupta, N and González, HM and González, KA and Hatzikotoulas, K and Hayden, KM and Heckbert, SR and Hidalgo, B and Huerta-Chagoya, A and Hughes, TM and Kardia, SLR and Kooperberg, CL and Launer, LJ and Longstreth, WT and , and , and Mandla, R and Mathias, RA and Morris, AP and Mosley, TH and Nasrallah, IM and Nyquist, P and Psaty, BM and Qi, Q and Raffield, LM and Rayner, NW and Reiner, AP and Satizabal, CL and Selvin, E and Sevilla-Gonzalez, MDR and Smith, AV and Smith, JA and Smith, K and Snively, BM and Southam, L and Sofer, T and Suzuki, K and Taylor, HJ and Udler, MS and Viaud-Martinez, KA and Wassertheil-Smoller, S and Wood, AC and Yanek, LR and Yin, X and Manning, AK and Rotter, JI and Rich, SS and Meigs, JB and Fornage, M and Seshadri, S and Morrison, AC and , and , }, title = {Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1352}, pmid = {40993182}, issn = {2399-3642}, support = {R00 AG066849/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; *Insulin Resistance/genetics ; Middle Aged ; Female ; Precision Medicine ; Cross-Sectional Studies ; Aged ; Metabolic Syndrome/genetics ; Adult ; }, abstract = {To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10[-5]) and European (PEA = 3.0 × 10[-8]) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.}, }
@article {pmid40991892, year = {2025}, author = {Dorovini-Zis, K and Li, H and Zhe, C and Zhang, B and Small, D and Taylor, TE}, title = {Mapping the expression of endothelial adhesion receptors for Plasmodium falciparum-infected erythrocytes in fatal cerebral malaria in Malawian children.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlaf104}, pmid = {40991892}, issn = {1554-6578}, support = {5R01AI34969//US National Institutes of Health/ ; }, abstract = {We investigated the expression and distribution of 5 cytoadhesion receptors for the Plasmodium falciparum erythrocyte membrane protein 1 in 12 regions of post-mortem brains of 50 Malawian children, that is, 27 with the clinical and pathological diagnosis of cerebral malaria (CM) and 23 with a non-malarial cause of death. We quantified the expression of each receptor by microvascular endothelium and the colocalization of receptor-expressing microvessels with sequestered infected red blood cells (iRBC) and calculated a receptor-independent sequestration ratio. There were differences in the level of expression and regional distribution of the five receptors: ICAM-1 was the most widely expressed receptor, followed by CD36, VCAM-1, E-selectin, and thrombospondin. Receptor-expressing microvessels were most numerous in the frontal lobe and least numerous in the brainstem and cerebellum. Colocalization of receptor-expressing endothelial cells with iRBC was present in all brain regions; it was highest for ICAM-1 and CD36 and greatest in the frontal lobe. The sequestration ratios were close to 100% for all receptors across all brain regions and were similar in cerebral and extracerebral microvessels. Receptor expression and colocalization ratios were greater in the brain than in the lung, heart, liver, spleen, and subcutaneous tissue. These differences in cerebral endothelial expression of cytoadhesion receptors and their preferential regional distribution may underpin differences in iRBC sequestration and lesion development in CM. Moreover, greater expression of these receptors in the brain vs peripheral organs may explain a comparatively greater degree of iRBC sequestration in the brain.}, }
@article {pmid40991418, year = {2025}, author = {Matsuk, VY and Khatib, TO and Marcus, LJ and Robinson, IE and Liu, Y and Pasupathy, JK and Shanmugam, M and Mouw, JK and Marcus, AI}, title = {Metabolic programming defines oxygen sensitive subpopulation hierarchies and patterning in collective invasion.}, journal = {Molecular biology of the cell}, volume = {}, number = {}, pages = {mbcE25070314}, doi = {10.1091/mbc.E25-07-0314}, pmid = {40991418}, issn = {1939-4586}, abstract = {Phenotypic heterogeneity - distinct molecular and behavioral variations within a population -significantly influences collective invasion and tumor progression. Here, we employ a molecular approach to explore how the underlying metabolic heterogeneity in non-small cell lung cancer (NSCLC) influences invasion and pack patterning. Assessing three-dimensional (3D) pack patterning revealed invasive heterogeneity across NSCLC cell lines and patient-derived samples. Flow cytometry identified IL13RA2 as a biomarker for invasive potential, enabling isolation of subpopulations with distinct invasive characteristics. By integrating a cell surface biomarker (IL13RA2±) with mitochondrial membrane potential (TMRM), we identified and isolated three distinct subpopulations. Two-dimensional (2D) analyses revealed differences in mitochondrial polarity and transcriptional programs associated with migration and oxygen-sensitivity. In 3D, these subpopulations invaded with distinct patterns, from contiguous circular packs to structured chains. Assessments under varied oxygen tension demonstrated that oxygen availability and subpopulation metabolism together influence collective invasion patterning. When recombined at ratios recapitulating the original population, both stochastic and opportunistic cooperative dynamics emerged, dependent on subpopulation composition and oxygen levels. Our molecular approach, integrating cell surface and metabolic characteristics, enables isolation of unique subpopulations and demonstrates that phenotypic and metabolic heterogeneity, population composition, and oxygen availability collectively pattern invasion packs and drive collective invasion.}, }
@article {pmid40964310, year = {2025}, author = {Ramsey, EL and Dobersch, S and Freie, B and Hong, NH and Wu, X and Kugel, S and Eisenman, RN and Carroll, PA}, title = {MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964310}, issn = {2692-8205}, abstract = {MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m[6]A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.}, }
@article {pmid40991382, year = {2025}, author = {Faulk, KE and Kairalla, JA and Hibbitts, E and Long-Boyle, JR and Devidas, M and August, A and Gore, L and Raetz, EA and Hunger, SP and Loh, ML and Teachey, DT and Brown, PA and Breese, EH and Kotecha, RS and Guest, E}, title = {Age-Based Pegaspargase Dosing is Safe and Achieves Therapeutic Levels in Infants with ALL: Report from COG AALL15P1.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017013}, pmid = {40991382}, issn = {2473-9537}, }
@article {pmid40987290, year = {2025}, author = {Reeves, DB and Rigau, DN and Romero, A and Zhang, H and Simonetti, FR and Varriale, J and Hoh, R and Zhang, L and Smith, KN and Montaner, LJ and Rubin, LH and Gange, SJ and Roan, NR and Tien, PC and Margolick, JB and Peluso, MJ and Deeks, SG and Schiffer, JT and Siliciano, JD and Siliciano, RF and Antar, AAR}, title = {Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.}, journal = {Cell systems}, volume = {}, number = {}, pages = {101402}, doi = {10.1016/j.cels.2025.101402}, pmid = {40987290}, issn = {2405-4720}, abstract = {To determine whether HIV persistence arises from the natural dynamics of memory (m)CD4+ T cells, we compare clonal dynamics of HIV proviruses and mCD4+ T cells from the same people living with HIV (PWH) on antiretroviral therapy and from matched HIV-seronegative people (N = 51). HIV proviruses are more clonal than mCD4+ T cells but similarly clonal to antigen-specific cells. Increasing reservoir clonality over time and differential decay of intact and defective proviruses are not explained by mCD4+ T cell kinetics alone. We develop and validate a stochastic model trained on 10 quantitative data metrics, which shows that negative selection against HIV-infected cells is necessary to explain all metrics. We estimate the strength of negative selection, finding that death of cells harboring intact and defective proviruses is infrequently (∼6% and ∼2% on average) due to HIV-specific factors. Thus, our data indicate that HIV persistence is mostly, but not entirely, driven by natural mCD4+ kinetics.}, }
@article {pmid40986647, year = {2025}, author = {Ribi, K and Cole, BF and Fleming, GF and Walley, BA and Francis, PA and Abdi, E and Burstein, HJ and Cheng, KL and Chia, SKL and Dakhil, SR and Davidson, NE and Della-Fiorentina, SA and Frith, AE and Levine, E and Lupichuk, S and Pritchard, K and Salim, M and Stearns, V and Stewart, J and Valero, V and van der Westhuizen, A and Pagani, O and Loi, S and Colleoni, M and Gelber, RD and Goldhirsch, A and Coates, AS and Regan, MM and Bernhard, J}, title = {Prognostic value of patient-reported depression in women with hormone-responsive early breast cancer in TEXT and SOFT.}, journal = {Cancer}, volume = {131}, number = {19}, pages = {e70094}, doi = {10.1002/cncr.70094}, pmid = {40986647}, issn = {1097-0142}, support = {//Pfizer/ ; /CA/NCI NIH HHS/United States ; //European Thoracic Oncology Program and International Breast Cancer Study Group Partners Foundation/ ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; Androstadienes/administration & dosage/therapeutic use ; Antidepressive Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/psychology/mortality/complications ; *Depression/drug therapy ; Disease-Free Survival ; Premenopause ; Prognosis ; Tamoxifen/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: Depression has been identified as an adverse mental health outcome in women with breast cancer (BC). Depression was investigated as a risk factor for poor survival in premenopausal women with hormone-responsive early BC treated in the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials.
METHODS: The data used were from a subset of patients who participated in TEXT or SOFT and completed the Center of Epidemiologic Studies-Depression scale. Associations between baseline depression-score categories and baseline characteristics were assessed using the Cochran-Mantel-Haenszel test controlling for antidepressant use. Multivariable proportional hazards regression models were used to test the association between baseline depression and disease-free survival (DFS) and overall survival (OS). Regression models were adjusted for factors known to be associated with outcomes, baseline antidepressant use, and early treatment cessation.
RESULTS: Forty percent (2287 of 5738) of the women enrolled in the SOFT and TEXT trials were included in this analysis (SOFT, n = 1259; TEXT, n = 1028). Twenty-seven percent of women reported mild-to-moderate or severe depression at baseline. Race (p = .001), body mass index (p = .02), family history (p = .02), and performance status (p =.007) were significantly associated with the severity of depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .04) for DFS were 1.34 (95% confidence interval [CI], 1.03-1.76) for women with mild-to-moderate depression and 1.34 (95% CI, 0.96-1.87) for those with severe depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .008) for OS were 1.68 for mild-to-moderate depression (95% CI, 1.15-2.44) and 1.67 for those with severe depression (95% CI, 1.05-2.66).
CONCLUSIONS: In premenopausal women with hormone-responsive early BC, depression at baseline is a risk factor for poorer DFS and OFS. Further investigation of the underlying interactive processes is needed.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00066703 (SOFT) and NCT00066690 (TEXT).}, }
@article {pmid40986340, year = {2025}, author = {Su, Y and Thelen, A and Wirth, LV and Jenkins, CM and Mak, SR and Chen, DG and Gottardo, R and Greenberg, PD}, title = {A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {39}, pages = {e2516951122}, doi = {10.1073/pnas.2516951122}, pmid = {40986340}, issn = {1091-6490}, support = {CA18029/GF/NIH HHS/United States ; CA225517/GF/NIH HHS/United States ; DRQ-13-22//Damon Runyon Cancer Research Foundation (DRCRF)/ ; Hartwell Innovation Award//Hartwell Foundation (HARTWELL)/ ; CA015704/GF/NIH HHS/United States ; }, mesh = {Humans ; *Immunotherapy, Adoptive/methods ; *Lymphocyte Activation/immunology ; *Receptors, Transforming Growth Factor beta/genetics/immunology/metabolism ; *Recombinant Fusion Proteins/genetics/immunology ; Interleukin-2/metabolism ; Signal Transduction ; STAT5 Transcription Factor/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; *Receptors, Interleukin-2/genetics/immunology/metabolism ; Phosphorylation ; Transforming Growth Factor beta ; Immunosuppression Therapy ; T-Lymphocytes/immunology ; }, abstract = {Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8[+] T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.}, }
@article {pmid40985344, year = {2025}, author = {Hausmann, O and Schobert, PP and Ose, J and Himbert, C and Pletneva, M and Jedrzkiewicz, J and Nguyen, A and Lin, T and Warby, CA and Hardikar, S and Peoples, AR and Strehli, I and Huang, LC and Cohan, JN and Pickron, B and Scaife, C and Li, CI and Grady, WM and Shibata, D and Toriola, AT and Schneider, M and Figueiredo, JC and Siegel, EM and Gigic, B and Herzig, S and Ilozumba, MN and Ulrich, CM}, title = {Associations of Biomarkers of Systemic Inflammation, Angiogenesis, and Cell-to-Cell Adhesion With Tumor Budding Among Early-Onset and Later-Onset Colorectal Cancer Patients.}, journal = {Cancer medicine}, volume = {14}, number = {18}, pages = {e71267}, pmid = {40985344}, issn = {2045-7634}, support = {//Stiftung LebensBlicke/ ; P30CA042014/CA/NCI NIH HHS/United States ; K07222060/NH/NIH HHS/United States ; R01CA189184/NH/NIH HHS/United States ; R01CA207371/NH/NIH HHS/United States ; R01CA254108/NH/NIH HHS/United States ; R03CA270473/NH/NIH HHS/United States ; U01CA206110/NH/NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; Angiogenesis ; *Biomarkers, Tumor/blood ; Cell Adhesion ; *Colorectal Neoplasms/pathology/blood ; *Inflammation/blood ; Intercellular Adhesion Molecule-1/blood ; Neoplasm Staging ; *Neovascularization, Pathologic/blood/pathology ; Prognosis ; }, abstract = {BACKGROUND: High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell-to-cell adhesion influence tumor budding.
METHODS: We investigated n = 132 stage I-III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence-based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and non-steroidal anti-inflammatory drug use.
RESULTS: The study population was predominantly non-Hispanic White (95%), with a mean age of 61 years; 56% were male. Most tumors were stage III (47%), located in the colon (64%), and exhibited low-grade tumor budding (58%). Soluble intercellular adhesion molecule 1 was inversely associated with tumor budding overall (M1: β = -0.57, p = 0.03), among females (M1: β = -0.81, p-value = 0.03) and later-onset (≥ 50 years) colorectal cancer (M1: β = -0.71, p-value = 0.008). C-reactive protein was positively associated with tumor budding in males (M1: β = 0.23, p = 0.001), while interleukin-8 (M1: β = 0.96, p-value = 0.01) and soluble vascular adhesion molecule 1 (M2: β = 1.48, p-value = 0.04) were positively associated with tumor budding in early-onset patients. However, these associations did not remain statistically significant after correction for multiple testing.
CONCLUSION: Overall, our findings do not provide evidence of a significant association between biomarkers of systemic inflammation, angiogenesis, and cell-to-cell adhesion with tumor budding count. We observed patterns for some biomarkers, yet none remained statistically significant after correction for multiple testing. These findings provide preliminary insights for future studies.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT02328677.}, }
@article {pmid40983593, year = {2025}, author = {Fitchett, G and Campbell, D and Chang, C and Hester, C and King, S and Peery, B and Saks, NT}, title = {Developing and implementing spiritual screening in healthcare: six successful models.}, journal = {Journal of health care chaplaincy}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/08854726.2025.2563472}, pmid = {40983593}, issn = {1528-6916}, abstract = {Healthcare chaplains recognize the importance of informed referrals for spiritual care; they are essential for spiritual care in outpatient settings. Research about the prevalence and harmful effects of religious/spiritual distress underscores the importance of effective methods for identifying patients who would benefit from spiritual care. Spiritual screening is a valuable way to help healthcare colleagues identify patients who would benefit from further assessment and spiritual care. To help spiritual care programs implement spiritual screening, in this article chaplains from six organizations with successful spiritual screening describe the development and implementation of their programs. The settings for these screening programs include hospital inpatients, oncology outpatient centers, palliative care, and population health. The descriptions include the screening questions used, how they are administered, and what it took to get them implemented. Common and unique features of these six approaches to spiritual screening are discussed along with areas for future research.}, }
@article {pmid40982684, year = {2025}, author = {Alencar, GF and Mohamed, AO and Burnett, MG and Jean, SS and Nelson, AR and Su, Y and Voillet, V and Bates, BM and Rodgers Suarez, M and Ruskin, SL and Trieu, L and Lam, JL and Bekiranov, S and Gottardo, R and Greenberg, PD and Anderson, KG}, title = {Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {39}, pages = {e2419888122}, doi = {10.1073/pnas.2419888122}, pmid = {40982684}, issn = {1091-6490}, support = {CA009657-26A1 CA266737 P30CA044579 CA018029 CA033084//HHS | NIH | National Cancer Institute (NCI)/ ; Ann and Sol Schreiber Mentored Investigator Training Grant//Ovarian Cancer Research Alliance (OCRA)/ ; no number//Parker Institute for Cancer Immunotherapy (PICI)/ ; no number//Lonza Houston (Lonza Houston, Inc.)/ ; no number//Celgene Corporation | Juno Therapeutics/ ; 5T32AI007496-29//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Animals ; Female ; *Ovarian Neoplasms/therapy/immunology/pathology/genetics ; Mice ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; *Immunotherapy, Adoptive/methods ; *Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors/immunology/metabolism ; Mesothelin ; Lymphocyte Activation Gene 3 Protein ; *Immune Checkpoint Inhibitors/pharmacology ; *T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Disease Models, Animal ; *Antigens, CD/immunology/metabolism/genetics ; Cell Line, Tumor ; Humans ; }, abstract = {The five-year survival rate for ovarian cancer patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to specifically target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (MSLN) contributes to the malignant and invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in a mouse model of ovarian cancer demonstrated that T cells engineered to express a T cell receptor (TCR) targeting MSLN (TCRMSLN) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function and improve therapeutic efficacy, but administration of monospecific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3, and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCRMSLN with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCRMSLN T cells treated with the triplet antibody combination increased expression of genes involved in interferon responses and metabolic function, and reduced expression of genes associated with exhaustion. These results suggest that strategies to disrupt multiple inhibitory pathways simultaneously may be necessary for improved adoptive T cell therapy efficacy in patients.}, }
@article {pmid40982561, year = {2025}, author = {Chen, C and Lovendahl, KN and Overbaugh, JM and Lee, KK}, title = {Interprotomer crosstalk in mosaic viral glycoprotein trimers provides insight into polyvalent immunogen co-assembly.}, journal = {PLoS pathogens}, volume = {21}, number = {9}, pages = {e1013143}, doi = {10.1371/journal.ppat.1013143}, pmid = {40982561}, issn = {1553-7374}, abstract = {SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines.}, }
@article {pmid40980587, year = {2025}, author = {Deo, R and Choudhary, MC and Glover, OT and Ignacio, RB and Boucau, J and Chew, KW and Moser, C and Currier, JS and Eron, JJ and Javan, AC and Giganti, MJ and Aga, E and Gibbs, M and Cohen, T and Streicher, K and Soboleva, K and Fletcher, CV and Daar, ES and Greninger, AL and Coombs, RW and Fischer, W and Hughes, MD and Smith, D and Wohl, DA and Barczak, AK and Li, JZ}, title = {Rapid Elimination of Culturable SARS-CoV-2 With Intramuscular or Intravenous Administration of Antiviral Monoclonal Antibody Therapy.}, journal = {Open forum infectious diseases}, volume = {12}, number = {9}, pages = {ofaf542}, pmid = {40980587}, issn = {2328-8957}, abstract = {We evaluated intramuscular (IM) versus intravenous (IV) administration of tixagevimab/cilgavimab in early COVID-19. Both routes achieved rapid elimination of culturable virus and minimal emergence of resistance. These results support IM delivery as a viable alternative to IV, with important implications for scalable deployment in future viral pandemics.}, }
@article {pmid40979096, year = {2025}, author = {Muhammad, M and Castro-Reyes, P and Chakoian, M and Duron, Y and Gay, S and Grant, H and Hempstead, B and Hoffman, L and Mapes, D}, title = {Community/patient group champion team retrospective look at engage for equity PLUS: Results from a post-intervention champion team focus group.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e179}, pmid = {40979096}, issn = {2059-8661}, abstract = {Community/patient voice has long been stifled in favor of the priorities of powerful health organizations that set the agenda for institutional practices and policies shaping health equity research. Academic Health Centers (AHC) and Clinical Translational Science Centers (CTSC) promote missions that are often unaligned with the realities of community and patient experiences when interacting with researchers and representatives from these institutions. Implementation science has increasingly adopted collaborative and participatory approaches to the design and implementation of health interventions co-created with community/patient group members as equal participants within community-academic partnerships. Community-based participatory research/community-engaged research are widely recognized as approaches to health intervention research that offers the potential for community-patient voice to be heard when the principles of authentic participatory research are adhered to throughout all aspects of the project. For AHC's and CTSC's to be fully engaged, the populations they serve must have access to institutional leadership and influence over decision-making about the organizational resources allocated to community/patient groups beyond efforts to cultivate a positive public image. The E2 community/patient champion team focus groups provide unique perspectives on how equitable institutional transformation can be accomplished in a retrospective assessment of the E2 PLUS Intervention.}, }
@article {pmid40964353, year = {2025}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Radford, C and Worczinski, J and Momot, A and Ahmadov, E and Burger, JA and Havenar-Daughton, C and Deshpande, S and Giovannoni, F and Corti, D and Kreer, C and Ercanoglu, MS and Schommers, P and Georgiev, IS and West, AP and Knüfer, J and Stumpf, R and Kroidl, A and Geldmacher, C and Maganga, L and William, W and Ntinginya, NE and Hoelscher, M and Yang, Z and Wei, Q and Renfrow, M and Green, TJ and Novak, J and van Gils, MJ and Gristick, HB and Gruell, H and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Identification of a broad and potent V3 glycan site bNAb targeting an N332gp120 glycan-independent epitope.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964353}, issn = {2692-8205}, abstract = {Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here, we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels[1-3] (GeoMean IC50 = 0.012 μg/mL, breadth = 69%, 217 virus strains) by targeting a N332gp120 glycan-independent V3 epitope, a site of Env vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryo-EM structure revealed contacts with the V3 [324]GD/NIR[327] motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs, and bivalent 007 IgG was up to ~300-fold more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure, and vaccine design.}, }
@article {pmid40978447, year = {2025}, author = {Shukla, S and Stingaciu, LR and Stanley, C and Agarwal, P and Cuneo, M and Stadler, AM and Myles, D}, title = {Dynamical Signatures of Thermotoga maritima Maltose-Binding Proteins Affected by Ligand Binding.}, journal = {ACS omega}, volume = {10}, number = {36}, pages = {41446-41456}, pmid = {40978447}, issn = {2470-1343}, abstract = {Functional segregation among protein isoforms depends on the interplay of their overall structures and the molecular dynamics of these structures. Thermotoga maritima maltose-binding protein (tmMBP) isoforms show size-dependent differential binding of maltose and malto-oligomers while maintaining remarkable fold conservation. This differential behavior needs detailed characterization in native-like aqueous conditions to understand the effects of protein dynamics on ligand binding and recognition. Small-angle neutron scattering (SANS), neutron spin echo (NSE) spectroscopy, and dynamic light scattering (DLS) were used in conjunction with previously published computational molecular dynamics (MD) simulations to understand the dynamic behavior of tmMBPs experimentally. SANS provided information on the overall structure of the molecules, while NSE was used to determine the dynamics in the nanosecond time scale. Both tmMBP2 and tmMBP3 have a bidomain architecture linked with a flexible hinge, with the binding pocket sitting in the cleft between the two domains. tmMBP2 and tmMBP3 showed different solution dynamics, with the translational and rotational components dominating the dynamics of both systems, resulting in a clear differentiation of their diffusion pattern. A faster dynamics component was also observed and was attributed to segmental dynamics. Differences observed between the ligand-free (apo) and ligand-bound (holo) states of the two proteins are attributed to conformational entropy. Our results highlight the intricacies of how structure and dynamics can together shape binding to a repertoire of substrates in structurally similar proteins.}, }
@article {pmid40978103, year = {2025}, author = {Bukavina, L and Isali, I and Parekh, S and Psutka, S and Uzzo, N and Leonard, S and Calaway, A and Patel, S and Grivas, P and Jia, A and Correa, A and Brown, JR and Kutikov, A and Ponsky, L and Uzzo, R and Sindhani, M and Catto, J and Wu, CW and Abbosh, PH}, title = {Genetic susceptibility and environmental risk factors in bladder cancer: Evidence from the UK biobank.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {11}, number = {3}, pages = {23523735251370863}, pmid = {40978103}, issn = {2352-3735}, abstract = {PURPOSE: This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility.
EXPERIMENTAL DESIGN: Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset.
RESULTS: Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer.
CONCLUSIONS: Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.}, }
@article {pmid40977057, year = {2025}, author = {Ebrahimi, E and Naudin, S and Dimou, N and Mayén, AL and Wang, M and Abnet, CC and Åkesson, A and Barnett, MJ and Bellocco, R and Berrington de Gonzalez, A and Bonn, SE and Chen, C and Christiani, DC and Crane, TE and Eliassen, AH and Freudenheim, JL and Gao, YT and Garcia-Closas, M and Gierach, G and Giovannucci, EL and Gram, IT and Håkansson, N and Hirabayashi, M and Hou, T and Huang, BZ and Huerta, JM and Jayasekara, H and Koh, WP and Lacey, JV and Lagerros, YT and Loftfield, E and MacInnis, RJ and Mannisto, S and Martinez, ME and McCullough, ML and Milne, RL and Moore, SC and Mucci, LA and Neuhouser, ML and Platz, EA and Poynter, JN and Prizment, AE and Rees, S and Robien, K and Rohan, TE and Sawada, N and Setiawan, VW and Shams-White, MM and Shu, XO and Sinha, R and Stampfer, MJ and Stolzenberg-Solomon, RZ and Thomson, CA and Um, CY and van den Brandt, PA and Visvanathan, K and Wang, R and Wang, SS and White, E and White, KK and Willet, WC and Wolk, A and Yano, Y and Yaun, SS and Yuan, JM and Zheng, W and Riboli, E and Smith-Warner, SA and Brennan, P and Ferrari, P}, title = {Alcohol consumption and upper aerodigestive tract squamous cell carcinoma: evidence from 28 prospective cohorts.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf230}, pmid = {40977057}, issn = {1460-2105}, abstract = {BACKGROUND: This study aimed to investigate the association between alcohol consumption and squamous cell cancers of the upper aerodigestive tract (UADT), using data from 28 cohorts within the Pooling Project of Prospective Studies of Diet and Cancer (DCPP).
METHODS: Individual-level data from 2,365,437 participants were pooled. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models to quantify the association between alcohol consumption (grams/day) and UADT cancers risk, adjusting for potential confounders. Analyses were conducted by sex, smoking status, geographic region, and alcoholic beverages.
RESULTS: Over a median follow-up of 15.5 years, 6,903 UADT cancer cases were identified. Alcohol consumption was positively associated with UADT cancers risk overall. Even at intakes as low as 5-<15 g/day the HR estimate was 1.12 (95% CI 1.03,1.21) compared with the reference group (0.1-<5 g/day). The HR10g/day (95% CI) was 1.16 (1.14,1.18) for women and 1.12 (1.11,1.13) for men (pheterogeneity<0.0001). HR10g/day estimates were 1.14 (1.13,1.15) in current, 1.10 (1.09,1.12) in former, and 1.15 (1.12,1.18) in never-smokers. Consistent UADT HR10g/day estimates were observed across all beverage types. HR10g/day estimates varied across geographic regions, with HR10g/day (95% CI) equal to 1.15 (1.14,1.17) in Europe-Australia, 1.13 (1.11,1.15) in Asia, and 1.11 (1.09,1.12) in North America (pheterogeneity<0.0001).
CONCLUSION: Alcohol consumption was associated with UADT cancer risk, irrespective of smoking status or beverage type. However, due to differential baseline risks, alcohol is expected to impact the UADT cancer burden more in smokers than never-smokers. These findings support public health strategies to reduce alcohol consumption.}, }
@article {pmid40975077, year = {2025}, author = {Mo, T and Joffe, M and Cubasch, H and Galukande, M and Parham, G and Pinder, L and Zietsman, A and Anderson, BO and Naamala, A and Kaggwa, A and Nakazibwe, T and Nteziryayo, A and Pontac, J and Offiah, SA and Angelica, A and Oyamienlen, CS and Ezeigbo, E and Iwuoha, K and Chen, WC and Walubita, E and Lusaka, M and Nyangasi, M and Mohammed, S and Narh, CT and Boucheron, P and Foerster, M and Schüz, J and Dos-Santos-Silva, I and McCormack, V}, title = {Breast cancer overall survival, annual risks of death, and survival gap apportionment in sub-Saharan Africa (ABC-DO): 7-year follow-up of a prospective cohort study.}, journal = {The Lancet. Global health}, volume = {13}, number = {10}, pages = {e1681-e1690}, pmid = {40975077}, issn = {2214-109X}, mesh = {Humans ; Female ; *Breast Neoplasms/mortality ; Africa South of the Sahara/epidemiology ; Prospective Studies ; Middle Aged ; Adult ; Follow-Up Studies ; Aged ; Young Adult ; }, abstract = {BACKGROUND: There are few estimates of breast cancer survival and its determinants at 5 years and beyond in sub-Saharan Africa. We aimed to estimate survival up to 7 years, estimate annual mortality risk, and apportion survival gaps.
METHODS: The African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort study was done at eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, South Africa, Uganda, and Zambia). We prospectively recruited women (aged ≥18 years) who attended hospital with suspected breast cancer. Vital status was updated telephonically once every 3 months for 7 years. We collected detailed sociodemographic, clinical, and treatment data. The primary outcome was overall survival. We estimated age-standardised net survival, conditional survival, and predicted survival gains if there were favourable shifts in the distribution of prognostic factors aligned with the WHO Global Breast Cancer Initiative (GBCI).
FINDINGS: Between Sept 8, 2014, and Dec 31, 2017, 2313 women were recruited and followed up to Jan 1, 2022, and for a further year in South Africa. We excluded 87 women without breast cancer, 14 women from small racial groups (eight White and six Asian women in South Africa), 57 women with previous treatment or possible recurrences, and two women without follow-up data. The remaining 2153 (93%) women were categorised by country and race, as follows: three groups in Namibia (60 White women, 50 mixed race women, and 367 Black women), two in South Africa (37 mixed race women and 638 Black women), and one group of Black women in each of Uganda (419 women), Zambia (198 women), and Nigeria (384 women). During follow-up to at most 7 years, 1323 (61%) of 2153 women died, 672 (31%) were alive at administrative censoring, and 158 (7%) were lost to follow-up, giving crude survival at 3 years, 5 years, and 7 years of 51%, 40%, and 33%, respectively. Large between-country variations in 5-year age-standardised net survival were observed: 35-42% in Zambia and Nigeria; 52-58% in Black women in Uganda, South Africa, and Namibia; and over 83% in non-Black Namibian women. The annual probability of death (1-year conditional net survival, censored before the COVID-19 pandemic) declined generally from 2-3 years after diagnosis, but remained at 8-21% for Black women in Namibia, Uganda, and Nigeria during the fifth year after diagnosis. Reaching the GBCI 60% stage I or II target and accessing treatment would lead to an approximate reduction in deaths by a third among Black women in Namibia, Nigeria, South Africa, Uganda, and Zambia.
INTERPRETATION: Survival after breast cancer is poor in several sub-Saharan African countries, with a substantial risk of death even among women who have survived beyond 3 years after diagnosis. Understanding and preventing deaths among longer-term breast cancer survivors requires further research.
FUNDING: National Cancer Institute, Susan G Komen, and International Agency for Research on Cancer.
TRANSLATIONS: For the Yoruba, Hausa, Igbo, Luganda and French translations of the abstract see Supplementary Materials section.}, }
@article {pmid40964312, year = {2025}, author = {Bansal, AM and Horowitz, LF and Yeung, M and Gujral, TS and Folch, A}, title = {BIOPRINTING OF MICRODISSECTED TUMOR "CUBOIDS" IN HYDROGELS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964312}, issn = {2692-8205}, abstract = {Microscale tumor models made from microdissected tumors that retain much of the original human tumor microenvironment (TME) are emerging as an alternative to preclinical animal models. We have introduced a drug testing approach that utilizes regularly-cut, cuboidal-shaped microdissected tissues, or "cuboids," as a way to maximize creation of microtissues from scarce biopsy materials. However, microtissues (e.g., cuboids, organoids, spheroids, etc.) can be difficult to place in precise locations, especially in applications that require their culture in hydrogels. Here, using cuboids from mouse tumor models, we demonstrate a simple bioprinting strategy for precise placement and immobilization of cuboids in hydrogel. We use a commercial bioprinter to bioprint -containing hydrogel into arrays of small hydrogel dots containing cuboids, or "cuboid dots," either onto a Transwell insert or into traps on a microplate. The hydrogel serves to immobilize the cuboids in place and provides a matrix to support cuboid viability. We demonstrate proof-of-concept applications for cancer drug testing and for protein profiling analysis. This approach will enable interface of cuboids with other devices, such as on top of a sensor or in a microfluidic platform. Furthermore, this automated process of dispensing and localizing cuboids (or other microtissue formats such as spheroids or organoids) could further their application to drug discovery and personalized medicine.}, }
@article {pmid40964006, year = {2025}, author = {Moosavi, D and Lim, U and Hullar, M and Rettenmeier, C and Kwee, S and Monroe, K and Ernst, T and Randolph, T and Wilkens, L and Marchand, LL and Lampe, J and Park, SY}, title = {Association Between Plant-Based Diet Quality and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in the Multiethnic Cohort Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40964006}, issn = {2693-5015}, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease (NAFLD), is a growing public health concern with limited effective treatments. Diet quality may influence MASLD risk, yet the role of plant-based diet quality across diverse populations remains unclear.
OBJECTIVE: To evaluate the associations of plant-based dietary patterns with liver fat content or MASLD prevalence in multiethnic older adults.
METHODS: We analyzed cross-sectional data on 1,598 participants in the Adiposity Phenotype Study (APS), nested within the Multiethnic Cohort Study. Scores for three established plant-based diet indices were computed from food frequency questionnaire responses: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). Liver fat was measured using MRI, and MASLD was defined, among participants reporting zero to low alcohol intakes. Multivariable linear models of liver fat and logistic models of MASLD were used to estimate their associations with the plant-based diet indices, adjusting for demographic, lifestyle, and anthropometric covariates.
RESULTS: Higher hPDI scores were associated with lower liver fat content (adjusted mean for 4th (5.39) vs. 1st quartile (6.52) and reduced likelihood of MASLD (OR for 4th vs. 1st quartile = 0.58 (95% CI: 0.41-0.81). When stratified across five racial and ethnic groups, stronger inverse associations were observed among Latino and White participants (p-heterogeneity = 0.001) than among African American, Japanese American, or Native Hawaiian participants. No consistent associations were observed for PDI or uPDI. Among hPDI components, higher nut and lower animal fat intakes were associated with lower liver fat and MASLD.
CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with lower liver fat and MASLD prevalence, with some racial and ethnic variation. These findings underscore the importance of plant-food quality and may inform dietary strategies for MASLD prevention in heterogeneous populations.}, }
@article {pmid40975076, year = {2025}, author = {Stover, J and Sonneveldt, E and Tam, Y and Horton, KC and Phillips, AN and Smith, J and Martin-Hughes, R and Ten Brink, D and Citron, DT and Kim, HY and Akullian, A and Mudimu, E and Pickles, M and Bershteyn, A and Williamson, J and Meyer-Rath, G and Jamieson, L and Sully, EA and White, JN and Heaton, A and Clark, RA and Tong, H and Richards, AS and McQuaid, CF and Houben, RMGJ and White, RG and Dimitrov, D and Kaftan, D}, title = {Effects of reductions in US foreign assistance on HIV, tuberculosis, family planning, and maternal and child health: a modelling study.}, journal = {The Lancet. Global health}, volume = {13}, number = {10}, pages = {e1669-e1680}, pmid = {40975076}, issn = {2214-109X}, mesh = {Humans ; *Tuberculosis/economics/prevention & control/epidemiology ; *HIV Infections/economics/prevention & control/epidemiology ; United States ; *Family Planning Services/economics ; Female ; *Child Health/economics ; Child ; Models, Theoretical ; Pregnancy ; *International Cooperation ; Global Health ; Developing Countries ; *Maternal Health/economics ; }, abstract = {BACKGROUND: The USA has traditionally been the largest donor to health programmes in low-income and middle-income countries (LMICs). In January 2025, almost all such funding was stopped and prospects for its resumption are uncertain. The suddenness of the funding cuts makes it difficult for national health programmes in LMICs to adapt. We aimed to estimate the impact of these cuts on deaths and other outcomes (new infections, number of family planning users, and unplanned pregnancies) for four health areas that have been a focus of a substantial amount of US foreign assistance: HIV, tuberculosis, family planning, and maternal and child health.
METHODS: We applied established mathematical models to the countries receiving US foreign assistance in each domain to estimate health impacts over the period 2025 to 2030. We used six models of HIV, three different approaches to estimate family planning impact, and one model each for tuberculosis and maternal and child health, applying these models to as many as 80 countries. We compared model projections assuming constant funding (status quo) with projections assuming complete elimination of US funding in each country. Some models also considered partial cuts or restoration of funding over time.
FINDINGS: A complete cessation of US funding without replacement by other sources would lead to drastic increases in deaths from 2025 to 2030: 4·1 million (range 1·6-6·6) additional AIDS-related deaths across 55 countries, 606 900 (95% uncertainty interval [UI] 466 000-768 800) additional tuberculosis deaths across 79 countries, 40-55 million additional unplanned pregnancies and 12-16 million unsafe abortions across 51 countries, and 2·5 million (1·3-4·5) additional child deaths from causes other than HIV and tuberculosis across 24 countries. Restoration of funding for HIV treatment but not prevention would avoid most of the increase in deaths but still result in nearly 1 million more new HIV infections from 2025 to 2030.
INTERPRETATION: Substantial progress has been made in improving global health in the past few decades. This progress has strengthened hope in reaching global development goals. However, the recent funding cuts threaten to change these trajectories and could lead to sharp increases in avoidable mortality for the poorest countries. Even a partial restoration of US funding would combat the most severe effects and provide time for countries that have received substantial US foreign assistance to adjust to the new funding landscape.
FUNDING: Economic and Social Research Council; Engineering and Physical Sciences Research Council; European and Developing Countries Clinical Trials Partnership; Gates Foundation; Global Fund to Fight AIDS, Tuberculosis, and Malaria; Open Philanthropy; UK Foreign, Commonwealth & Development Office; UK Medical Research Council; UN Population Fund; UNAIDS; US National Institute of Allergy and Infectious Diseases; University of Edinburgh; US National Institutes of Health; US President's Emergency Plan for AIDS Relief; Wellcome Trust; World Bank; WHO.}, }
@article {pmid40975064, year = {2025}, author = {Nishida-Aoki, N and Zhu, S and Chan, M and Kang, Y and Fujita, M and Jiang, X and McCabe, M and Vaz, JM and Davidson, NE and Ghajar, CM and Hansen, K and Welm, AL and Pillarisetty, VG and Gujral, TS}, title = {Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102357}, doi = {10.1016/j.xcrm.2025.102357}, pmid = {40975064}, issn = {2666-3791}, abstract = {Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.}, }
@article {pmid40974099, year = {2025}, author = {Dreyzin, A and Ware, M and Stumbras, K and Kairalla, J and Hibbitts, E and Mossman, B and Balsamo, L and Rodwin, R and Ness, KK and Conley, CC and Raetz, E and Devidas, M and Sung, L and Loh, M and Hunger, SP and Schore, RJ and Angiolillo, A and Kadan-Lottick, N}, title = {Caregivers' Perspectives on Changes in Family Life During B-ALL Therapy: A Qualitative Study From the Children's Oncology Group.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e32057}, doi = {10.1002/pbc.32057}, pmid = {40974099}, issn = {1545-5017}, support = {//Children's Oncology Group/ ; U10CA095861/CA/NCI NIH HHS/United States ; U10CA180886-06S1/NH/NIH HHS/United States ; U10CA98543/NH/NIH HHS/United States ; U10CA98413/NH/NIH HHS/United States ; U10CA180886/NH/NIH HHS/United States ; U10CA180899//NCTN Network Group Operations Center/ ; UG1CA189955//NCTN Statistics and Data Center/ ; //NCORP Grant for Cancer Control Studies/ ; T32CA261787//St. Baldrick's Foundation/ ; }, abstract = {BACKGROUND: Treatment of pediatric B-acute lymphoblastic leukemia (B-ALL) impacts both patients and their caregivers. An understanding of family functioning during therapy can inform family-centered care. We aimed to prospectively identify negative and positive changes in family life as perceived by caregivers throughout ALL therapy.
METHODS: Caregivers of children aged ≥4 years with average-risk B-ALL enrolled on the Children's Oncology Group trial AALL0932 who consented to an ancillary study were asked: "How has family life changed since your child's diagnosis of leukemia for the better or for the worse?" Written free responses were collected at approximately 2, 8, 17, 26 (end of therapy for females), and 38 (end of therapy for males) months post-diagnosis. Inductive content analysis was used to create codes, subcategories, and categories. Descriptive statistics were used to characterize the sample and frequencies of reported codes.
RESULTS: Overall, 994 responses were collected from caregivers of 468 children across all timepoints. Twenty-seven individual codes were identified, categorized by negative changes (reported by 89% of caregivers) and positive changes (reported by 58% of caregivers). Subcategories of negative changes, including changes in daily routines, work and finance, patient health and care needs, effects on other family members, and emotional changes, were identified across all timepoints, but were most prevalent early in therapy. Importantly, positive changes were also identified, including family support, community support, and changes in outlook.
CONCLUSION: This study identifies negative and positive family changes perceived by caregivers of children undergoing B-ALL therapy that can inform future interventions to better support families.}, }
@article {pmid40974097, year = {2025}, author = {Deslandes, B and Wu, X and Lee, MA and Goudswaard, LJ and Jones, GW and Gsur, A and Lindblom, A and Ogino, S and Vymetalkova, V and Wolk, A and Wu, AH and Huyghe, JR and Peters, U and Phipps, AI and Thomas, CE and Pai, RK and Grant, RC and Buchanan, DD and Yarmolinsky, J and Gunter, MJ and Zheng, J and Hazelwood, E and Vincent, EE}, title = {Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development.}, journal = {Journal of leukocyte biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jleuko/qiaf131}, pmid = {40974097}, issn = {1938-3673}, abstract = {Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells - a highly dynamic lymphocyte subtype - undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified six genes - FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258 - with strong evidence for a causal role in CRC development (FDR-P<0.05; colocalisation H4>0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.}, }
@article {pmid40974095, year = {2025}, author = {Kistler, K and Bedford, T}, title = {Seasonal influenza viruses show distinct adaptive dynamics during growth in chicken eggs.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msaf227}, pmid = {40974095}, issn = {1537-1719}, abstract = {Human influenza viruses are grown in chicken eggs for vaccine production. Sequences of these egg-passaged viruses give us the opportunity to examine the evolution that occurs when these human viruses are subjected to the selective pressure of growing in chicken eggs, which (among other things) express different sialic acid receptors. The repetition of this evolutionary experiment in hundreds of strains over the past several decades allows us to identify mutations that adapt the virus to eggs and epistatic constraints that influence them. We analyze influenza A/H3N2, A/H1N1pdm, B/Vic and B/Yam sequences that were passaged in eggs and find that almost all of the adaptive mutations are located around the receptor-binding pocket of hemagglutinin (HA). We observe epistatic interactions both between adaptive mutations and between these mutations and the continually-evolving human influenza HA background sequence. Our results show that this background dependence is greatest for influenza A/H3N2, then A/H1N1pdm, with B/Vic and B/Yam showing little-to-no background dependence. We find that the total number of adaptive mutations and the length of adaptive walk also follow the same pattern between the influenza subtypes, suggesting that background dependence, number of adaptive mutations, and extent of additive versus epistatic interactions may all be related features of the fitness landscape.}, }
@article {pmid40973225, year = {2025}, author = {Ch'en, PY and Zhang, Y and Hippe, DS and Akaike, T and Miller, NJ and Church, C and Lachance, K and Finberg, A and Gooley, T and Hall, E and Bhatia, S and Nghiem, P}, title = {Real-world outcomes of patients receiving salvage therapies for immune checkpoint inhibitor-resistant Merkel cell carcinoma: a rationale for future clinical trials.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {9}, pages = {}, doi = {10.1136/jitc-2025-012660}, pmid = {40973225}, issn = {2051-1426}, mesh = {Humans ; *Salvage Therapy/methods ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Carcinoma, Merkel Cell/drug therapy/mortality/pathology ; Male ; Female ; Aged ; Middle Aged ; *Drug Resistance, Neoplasm ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/mortality ; Treatment Outcome ; Prospective Studies ; }, abstract = {BACKGROUND: Merkel cell carcinoma is an aggressive skin cancer that progresses to advanced/metastatic disease in~40% of patients. First-line immune checkpoint inhibitors (ICI) that block the programmed cell death protein-1/programmed death-ligand 1 axis provide 3-year progression-free responses in only~40% of patients. The relative efficacy of salvage therapies in this setting is unclear.
METHODS: In a prospectively enrolled single-center cohort, 106 patients had disease progression during or shortly after ICI and received at least one local or systemic salvage therapy. Baseline disease characteristics, treatments, and outcomes data were collected. Patients were stratified by primary resistance (no response to initial ICI) or acquired resistance (loss of ICI response after initial benefit). Primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS). Associations between salvage therapies and outcomes were evaluated using Cox models with time-varying covariates for treatments and adjustments for disease burden and ICI resistance type.
RESULTS: In this cohort, 44 patients (42%) met criteria for primary resistance and 31 (29%) had acquired resistance. Median PFS from salvage initiation was more than double for patients with acquired versus primary resistance (9.5 vs 4.7 months; p=0.006). Median DSS was not reached for acquired resistance and 14.3 months for primary resistance (p=0.006). A minority of patients (n=14) survived ≥3 years after salvage initiation, typically following customized, multimodal salvage strategies. Among salvage regimens (ICI alone, ICI+radiation therapy (RT), chemotherapy, chemotherapy+ICI), only ICI+RT had a statistically significant association with improved DSS relative to ICI alone (after adjustment, including disease burden and ICI resistance type: adjusted HR 0.35, 95% CI 0.14 to 0.91).
CONCLUSIONS: Patients with acquired resistance receiving salvage therapy have improved survival compared with those with primary resistance. While the addition of radiation to ICI was clearly associated with improved DSS, there continues to be a major need for new approaches to address ICI-resistant disease. Nevertheless, a durable benefit in select patients is possible via sequential, individualized, multidisciplinary treatments. We anticipate these data will be relevant for the design of clinical trials for this challenging ICI-resistant setting.}, }
@article {pmid40972808, year = {2025}, author = {Bhat, P and Van Amburg, JC and Potts, CR and Gracie, TJ and Cartailler, JA and Parker, AC and Savona, MR and Lu, R and Lee, SC and Welner, RS and Bick, AG and Jr, PBF}, title = {A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.}, journal = {Experimental hematology}, volume = {}, number = {}, pages = {105252}, doi = {10.1016/j.exphem.2025.105252}, pmid = {40972808}, issn = {1873-2399}, abstract = {Myelodysplastic syndromes (MDS) are a group of malignant clonal disorders that are characterized by functional impairment of hematopoiesis, morphologic dysplasia, and genetic heterogeneity[1]. While less likely to transform to acute leukemia, lower-risk MDS (LR-MDS) include patients with IPSS-M moderate low risk, low risk, and very low risk patients[2] and have a limited median survival of 3 to 10 years[3]. Further, there is growing interest in discovering translational targets of LR-MDS pathophysiology. Clonal populations within the hematopoietic stem and progenitor (HSPC) to myeloid differentiation spectrum are widely considered to be a major contributor to MDS pathophysiology[4]. A granular assessment of cell-type and lineage-specific states that contribute to LR-MDS pathophysiology remains to be elucidated. Here, we leverage single-cell transcriptomics to characterize cell states across the HSPC-myeloid differentiation landscape in LR-MDS. We develop a 30-gene score to classify LR-MDS HSPCs and identify novel molecular features of LR-MDS. The genes in our score suggest dysfunction in vesicular trafficking, which we further resolve across the myeloid differentiation axis. The gene products of vesicular trafficking-related pathways may be suitable translational targets for LR-MDS. TEASER ABSTRACT: We leveraged single-cell transcriptomics to differentiate low-risk MDS and healthy cells from patient bone marrow samples. A combination approach of network analysis and classification was used to identify a 30-gene signature that distinguishes MDS HSPCs from HD HSPCs. Upregulation of pathways related to protein translation, pro-inflammatory cytokine production, and vesicular trafficking were observed. Lastly, we stratify the thirty genes by their expression across the HSPC-myeloid differentiation axis and highlight divergent expression patterns in genes related to vesicular trafficking components.}, }
@article {pmid40972633, year = {2025}, author = {Agnandji, ST and Bok, J and Alabi, A and Kabwende, AL and Mbouna, A and Bie, J and Moukiti, E and Lalremruata, A and Esen, M and Kreidenweiss, A and Kc, N and Sim, BKL and Richie, TL and Preston Church, LW and McCall, MBB and Hoffman, SL and Kremsner, PG and Mordmüller, B}, title = {Safety, tolerability, and protective efficacy of a radiation-attenuated, whole sporozoite malaria vaccine in children in Gabon: a randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00434-7}, pmid = {40972633}, issn = {1474-4457}, abstract = {BACKGROUND: Highly effective malaria vaccines are crucial to further reduce the burden of malaria. The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) Vaccine protects adults; however, there are insufficient efficacy data in child populations. We aimed to assess the safety and efficacy of the PfSPZ Vaccine in children aged 1-12 years in Gabon.
METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was conducted at the Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. Healthy children were stratified by age (1-2, 3-6, and 7-12 years) and allocated 2:1 by block randomisation to receive 9·0 × 10[5] PfSPZ Vaccine or placebo (normal saline), administered by direct venous inoculation on days 1, 8, and 29. Artemether-lumefantrine was given before the third vaccination to clear latent parasitaemia. The co-primary endpoints were safety, evaluated in the intention-to-treat population by severe adverse events within 7 days (solicited) and 28 days (unsolicited) of vaccination and by serious adverse events; and vaccine efficacy, measured as time to first P falciparum-positive thick blood smear (TBS), 2-26 weeks after immunisation in those who received three vaccinations (ie, the modified intention-to-treat population). The trial was registered at ClinicalTrials.gov, NCT03521973, and is complete.
FINDINGS: Between June 21, 2018, and April 30, 2019, 345 children were assessed for eligibility, of whom 200 were enrolled to the study: 134 were allocated to receive PfSPZ Vaccine and 66 to receive placebo. 192 participants received three vaccinations and comprised the modified intention-to-treat population. Systemic adverse events were reported by 33 (25%) of 134 participants in the vaccine group (47 events) and 15 (23%) of 66 participants in the placebo group (25 events); subjective fever was the most reported event in both groups. Three grade 3 systemic adverse events were reported (two cases of elevated body temperature and one case of subjective fever), all in the placebo group. 32 serious adverse events were reported across 22 study participants, 13 (10%) of 134 in the vaccine group and nine (14%) of 66 in the placebo group, all of which were considered unrelated to the intervention. There were no treatment-related deaths. 25 (19%) of 129 vaccine recipients and 14 (23%) of 63 placebo recipients became TBS-positive for P falciparum at 2-26 weeks after vaccination. The age-stratum-adjusted vaccine efficacy (1 - hazard ratio) was 9% (95% CI -75 to 53; p=0·78).
INTERPRETATION: PfSPZ Vaccine is well tolerated and safe, but it did not prevent P falciparum infection in children in Gabon. Whether presumptive treatment during immunisation or more potent PfSPZ vaccines can establish vaccine efficacy is currently under investigation.
FUNDING: German Center for Infection Research, European and Developing Countries Clinical Trials Partnership, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.}, }
@article {pmid40972587, year = {2025}, author = {Wellington, R and Cheng, X and Dutta, S and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S}, title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102641}, doi = {10.1016/j.stemcr.2025.102641}, pmid = {40972587}, issn = {2213-6711}, abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE) via endothelial-to-hematopoietic transition (EHT). While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, bona fide HSC generation from iPSCs remains challenging. We map single-cell dynamics of EHT from iPSCs and integrate it with human embryo datasets to identify ligand-receptor interactions that drive transcriptional divergence between iPSC-derived and embryonic cell states. The expression of endothelial genes predicted to be regulated by FGF signaling was incompletely repressed during iPSC-derived EHT. FGF activity declined at the onset of EHT to enable normal hematopoiesis in the zebrafish, and chemical inhibition of FGF signaling during EHT enhanced HSC and progenitor generation in the zebrafish and from iPSCs. In summary, we generate a single-cell map of iPSC-derived EHT, identify ligand-receptor interactions that can improve iPSC differentiation, and uncover elevated FGF signaling as a barrier to hematopoiesis.}, }
@article {pmid40972578, year = {2025}, author = {Wang, N and Ockerman, FP and Zhou, LY and Grove, ML and Alkis, T and Barnard, J and Bowler, RP and Clish, CB and Chung, S and Drzymalla, E and Evans, AM and Franceschini, N and Gerszten, RE and Gillman, MG and Hutton, SR and Kelly, RS and Kooperberg, C and Larson, MG and Lasky-Su, J and Meyers, DA and Woodruff, PG and Reiner, AP and Rich, SS and Rotter, JI and Silverman, EK and Vasan, RS and Weiss, ST and Wong, KE and Wood, AC and Wu, L and , and Yarden, R and Blackwell, TW and Smith, AV and Chen, H and Raffield, LM and Yu, B}, title = {Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2025.08.022}, pmid = {40972578}, issn = {1537-6605}, abstract = {Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.}, }
@article {pmid40972035, year = {2025}, author = {Watling, CZ and Petrick, JL and Graubard, BI and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, JM and Hofmann, JN and Huang, WY and Kang, JH and Koshiol, J and Loftfield, E and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Palmer, JR and Purdue, MP and Rosenberg, L and Sesso, HD and Shrubsole, M and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Watts, EL and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Campbell, PT and Barupal, D and Mcglynn, KA}, title = {Pre-diagnostic circulating bile acid concentrations and liver cancer risk: a nested case-control analysis of 12 cohorts.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf086}, pmid = {40972035}, issn = {2515-5091}, abstract = {BACKGROUND: Bile acids are produced in the liver and are important for lipid digestion. Higher circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk.
METHODS: We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen pre-diagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk.
RESULTS: Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] of glycocholic acid, 95% CI: 1.32, 1.24-1.40; glycochenodeoxycholic acid: 1.33, 1.24-1.43; taurocholic acid: 1.28, 1.22-1.35; and taurchenodeoxycholic acid: 1.32, 1.24-1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16-1.39). When analyses were separated into the two main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all p-values < 0.001) that showed positive significant associations with HCC but not ICC.
CONCLUSIONS: These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.}, }
@article {pmid40971983, year = {2025}, author = {Carone, M and Wolock, CJ and Olivas-Martinez, A and Rotnitzky, A and Gilbert, PB}, title = {Immune Correlates and Vaccine Immunobridging: Statistical Innovations, Challenges, and Opportunities.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf451}, pmid = {40971983}, issn = {1537-6613}, support = {/NH/NIH HHS/United States ; }, abstract = {In immunobridging, an investigational vaccine is approved based on a randomized trial of this vaccine versus an approved vaccine with an immunogenicity primary endpoint. Justification for immunobridging requires demonstration that meeting trial success criteria implies the investigational vaccine provides worthwhile protection against a relevant endpoint for a context of use. We consider recent statistical approaches whose integration supports immunobridging: (1) variable importance prediction analysis characterizing immune markers as correlates of risk; (2) controlled risk causal analysis evaluating markers as correlates of protection; and (3) transportability analysis combining data from efficacy and immunobridging trials for estimating investigational versus approved relative-vaccine efficacy.}, }
@article {pmid40964329, year = {2025}, author = {Semenova, G and Frank, S and Dumpit, R and Han, W and Coleman, I and Gulati, R and Morrissey, C and Haffner, MC and Nelson, PS and Lee, JK}, title = {Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964329}, issn = {2692-8205}, abstract = {Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied in the treatment of hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC and the mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using a new integrated approach for custom ADC design and multiplexing. To nominate rational combinations of ADC targets and ADC payloads, we (1) examined protein co-expression of three clinically relevant surface antigens-B7 homolog 3 (B7-H3), prostate specific membrane antigen (PSMA), and six-transmembrane epithelial antigen of prostate-1 (STEAP1)-in a series of human mCRPC samples and (2) screened established ADC payloads and their combinations in mCRPC cell lines with different phenotypes. We identified synergistic interactions between DNA-damaging payloads and Bcl-xL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway. The functional relevance of isolated p53 loss and impaired PC responses to three genotoxic ADCs (B7-H3-seco-DUBA, PSMA-SG3249, and STEAP1-DXd) and their combinations with A-1331852 was established using genetic knockout models. Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC.}, }
@article {pmid40951278, year = {2025}, author = {Peoples, AR and Obón-Santacana, M and Kim, AE and Kawaguchi, ES and Fu, Y and Qu, C and Moratalla-Navarro, F and Morrison, J and Lin, Y and Arndt, V and Berndt, SI and Bien, SA and Bishop, DT and Bouras, E and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Conti, DV and Corley, DA and Devall, MA and Dimou, N and Drew, DA and Gruber, SB and Gunter, MJ and Harlid, S and Harrison, TA and Hoffmeister, M and Hsu, L and Huyghe, JR and Keku, TO and Kundaje, A and Lewinger, JP and Li, L and Lynch, BM and Marchand, LL and Martín, V and Murphy, N and Newton, CC and Ogino, S and Hardikar, S and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Pinchev, M and Platz, EA and Potter, JD and Rennert, G and Ruiz-Narvaez, EA and Sakoda, LC and Schoen, RE and Shcherbina, A and Stern, MC and Su, YR and Thomas, CE and Tian, Y and Tsilidis, KK and Um, CY and van Duijnhoven, FJB and van Guelpen, B and Visvanathan, K and Wang, J and White, E and Wolk, A and Woods, MO and Wu, AH and Ulrich, CM and Peters, U and Gauderman, WJ and Moreno, V}, title = {Genetic risk factors modulate the association between physical activity and colorectal cancer.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40951278}, issn = {2693-5015}, support = {75N92021D00005/WH/WHI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; R01 CA244588/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U01 CA084968/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis.
METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity.
RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10[- 8]). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10[- 8]). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82).
CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.}, }
@article {pmid40661642, year = {2025}, author = {Gao, J and Brusselmans, M and Carvalho, LM and Suchard, MA and Baele, G and Matsen, FA}, title = {Biological causes and impacts of rugged tree landscapes in phylodynamic inference.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661642}, issn = {2692-8205}, support = {R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Phylodynamic analysis has been instrumental in elucidating the epidemiological and evolutionary dynamics of pathogens. The Bayesian approach to phylodynamics integrates out phylogenetic uncertainty, which is typically substantial in phylodynamic datasets due to low genetic diversity. Bayesian phylodynamic analysis does not, however, scale with modern datasets, partly due to difficulties in traversing tree space. Here, we set out to characterize tree space of phylodynamic inference and assess its impacts on analysis difficulty and key biological estimates. By running extensive Bayesian analyses of 15 classic large phylodynamic datasets and carefully analyzing the posterior samples, we find that the posterior landscape in tree space ("tree landscape") is diffuse yet rugged, leading to widespread tree sampling problems that usually stem from the sequences in a small part of the tree. We develop clade-specific diagnostics to show that a few sequences-including putative recombinants and recurrent mutants-frequently drive tree space ruggedness and sampling problems, although existing data-quality tests show limited power to detect such sequences. The sampling problems can significantly impact phylodynamic inferences or even distort major biological conclusions; the impact is usually stronger on "local" estimates (e.g., introduction history) that are associated with particular clades than on "global" parameters (e.g., demographic trajectory) that are governed by the general tree shape. We evaluate existing and newly-developed MCMC diagnostics, and offer strategies for optimizing MCMC settings and mitigating impacts of the sampling problems. Our findings highlight the need for and directions to develop efficient traversal over the rugged tree landscape, ultimately advancing scalable and reliable phylodynamics.}, }
@article {pmid40502094, year = {2025}, author = {Hurlburt, NK and Lubow, J and Goo, L and Pancera, M}, title = {Structural basis for antibody cross-neutralization of Dengue and Zika viruses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40502094}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; }, abstract = {Safe and effective vaccines against co-circulating mosquito-borne orthoflaviviruses such as Zika virus (ZikV) and the four serotypes of Dengue virus (DenV1-4) must elicit broadly neutralizing antibodies (bnAbs) to prevent the risk of enhancement of infection by non-neutralizing antibodies. We recently discovered new orthoflavivirus-directed bnAbs, including F25.S02, which neutralizes DenV1-4 and ZikV with comparable or superior potency to the previously characterized E dimer epitope (EDE) bnAbs. Mutagenesis studies of viral envelope proteins showed that the epitope specificity of F25.S02 is distinct from EDE1 bnAbs. Here, we used cryoEM and X-ray crystallography to understand the basis of cross-neutralization of F25.S02 at the molecular level. We obtained a ~4.2 Å cryoEM structure of F25.S02 Fab bound to a stabilized DenV3 soluble E protein dimer and a 2.3 Å crystal structure of F25.S02 Fab bound to ZikV soluble E protein dimer. Like previously described EDE1 bnAbs, the structural epitope of F25.S02 is at the E dimer interface, encompassing predominantly conserved regions in domain II, including the fusion loop. However, unlike EDE1 bnAbs, F25.S02 binding is almost entirely dependent on the heavy chain and is shifted slightly away from the dimer symmetry axis. Our findings emphasize the importance of this cross-neutralizing site of vulnerability for DenV and ZikV that can facilitate rational design of vaccines and therapeutics.}, }
@article {pmid40971753, year = {2025}, author = {Loeb, S and Keith, SW and Gross, L and Hartman, RL and Beer, TM and Brierley, KL and Cheng, HH and Couvillon, A and Dicker, AP and Friedman, S and Gomella, LG and Karsh, L and Kelly, WK and Lallas, CD and Leader, AE and Mann, MJ and Mark, JR and Mille, P and Paller, CJ and Rana, HQ and Sokolova, AO and Trabulsi, EJ and Whang, YE and Giri, VN}, title = {Patient-Reported Outcomes From Males Regarding Germline Testing for Prostate Cancer: Results From the PROGRESS Registry.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500571}, doi = {10.1200/PO-25-00571}, pmid = {40971753}, issn = {2473-4284}, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis ; Middle Aged ; Registries ; *Genetic Testing ; *Patient Reported Outcome Measures ; Aged ; Germ-Line Mutation ; Adult ; }, abstract = {PURPOSE: Prostate cancer (PCA) germline testing (GT) informs precision therapy, cancer screening, and hereditary cancer risk for patients and families. To support patient-centered PCA GT, studying patient-reported outcomes (PROs) is essential.
METHODS: PROGRESS was a national patient-driven registry (January 2021-April 2022) for English-speaking males older than 18 years with previous/current PCA GT and Internet access. Surveys collected demographics, PCA history, family cancer history, mode of genetics care delivery, satisfaction with genetic counseling, decisional conflict, cancer genetics knowledge, and attitudes toward GT. Multiple linear regression modeling was used to estimate and draw inferences (α = .05) on strength of relationships between participant characteristics and PROs.
RESULTS: Analyses focused on 414 participants: White (88%), Black (3%), Asian (6%), and mixed/other (3%). Most participants were non-Hispanic (95.2%) and 46.9% had PCA. Genetic results were positive (pathogenic/likely pathogenic variants; mutations) in 27.9%. The three most common modes of genetics care were meeting with genetics professional (in-person or remotely; 30.9%), discussing with doctor (21.1%), and using website (20.8%). In covariate-adjusted models, satisfaction scores were highest with pretest counseling by phone (β = 1.31; 95% CI, 0.26 to 2.36) or discussion with doctor (β = 1.25; 95% CI, 0.38 to 2.12). Lower decisional conflict scores were reported for pretest counseling by phone (β = -3.76; 95% CI, -7.28 to -0.24). Males with mutations reported higher GT benefit scores (β = .30; 95% CI, 0.02 to 0.59) and importance of GT (β = .34; 95% CI, 0.08 to 0.61). Asian Americans reported lower GT satisfaction (β = -2.91; 95% CI, -4.34 to -1.48) and higher decisional conflict (β = 8.93; 95% CI, 4.36 to 13.51).
CONCLUSION: PROGRESS Registry informs the first comprehensive report of PROs among males undergoing PCA GT, providing insights into opportunities to improve patient experience and leverage the benefit of GT.}, }
@article {pmid40971752, year = {2025}, author = {Raychaudhuri, R and Garraway, IP and Maxwell, KN and Rettig, M and Desai, H and Schoen, MW and Schweizer, MT and Beltran, H and Nelson, PS and Montgomery, B}, title = {Prognostic Significance of RB1 Alterations on Outcomes in Metastatic Prostate Cancer.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500341}, doi = {10.1200/PO-25-00341}, pmid = {40971752}, issn = {2473-4284}, mesh = {Humans ; Male ; Aged ; *Retinoblastoma Binding Proteins/genetics ; Prognosis ; Retrospective Studies ; Middle Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/mortality/pathology ; *Ubiquitin-Protein Ligases/genetics ; Neoplasm Metastasis ; *Prostatic Neoplasms/genetics/mortality/pathology ; }, abstract = {PURPOSE: Emerging evidence suggests that RB1 inactivation may be a strong predictor of poor survival for men with prostate cancer (PC); however, large-scale validation is lacking.
METHODS: We analyzed whether RB1 alterations are associated with inferior survival in advanced PC and evaluated the impact of co-occurring genomic alterations on outcomes using retrospective data from the Veteran's Health Administration and Veterans Affairs Multi-Omics Analysis Platform for Prostate Cancer from 2016 to 2023.
RESULTS: The primary outcome was overall survival (OS) from onset of metastatic castration-resistant prostate cancer (mCRPC), as well as OS from initiation of life-prolonging therapy other than androgen deprivation therapy, and time to development of mCRPC. Eighty-seven (3.5%) of the 2,512 included patients had an RB1 alteration detected. The median age at diagnosis in the RB1-altered group was 71 (IQR, 65-76) years, and 68 (IQR, 62-73) years in the RB1 wild-type group. The median overall survival from diagnosis of mCRPC was 1.31 years (95% CI, 0.89 to 1.84) in those with an RB1 alteration compared with 2.99 years (95% CI, 2.79 to 3.23). RB1 alteration alone conferred similar poor prognosis when compared with patients who had combined PTEN and TP53 alterations. A dose effect was seen with increasing numbers of tumor suppressor genes (TSGs-RB1, TP53, and PTEN) conferring poorer outcomes. The median survival of patients from diagnosis of mCRPC with zero, one, two, and three TSGs was 3.74, 2.61, 1.61, and 0.87 years, respectively. BRCA2 alterations were not associated with significantly worse outcomes unless accompanied by RB1 alteration.
CONCLUSION: In this large, real-world cohort of men with mCRPC, RB1 alterations emerged as a strong indicator of poor prognosis and can be used to stratify studies alone or in conjunction with other TSG alterations.}, }
@article {pmid40971674, year = {2025}, author = {Dinan, MA and Stratton, KL and Leisenring, WM and Yasui, Y and Chow, EJ and Tonorezos, ES and Moskowitz, CS and Yeh, JM and Noyd, D and Armstrong, GT and Oeffinger, KC}, title = {Treatment exposure-based risk-stratification for care of survivors of childhood cancer: a report from the childhood cancer survivor study.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf268}, pmid = {40971674}, issn = {1460-2105}, abstract = {BACKGROUND: Treatment exposure-based risk-stratification of long-term cancer survivors may help inform health care in survivorship clinics. We used the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to test a modified, exposure-based strata previously developed within United Kingdom to classify survivors with respect to risk of late morbidity and health-related mortality.
METHODS: Five-year survivors of childhood cancer were categorized into low, medium, and high-risk groups based on treatment exposures and diagnosis. Primary endpoints included cumulative health-related (ie, non-recurrence, non-external) late mortality and cumulative incidence of severe or fatal (CTCAE grade 3-5) chronic health conditions conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic health conditions. Cox proportional hazards models were adjusted for sex, race, ethnicity, and age at diagnosis.
RESULTS: Among 15,346 survivors diagnosed 1970-1999, the risk of developing a severe chronic condition by age 35 was 11.9% (95% CI 9.9-14.3%), 15.1% (13.7-16.6%) and 25.4% (24.3-26.5%) for low, medium, and high-risk survivors, respectively, and 6.9% (6.1-7.9%) for siblings. Multivariable analysis confirmed higher likelihood of developing a chronic condition in high (hazard ratio [HR] 2.9, 2.5- 3.4) and medium (HR 1.5, 1.3- 1.8) vs the low-risk group. Health-related mortality was similarly increased among high (HR 5.1, 3.8-7.0) and medium (HR 2.5, 1.8-3.4) risk groups, as well as Black vs Non-Hispanic White survivors (HR 1.7, 1.3-2.1).
CONCLUSIONS: Exposure-based risk categorizations can provide generalized risk stratification regarding future chronic health conditions and early mortality and may be useful in guiding management of childhood cancer survivors.}, }
@article {pmid40971295, year = {2025}, author = {Ishida, T and Mercoli, J and Heck, AM and Phelps, I and Varnum-Finney, B and Dozono, S and Nourigat-McKay, C and Kraskouskas, K and Wellington, R and Waltner, O and Jackson, DL and Delaney, C and Rafii, S and Bernstein, ID and Aldinger, KA and , and Trapnell, C and Zhao, HG and Hadland, B}, title = {Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.}, journal = {Cell reports}, volume = {44}, number = {10}, pages = {116289}, doi = {10.1016/j.celrep.2025.116289}, pmid = {40971295}, issn = {2211-1247}, abstract = {Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.}, }
@article {pmid40970704, year = {2025}, author = {Lewis, KN and Zepeda-Rivera, MA and Baryiames, AA and Jones, DS and LaCourse, KD and Bullman, S and Johnston, CD}, title = {Complete genome sequence for Slackia exigua strain SB208, isolated from a human colonic adenocarcinoma.}, journal = {Microbiology resource announcements}, volume = {}, number = {}, pages = {e0044525}, doi = {10.1128/mra.00445-25}, pmid = {40970704}, issn = {2576-098X}, abstract = {We report the complete genome sequence of Slackia exigua SB208, isolated from the resected tumor tissue of a treatment-naïve patient with colorectal cancer. This genome is composed of a single chromosome that is approximately 2 Mb in length with an overall guanine-cytosine (GC) content of 62.5%.}, }
@article {pmid40968359, year = {2025}, author = {Li, Z and M Patel, Z and Song, D and Yasa, SN and Cannoodt, R and Yan, G and Li, JJ and Pinello, L}, title = {Systematic benchmarking of computational methods to identify spatially variable genes.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {285}, pmid = {40968359}, issn = {1474-760X}, support = {1R35HG010717-01//National Human Genome Research Institute (NHGRI)/ ; }, mesh = {*Benchmarking ; *Computational Biology/methods ; Algorithms ; *Gene Expression Profiling/methods ; Humans ; Transcriptome ; }, abstract = {BACKGROUND: Spatially resolved transcriptomics offers unprecedented insight by enabling the profiling of gene expression within the intact spatial context of cells, effectively adding a new and essential dimension to data interpretation. To efficiently detect spatial structure of interest, an essential step in analyzing such data involves identifying spatially variable genes (SVGs). Despite researchers having developed several computational methods to accomplish this task, the lack of a comprehensive benchmark evaluating their performance remains a considerable gap in the field.
RESULTS: Here, we systematically evaluate 14 methods using 96 spatial datasets and 6 metrics. We compare the methods regarding gene ranking and classification based on real spatial variation, statistical calibration, and computation scalability and investigate the impact of identified SVGs on downstream applications such as spatial domain detection. Finally, we explore the applicability of the methods to spatial ATAC-seq data to examine their effectiveness in identifying spatially variable peaks (SVPs). Overall, SPARK-X outperforms other benchmarked methods and Moran's I achieves a competitive performance, representing a strong baseline for future method development. Moreover, our results reveal that most methods are poorly calibrated, and more specialized algorithms are needed to identify spatially variable peaks.
CONCLUSIONS: Our benchmarking provides a detailed comparison of SVG detection methods and serves as a reference for both users and method developers.}, }
@article {pmid40968289, year = {2025}, author = {Kim, E and Helfrich, C and Yoon, H and Chue, B and Ho, E and Aramaki, T and Duggan, C}, title = {Effects of a clinic-referred telemedical intervention to improve exercise uptake during chemotherapy.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {10}, pages = {861}, pmid = {40968289}, issn = {1433-7339}, mesh = {Humans ; Female ; Middle Aged ; Male ; Quality of Life ; *Neoplasms/drug therapy/rehabilitation/pathology ; *Exercise Therapy/methods ; Telemedicine ; Aged ; *Antineoplastic Agents/therapeutic use ; *Exercise ; Adult ; }, abstract = {PURPOSE: We successfully implemented the American College of Sports Medicine's (ACSM's) Exercise is Medicine® (EIM) initiative in a community oncology clinic. This study evaluated the impact of the evidence-based exercise intervention, adhering to ACSM guidelines on patient outcomes.
METHODS: Using a quasi-experimental research design, An experienced ACSM-certified cancer exercise trainer delivered a 12-week biweekly, online group exercise intervention to 19 patients undergoing chemotherapy. Fifteen (78.8%) completed pre/post-self-report surveys on the program's acceptability and impact, change in physical activity vital signs (PAVS), and health-related quality of life (HRQOL). We also assessed exercise uptake and PAVS at each clinic visit. Data were analyzed using t-tests and content analysis.
RESULTS: On average, participants were 60 years, female (94%), non-Latino/White (60%), had stage IV cancer (92.3%), And had been receiving chemotherapy for An average of 10 months. The intervention was acceptable (86.4% enrollment) and had excellent retention (89.5%), with moderate adherence (68%). No adverse events were reported. Reasons for lack of adherence were medical reasons and treatment side effects. Compared to baseline, participants reported non-statistically significant increased aerobic exercise and improvements in HRQOL post-intervention. Participants rated the intervention as satisfactory, acceptable, and suitable (all > 4 out of 5 on a Likert scale). In open-text comments, six (40%) of the participants appreciated being asked about PAVS at the clinic, while three (20%) did not.
CONCLUSIONS: Patients undergoing chemotherapy, the majority of whom had stage IV cancer, could safely participate in an online group exercise program. Larger studies among different patient populations are needed.}, }
@article {pmid40966708, year = {2025}, author = {Bagshaw, P and Potter, JD and Bagshaw, S}, title = {The problem with ten-year private healthcare contracts.}, journal = {The New Zealand medical journal}, volume = {138}, number = {1622}, pages = {119-120}, doi = {10.26635/6965.7171}, pmid = {40966708}, issn = {1175-8716}, }
@article {pmid40966492, year = {2025}, author = {Desai, M and Sharma, SV and Fokom Domgue, J and Chido-Amajuoyi, O and Yu, R and Chan, W and Darkoh, C and Shete, S}, title = {Healthcare professionals' awareness of and barriers to shared-clinical-decision-making for HPV vaccination among adults 27-45 years.}, journal = {Human vaccines & immunotherapeutics}, volume = {21}, number = {1}, pages = {2560061}, doi = {10.1080/21645515.2025.2560061}, pmid = {40966492}, issn = {2164-554X}, mesh = {Humans ; *Papillomavirus Vaccines/administration & dosage ; Adult ; Cross-Sectional Studies ; Female ; Middle Aged ; *Health Personnel/psychology/statistics & numerical data ; Male ; *Papillomavirus Infections/prevention & control ; Texas ; *Vaccination/psychology/statistics & numerical data ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; *Decision Making, Shared ; *Clinical Decision-Making ; }, abstract = {The Advisory Committee on Immunization Practices recommends human papillomavirus (HPV) vaccination for inadequately vaccinated adults aged 27-45 based on shared clinical decision-making (SCDM). However, little is known about awareness and barriers to SCDM among US healthcare providers (HCPs), especially in Texas, where HPV vaccination rates are below the national average. Between January and April 2021, we conducted a population-based cross-sectional survey (12% response rate) of HCPs licensed in Texas to assess the prevalence and factors associated with awareness of the SCDM recommendation. HCPs were asked if they were aware and if they foresaw any barriers in implementing SCDM for HPV vaccine recommendation. Among the 1,279 respondents, 54.26% were aware of this recommendation. HCPs practicing as gynecologists/obstetricians (adjusted odds ratio [aOR]: 6.12; 95%CI: 2.60-14.40, p < .001), those working in Federally Qualified Health Centers (aOR: 2.13, 95%CI: 1.24-3.65, p = .006) or group practices (aOR: 1.68, 95%CI: 1.22-2.30, p = .001), those seeing ≤ 100 patients/week (aOR: 1.70, 95%CI: 1.15-2.51, p = .008), those who had received formal training on HPV vaccination promotion and counseling within the past two years (aOR: 3.42, 95%CI: 2.29-5.10, p = < 0.001), between two and five years ago (aOR: 2.35, 95%CI: 1.67-3.30, p = < 0.001), and more than five years ago (aOR: 1.70, 95%CI: 1.16-2.50, p = .006) had significantly higher odds of awareness of SCDM recommendation. HCPs practicing as nurse practitioners/advanced nurse practitioners (aOR: 0.56; 95%CI: 0.38-0.82, p = .003), physician assistants (aOR: 0.62; 95%CI: 0.41-0.94, p = .023), aged 55 years or older (aOR: 0.57; 95%CI: 0.32-0.99, p = .046), Asian (aOR: 0.59, 95%CI: 0.43-0.81, p = .001) and non-Hispanic Black (aOR: 0.62, 95%CI: 0.40-0.97, p = .037) had significantly lower odds of awareness of SCDM recommendation. Overall, 44.96% of HCPs anticipated no barriers and planned to engage in SCDM, while 18.32% cited time commitment as an anticipated barrier. Internists cited time commitment (39.13%) as an anticipated barrier more frequently than other specialties, while physician assistants were more frequently unclear about how to implement SCDM (12.36%). We found limited awareness of the SCDM recommendation guideline for HPV vaccination among Texas HCPs. Therefore, training HCPs to use decision aids to actively engage patients in the SCDM process could improve HPV vaccination rates among unvaccinated adults aged 27-45.}, }
@article {pmid40966481, year = {2025}, author = {Lee, SJ and Logan, B and Horowitz, MM and Dehn, JG and Pidala, J and Grunwald, MR and Westervelt, P and Farhadfar, N and Hogan, WJ and Bashey, A and Hayes-Lattin, B and Hill, L and Brunstein, C and Arai, S and Srour, SA and Symons, H and Uberti, J and Vasu, S and Pusic, I and Juckett, M and Leifer, E and He, N and Devine, S and Shaw, BE and Ciurea, SO}, title = {Primary Results From Blood and Marrow Transplant Clinical Trials Network 1702: Clinical Transplant-Related Long-Term Outcomes of Alternative Donor Allogeneic Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500206}, doi = {10.1200/JCO-25-00206}, pmid = {40966481}, issn = {1527-7755}, abstract = {PURPOSE: The likelihood of finding a human leukocyte antigen (HLA)-matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood).
METHODS: This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups.
RESULTS: A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation.
CONCLUSION: Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.}, }
@article {pmid40966421, year = {2025}, author = {Ramsower, CA and Wright, G and Li, H and Cerhan, JR and Maurer, MJ and Mwangi, R and Rosenthal, AC and Novak, AJ and Link, BK and Witzig, TE and Habermann, TM and Kridel, R and LeBlanc, ML and Shadman, M and Smith, SM and Friedberg, JW and Scott, DW and Steidl, C and Staudt, LM and Rimsza, LM}, title = {Development and Validation of a Gene Expression Signature to Predict Early Events in Patients with Follicular Lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016827}, pmid = {40966421}, issn = {2473-9537}, abstract = {Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events such as transformation or progression have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, if a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from two immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase III clinical trial, where it assigned 169 to the low-risk group with 29 events before 24 months (17.2%) and 63 to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high risk group relative to patients who were classified into the low risk group was 2.2 (95% CI: 1.41 to 3.51). An upfront GEP biomarker such as the FL24Cx, rigorously validated in a clinical laboratory, with a clinically-relevant turn-around time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.}, }
@article {pmid40966416, year = {2025}, author = {Ferreira, AC and Dutta, D and Rowan, CM and Renbarger, J and Cooke, KR and Carpenter, PA and Krance, RA and Duncan, CN and Cruz, CRY and Jacobsohn, DA and Bollard, CM and Hill, E and Paczesny, S}, title = {Risk Biomarkers of Chronic Graft-versus-host disease in Children aged 10 years or younger and Children/adults Older than 10 years.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016624}, pmid = {40966416}, issn = {2473-9537}, abstract = {Assessment of risk biomarkers of chronic GVHD (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) in pediatric patients is lacking. We conducted a prospective study of 318 patients: (129 children ≤10 years and 189 children/adults >10 years). Six plasma biomarkers [CXCL9, interleukin-1 receptor-like 1 (IL1RL1), regenerating-islet-derived-3-alpha (REG3α), matrix metallopeptidase-3 (MMP3), dickkopf-WNT signaling pathway inhibitor-3 (DKK3), and sCD163] were assessed at Day (D)100 post-HCT. We performed D100 landmark analyses for cGVHD, stratifying at ≤10 years vs >10 yr and dichotomizing markers using Youden's index. IL1RL1 is associated with future cGVHD in both groups: ≤10 years [hazard ratio (HR) 95% confidence interval (CI): 2.35 (1.08, 5.12), p=0.03] and >10 years [HR (95% CI): 2.09 (1.22, 3.59), p=0.01], as is DKK3: ≤10 years [HR (95% CI): 2.39 (1.05, 5.42), p=0.04] and >10 years [HR (95% CI): 2.10 (1.20, 3.66), p=0.01]. CXCL9, REG3α, and MMP3 are associated with cGVHD in patients >10 years [HR (95% CI): CXCL9: 2.37 (1.08, 5.21), p=0.03; REG3α: 1.71 (1.03, 2.82), p=0.04; MMP3: 2.36 (1.33, 4.16), p=0.003]. This 5-marker panel has an AUC of 0.71 in children ≤10 years and 0.72 in children/adults >10 years for cGVHD risk, and 0.86 in children ≤10 years and 0.80 in children/adults >10 years for moderate/severe cGVHD risk. A 5-biomarker panel (IL1RL1, REG3α, MMP3, DKK3, and sCD163) was associated with TRM in both groups. Biomarkers measured 3 months post-HCT predict susceptibility and/or are prognostic for cGVHD and TRM in both children aged ≤10 years and children/adults >10 years, allowing for additional risk stratification.}, }
@article {pmid40963258, year = {2025}, author = {Santiago-Torres, M and Mull, KE and Shi, D and Alexander, AC and Nollen, NL and Sullivan, BM and Zvolensky, MJ and Bricker, JB}, title = {Intersectionality in cigarette smoking cessation: A latent class analysis to predict 12-month cessation in a randomized controlled trial.}, journal = {Addiction (Abingdon, England)}, volume = {}, number = {}, pages = {}, doi = {10.1111/add.70185}, pmid = {40963258}, issn = {1360-0443}, support = {R01CA192849/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Currently, smoking cessation intervention research on marginalized populations focuses on a single attribute (e.g. race). However, these attributes intersect and research on this intersectionality has been rare. This study applied latent class analysis (LCA) to examine how multiple theory-driven baseline factors interact and predict 12-month 30-day point prevalence abstinence from cigarette smoking in 2415 adult participants in a digital smoking cessation intervention.
DESIGN: Theory-based analysis of a randomized trial with 12-month smoking cessation follow-up.
SETTING: United States (US).
PARTICIPANTS: A total of 2415 adults who smoke that were recruited from all 50 US states and enrolled in the trial between May 2017 and September 2018.
INTERVENTION AND COMPARATOR: In the parent RCT, participants were randomized to receive iCanQuit, an Acceptance and Commitment Therapy-based smartphone smoking cessation app (n = 1214) or QuitGuide, a US Clinical Practice Guidelines-based smoking cessation app (n = 1201) for 12 months.
MEASUREMENTS: Guided by Sheffer et al.,six theory-based factors were examined, including social identities: gender, race and ethnicity, marital status, sexual and gender minority (SGM) identity and socio-economic status (SES; education, income, employment); and lived experiences: positive screen for experiencing depression symptoms. Social identity and lived experiences data were collected via baseline questionnaires. The primary smoking cessation outcome was self-reported complete-case 30-day point prevalence abstinence at 12 months. SAS PROC LCA was used to identify classes based on the six selected factors and to predict 12-month smoking cessation.
FINDINGS: A 4-class model showed the best goodness-of-fit statistics and interpretability. Participants in class 1 (n = 352, 14.6%) were more likely to be women, individuals of Black race and those with single marital status. Participants in class 2 (n = 322, 13.3%) were more likely to be men, SGM individuals and socioeconomically advantaged, as indicated by higher education, higher income or employment. Participants in class 3 (n = 368, 15.2%) were socioeconomically disadvantaged and screened positive for experiencing depression symptoms at baseline (CES-D ≥ $$ \ge $$ 16). Finally, participants in class 4 (n = 1373, 56.9%) were more likely to be women, individuals of White race and married. Class 2 had the highest smoking cessation rate (32.8%) at 12 months, followed by class 1 (27.3%), class 4 (24.2%) and class 3 (15.4%). Compared with class 2, class 3 had 63% lower odds of quitting smoking (odds ratio = 0.37; 95% confidence interval = 0.20-0.71, P = 0.016).
CONCLUSIONS: People with both socioeconomic disadvantage and symptoms of depression appear to have a harder time quitting smoking than other people who try to quit.}, }
@article {pmid40961411, year = {2025}, author = {Siddiqui, NS and Bouchi, Y and Shah, SJH and Alqarni, S and Sood, S and Lee, Y and Park, J and Kang, J}, title = {Clinician's Artificial Intelligence Checklist and Evaluation Questionnaire: Tools for Oncologists to Assess Artificial Intelligence and Machine Learning Models.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500067}, doi = {10.1200/CCI-25-00067}, pmid = {40961411}, issn = {2473-4276}, mesh = {Humans ; *Artificial Intelligence/standards ; *Machine Learning ; Surveys and Questionnaires ; *Checklist ; *Oncologists ; *Medical Oncology/methods/standards ; *Neoplasms/diagnosis/therapy ; }, abstract = {Advancements in oncology are accelerating in the fields of artificial intelligence (AI) and machine learning. The complexity and multidisciplinary nature of oncology necessitate a cautious approach to evaluating AI models. The surge in development of AI tools highlights a need for organized evaluation methods. Currently, widely accepted guidelines are aimed at developers and do not provide necessary technical background for clinicians. Additionally, published guides introducing clinicians to AI in medicine often lack user-friendly evaluation tools or lack specificity to oncology. This paper provides background on model development and proposes a yes/no checklist and questionnaire designed to help oncologists effectively assess AI models. The yes/no checklist is intended to be used as a more efficient scan of whether the model conforms to published best standards. The open-ended questionnaire is intended for a more in-depth survey. The checklist and the questionnaire were developed by clinical and AI researchers. Initial discussions identified broad domains, gradually narrowing to model development points relevant to clinical practice. The development process included two literature searches to align with current best practices. Insights from 24 articles were integrated to refine the questionnaire and the checklist. The developed tools are intended for use by clinicians in the field of oncology looking to evaluate AI models. Cases of four AI applications in oncology are analyzed, demonstrating utility in real-world scenarios and enhancing case-based learning for clinicians. These tools highlight the interdisciplinary nature of effective AI integration in oncology.}, }
@article {pmid40960399, year = {2025}, author = {Lotter, W and Hippe, DS and Oshiro, T and Lowry, KP and Milch, HS and Miglioretti, DL and Elmore, JG and Lee, CI and Hsu, W}, title = {Influence of Mammography Acquisition Parameters on AI and Radiologist Interpretive Performance.}, journal = {Radiology. Artificial intelligence}, volume = {}, number = {}, pages = {e240861}, doi = {10.1148/ryai.240861}, pmid = {40960399}, issn = {2638-6100}, abstract = {"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To evaluate the impact of screening mammography acquisition parameters on the interpretive performance of AI and radiologists. Materials and Methods The associations between seven mammogram acquisition parameters-mammography machine version, kVp, x-ray exposure delivered, relative x-ray exposure, paddle size, compression force, and breast thickness-and AI and radiologist performance in interpreting two-dimensional screening mammograms acquired by a diverse health system between December 2010 and 2019 were retrospectively evaluated. The top 11 AI models and the ensemble model from the Digital Mammography DREAM Challenge were assessed. The associations between each acquisition parameter and the sensitivity and specificity of the AI models and the radiologists' interpretations were separately evaluated using generalized estimating equations-based models at the examination level, adjusted for several clinical factors. Results The dataset included 28,278 screening two-dimensional mammograms from 22,626 women (mean age 58.5 years ± 11.5 [SD]; 4913 women had multiple mammograms). Of these, 324 examinations resulted in breast cancer diagnosis within 1 year. The acquisition parameters were significantly associated with the performance of both AI and radiologists, with absolute effect sizes reaching 10% for sensitivity and 5% for specificity; however, the associations differed between AI and radiologists for several parameters. Increased exposure delivered reduced the specificity for the ensemble AI (-4.5% per 1 SD increase; P < .001) but not radiologists (P = .44). Increased compression force reduced the specificity for radiologists (-1.3% per 1 SD increase; P < .001) but not for AI (P = .60). Conclusion Screening mammography acquisition parameters impacted the performance of both AI and radiologists, with some parameters impacting performance differently. ©RSNA, 2025.}, }
@article {pmid40959943, year = {2025}, author = {Chao, HX and Ma, T and Hegerova, L and Nester, T and Sen, N and Er, L and Harris, S and Lockwood, T and Buchan, JG and Lannert, KW and Gasper, J and Goffena, J and Zalusky, MPG and Storz, SHR and Montemayor-Garcia, C and Pagano, MB and Johnsen, JM and Panch, SR and Miller, DE}, title = {Long-read DNA sequencing resolves a rare case of alloimmune hemolysis mimicking autoimmune hemolysis.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18403}, pmid = {40959943}, issn = {1537-2995}, support = {DP5OD033357/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Immune hemolytic anemia poses a significant challenge in transfusion medicine, as identification of underlying alloantibodies can be masked by warm and/or cold autoantibodies. This increases the risk of transfusing incompatible blood, which can precipitate or exacerbate hemolysis. Identifying alloantibodies in the presence of autoantibodies remains difficult with standard serologic and genotypic methods, often delaying accurate diagnosis and appropriate transfusion strategies.
CASE REPORT: We describe a 63-year-old woman with autoimmune hemolytic anemia who suffered near-fatal hemolysis following transfusion. Despite extensive serologic and genotypic testing, the cause of her hemolytic transfusion reactions remained elusive. Given her clinical course and transfusion history, we hypothesized that her acute hemolytic transfusion reactions could be due to immune sensitization to a high-incidence RBC antigen. Research whole-genome long-read sequencing (LRS) revealed homozygosity for a rare KEL*02N.16 allele, consistent with a rare Ko phenotype, which was validated by Sanger sequencing. Retrospective serologic testing with Ko RBCs further confirmed alloimmunization within the Kell system.
CONCLUSION: This case highlights the limitations of conventional serologic and genotypic methods in detecting rare blood group phenotypes, and emphasizes the diagnostic power of long-read sequencing in transfusion medicine. Early molecular testing in complex hemolytic cases can facilitate targeted transfusion strategies, reduce the risk of severe hemolysis, and improve patient outcomes. As sequencing technologies become more accessible, they have the potential to revolutionize blood group typing and alloimmunization risk assessment in clinical practice.}, }
@article {pmid40956886, year = {2025}, author = {Sefik, E and Philbrick, W and Zhang, F and Agrawal, K and Van Lee, B and Sam, J and Karatepe, K and Zheng, Y and Liang, K and Peng, S and Mirza, H and Rangavajhula, A and Simon, P and Arun, N and Babu, P and Eynon, E and Chiorazzi, M and Shan, L and Halene, S and Luo, HR and Rongvaux, A and Kluger, Y and Flavell, RA}, title = {Humanization of CD47 enables development of functional human neutrophils via postirradiation remodeling of the bone marrow.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {38}, pages = {e2426546122}, doi = {10.1073/pnas.2426546122}, pmid = {40956886}, issn = {1091-6490}, support = {AWD0002623//F. Hoffmann-La Roche Ltd./ ; na//Celiac Disease Foundation/ ; DRG-2316-18//Damon Runyon Cancer Research Foundation (DRCRF)/ ; }, mesh = {Animals ; *Neutrophils/immunology/cytology/metabolism/radiation effects ; Humans ; Mice ; *CD47 Antigen/genetics/metabolism/immunology ; *Bone Marrow/radiation effects/metabolism/immunology ; Mice, Inbred C57BL ; Myelopoiesis ; Mice, Transgenic ; }, abstract = {Murine and human immune systems differ significantly, particularly within the myeloid lineage. Humanized mice, generated by transplanting human hematopoietic stem, progenitor cells into genetically modified mice, are invaluable to study human immune development and function in vivo. However, a major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a humanized mouse model, named MaGIC for genes replaced, in the C57Bl/6 N strain, which improves human myelopoiesis and enables development of functional human neutrophils. In MaGIC mice, human cytokines M-CSF/CSF1(M), GM-CSF/CSF2(G) and IL-6(I) are knocked-in replacing mouse genes and murine IL2rg and Rag1(a) are deleted. Human THPO in these mice supports human hematopoiesis. More importantly, insertion of human CD47 (C) under the control of endogenous mouse CD47 promoter enables xenotransplantation and human neutrophil development. MaGIC mice support all human neutrophil subsets found in human bone marrow and blood, a major improvement. This is achieved by creating a niche postirradiation for human granulocyte-macrophage progenitors via reduced murine CD47 and physiological levels of human CD47. These mice also have mature human monocytes, tissue macrophages, alveolar macrophages, dendritic cells, and NK cells, enabled by humanized M-CSF and GM-CSF. Human neutrophils in MaGIC mice are fully functional in chemotaxis, phagocytosis, reactive oxygen species production, and neutrophil extracellular trap formation in response to inflammation. MaGIC mice address critical gaps in current models and enable incisive translational research on human neutrophils, advancing studies in infectious, autoimmune, and inflammatory diseases.}, }
@article {pmid40956611, year = {2025}, author = {Bose, A and Bankhead Iii, A and Coleman, I and Persse, T and Han, W and Galipeau, P and Hanratty, B and Chu, T and Lucas, J and Li, D and Bilkis, R and Itagi, P and Hassan, S and Beightol, M and Ko, M and Dumpit, R and Haffner, M and Pritchard, C and Ha, G and Nelson, PS}, title = {Multiomic assessments of LNCaP and derived cell strains reveal determinants of prostate cancer pathobiology.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI194727}, pmid = {40956611}, issn = {1558-8238}, abstract = {A cornerstone of research to improve cancer outcomes involves studies of model systems to identify causal drivers of oncogenesis, understand mechanisms leading to metastases, and develop new therapeutics. While most cancer types are represented by large cell line panels that reflect diverse neoplastic genotypes and phenotypes found in patients, prostate cancer is notable for a very limited repertoire of models that recapitulate the pathobiology of human disease. Of these, Lymph node carcinoma of the prostate (LNCaP) has served as the major resource for basic and translational studies. Here, we delineated the molecular composition of LNCaP and multiple substrains through analyses of whole genome sequences, transcriptomes, chromatin structure, AR cistromes, and functional studies. Our results determined that LNCaP exhibits substantial subclonal diversity, ongoing genomic instability and phenotype plasticity. While several oncogenic features were consistently present across strains, others were unexpectedly variable such as ETV1 expression, Y chromosome loss, a reliance on WNT and glucocorticoid receptor activity, and distinct AR alterations maintaining AR pathway activation. These results document the inherent molecular heterogeneity and ongoing genomic instability that drive diverse prostate cancer phenotypes and provide a foundation for the accurate interpretation and reproduction of research findings.}, }
@article {pmid40950478, year = {2025}, author = {Xu, S and Hudson, A and Janes, HE and Tomaras, GD and Ackerman, ME}, title = {Candidate Correlates of Protection in the HVTN505 HIV-1 Vaccine Efficacy Trial Identified by Positive-Unlabeled Learning.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950478}, abstract = {With a goal of unveiling mechanisms by which vaccines can provide protection against HIV-1 acquisition, several studies have explored correlates of risk of HIV-1 acquisition in HVTN 505, which was a phase IIb trial conducted to assess the safety and efficacy of a DNA plasmid and recombinant adenovirus serotype 5-vectored HIV vaccine regimen among individuals in the United States who were vulnerable to acquiring HIV. While this trial failed to meet its predetermined efficacy criteria, both immunological and virological correlates of reduced risk of acquisition have been reported, suggesting that at least some vaccine recipients were protected from some viruses. In this work, we describe application of a novel Positive-Unlabeled machine learning-based approach to infer protection status among vaccine recipients that did not acquire HIV, resulting in improved power to detect potential correlates of immunity. Having established the analytical robustness of protection status predictions using cross-validation and permutation testing strategies, we report increased confidence in previously identified correlates of risk, such as vaccine-elicited anti-HIV-1 Env glycoprotein IgG3 antibodies and antibody-dependent phagocytosis, and the new observation of an inverse correlation between inferred vaccine-mediated protection and virus-specific IgA responses. Though its biological validity is not established, this inference approach offers a new means to use case-control datasets to identify candidate markers of effective immune responses in the context of low vaccine efficacy.}, }
@article {pmid40950047, year = {2025}, author = {Eldred, KC and Wooten, M and Janssens, DH and Hahn, J and Neph, SJ and Edgerton, SJ and Wyatt-Draher, G and Sherman, SM and Ranchalis, JE and Stergachis, AB and Reh, TA and Henikoff, S}, title = {CUT&TIME captures the history of open chromatin in developing neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950047}, issn = {2692-8205}, abstract = {Chromatin structure plays a central role in defining cell identity by regulating gene expression. During development, shifts in chromatin structure facilitate changes in gene expression needed to specify distinct cell types. To understand how changes in chromatin structure influence the developmental trajectory of neural progenitor cells, we developed CUT&TIME, a technique that uses a hyperactive 6-methyl adenosine (6mA) methyltransferase pulsed in living cells to map historical chromatin accessibility genome-wide in single cells. We show that CUT&TIME produces a record of the chromatin landscape during neurogenesis in the developing retina, specifically as neural progenitors produce the major projection neuron type, retinal ganglion cells (RGCs). We further show that this method is compatible with single cell profiling technologies, which allows us to visualize and capture the diversity of chromatin states that produce RGCs. Additionally, we identify changes in promoter accessibility associated with the transition from progenitor to RGC. Together, these data demonstrate that CUT&TIME captures a historical record of chromatin structure, which can be used to identify early changes in accessibility associated with cell-fate commitment.}, }
@article {pmid40949756, year = {2025}, author = {Visani, GM and Pun, MN and Minervina, AA and Bradley, P and Thomas, P and Nourmohammad, A}, title = {T-cell receptor specificity landscape revealed through de novo peptide design.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40949756}, issn = {2331-8422}, abstract = {T-cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. An effective binding between T-cell receptors (TCRs) and pathogen-derived peptides presented on Major Histocompatibility Complexes (MHCs) mediate an immune response. However, predicting these interactions remains challenging due to limited functional data on T-cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC class I alleles, and to design novel immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based, physics-guided machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, the implicit physical reasoning in HERMES enables us to make accurate predictions of both TCR-pMHC binding affinities and T-cell activities across diverse viral epitopes and cancer neoantigens, achieving up to 0.72 correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems targeting viral and cancer peptides, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T-cells at success rates of up to 50%. Lastly, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC complexes, offering key insights into T-cell specificity in both humans and mice. Our approach provides a platform for immunogenic peptide and neoantigen design, as well as for evaluating TCR specificity, offering a computational framework to inform design of engineered T-cell therapies and vaccines.}, }
@article {pmid40963735, year = {2023}, author = {Shao, Y and Todd, K and Shutes-David, A and Millard, SP and Brown, K and Thomas, A and Chen, K and Wilson, K and Zeng, QT and Tsuang, DW}, title = {Identifying Probable Dementia in Undiagnosed Black and White Americans Using Machine Learning in Veterans Health Administration Electronic Health Records.}, journal = {Big data and cognitive computing}, volume = {7}, number = {4}, pages = {}, pmid = {40963735}, issn = {2504-2289}, support = {R56 AG059739/AG/NIA NIH HHS/United States ; }, abstract = {The application of natural language processing and machine learning (ML) in electronic health records (EHRs) may help reduce dementia underdiagnosis, but models that are not designed to reflect minority populations may instead perpetuate underdiagnosis. To improve the identification of undiagnosed dementia, particularly in Black Americans (BAs), we developed support vector machine (SVM) ML models to assign dementia risk scores based on features identified in unstructured EHR data (via latent Dirichlet allocation and stable topic extraction in n = 1 M notes) and structured EHR data. We hypothesized that separate models would show differentiation between racial groups, so the models were fit separately for BAs (n = 5 K with dementia ICD codes, n = 5 K without) and White Americans (WAs; n = 5 K with codes, n = 5 K without). To validate our method, scores were generated for separate samples of BAs (n = 10 K) and WAs (n = 10 K) without dementia codes, and the EHRs of 1.2 K of these patients were reviewed by dementia experts. All subjects were age 65+ and drawn from the VA, which meant that the samples were disproportionately male. A strong positive relationship was observed between SVM-generated risk scores and undiagnosed dementia. BAs were more likely than WAs to have undiagnosed dementia per chart review, both overall (15.3% vs. 9.5%) and among Veterans with >90th percentile cutoff scores (25.6% vs. 15.3%). With chart reviews as the reference standard and varied cutoff scores, the BA model performed slightly better than the WA model (AUC = 0.86 with negative predictive value [NPV] = 0.98, positive predictive value [PPV] = 0.26, sensitivity = 0.61, specificity = 0.92 and accuracy = 0.91 at >90th percentile cutoff vs. AUC = 0.77 with NPV = 0.98, PPV = 0.15, sensitivity = 0.43, specificity = 0.91 and accuracy = 0.89 at >90th). Our findings suggest that race-specific ML models can help identify BAs who may have undiagnosed dementia. Future studies should examine model generalizability in settings with more females and test whether incorporating these models into clinical settings increases the referral of undiagnosed BAs to specialists.}, }
@article {pmid40956289, year = {2025}, author = {Lima, SM and Minlikeeva, AN and Johnson, CE and Guertin, KA and Bandera, EV and Zheng, W and Bethea, TN and Petrick, JL and Joslin, CE and Myers, ER and Harris, HR and Peres, LC and Setiawan, VW and Wu, AH and Rosenberg, L and Schildkraut, JM and Ochs-Balcom, HM}, title = {Regular physical inactivity and ovarian cancer risk in the Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1160}, pmid = {40956289}, issn = {1538-7755}, abstract = {BACKGROUND: Regular physical inactivity may increase ovarian cancer risk, but few studies have investigated whether this association is similar among Black and White women.
METHODS: In a pooled nested case-control within the Ovarian Cancer in Women of African Ancestry consortium, logistic regression models evaluated regular recreational physical inactivity with risk of epithelial ovarian cancer among Black (223 cases; 1,472 controls) and White women (985 cases; 6,212 controls) enrolled in four cohort studies. Models were further stratified by histological type.
RESULTS: Regular physical inactivity was not associated with risk of overall ovarian cancer among Black (OR=1.16, 95% confidence interval (CI): 0.83-1.61) or White women (OR=1.03, 95% CI: 0.87-1.23). We did not detect associations according to histological type.
CONCLUSIONS: Physical inactivity was not associated with ovarian cancer among Black or White women in a consortium of cohort studies.
IMPACT: These results are counter to case control-based studies and emphasize the complexity of investigating physical activity prospectively.}, }
@article {pmid40954009, year = {2025}, author = {Jindal, T and Jiang, CY and Alhalabi, O and Nguyen, CB and Oh, E and Tsung, I and Bakaloudi, DR and Talukder, R and Davidsohn, M and Freeman, D and Epstein, IY and Ding, CC and Nizam, A and Glover, MJ and Khaki, AR and Taylor, AK and Lemke, E and Jang, A and Evans, ST and Shin, D and Pywell, C and Basu, A and Bilen, MA and Zakharia, Y and Barata, P and Milowsky, MI and Brown, J and Kilari, D and Emamekhoo, H and Hoimes, CJ and Shah, S and Davis, NB and Gupta, S and Grivas, P and Bellmunt, J and Alva, A and Campbell, MT and Koshkin, VS}, title = {Outcomes with Enfortumab Vedotin in Patients with Histologic Subtypes of Advanced Urothelial Carcinoma: Analysis of the UNITE Study.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.09.003}, pmid = {40954009}, issn = {1873-7560}, }
@article {pmid40953734, year = {2025}, author = {Salit, RB and Fan, X and Gooley, TA and Halpern, AB and Ratsamee, N and Marshall, A and Scott, BL and Deeg, HJ}, title = {Pre-Hematopoietic Cell Transplant Ruxolitinib in Transplant-Eligible Patients with Myelofibrosis: Long-Term Outcomes of a Phase II Prospective Study.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.020}, pmid = {40953734}, issn = {2666-6367}, abstract = {BACKGROUND: Ruxolitinib (Rux), the first FDA-approved JAK-inhibitor for the treatment of myelofibrosis (MF), was initially studied in patients who were ineligible for hematopoietic cell transplantation (HCT). However, the resultant decrease in splenomegaly and improvement in symptoms allowed some of the study patients to become HCT eligible. We aimed to determine if giving Rux to HCT-eligible MF patients would yield favorable HCT outcomes in relation to a historical cohort at our center.
METHODS: We conducted a single-arm Phase II prospective single-center study of Rux followed by HCT in adult patients with primary and secondary MF between 2014 - 2020. Patients were not required to have symptoms or splenomegaly. Patients took Rux for at least 8 weeks (no maximum) prior to start of conditioning and tapered off by Day - 4 of HCT conditioning.
RESULTS: 101 patients were enrolled on study of which 61 (60%) proceeded to HCT (59% primary MF, 70% DIPSS intermediate-2 or high-risk), median age 57 years (range 34 -71) after a median of 7 months (range: 2-89) on Rux. Patients engrafted at a median of 20 days; there was one primary graft failure. Non-relapse mortality (NRM) was 13% at 1-year compared to 26% in our historical cohort. With a median follow-up of 5.6 years among survivors, overall survival (OS) was 79% (95% CI 69-90) at 2 years compared to 67% in our historical cohort; 5- year survival was 74% (95%CI 64-86). The hazard ratio (HR) of death for those who had a Rux response relative to those who did not was HR = 0.57 (95% CI, 0.20-1.61, p = 0.29).
CONCLUSION: In a prospective Phase II study, patients receiving pre-HCT Rux had encouraging NRM and survival rates relative to historical patients at our center who proceeded to HCT without prior Rux.}, }
@article {pmid40952729, year = {2025}, author = {Rossouw, JE and Aragaki, AK and Manson, JE and Szmuilowicz, ED and Harrington, LB and Johnson, KC and Allison, M and Haring, B and Saquib, N and Shadyab, AH and Rexrode, KM and Liu, L and Mouton, CP and LaCroix, AZ}, title = {Menopausal Hormone Therapy and Cardiovascular Diseases in Women With Vasomotor Symptoms: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, pmid = {40952729}, issn = {2168-6114}, abstract = {IMPORTANCE: Identification of appropriate patients for treatment of vasomotor symptoms (VMS) with menopausal hormone therapy (HT) is challenging.
OBJECTIVE: To assess risk of cardiovascular disease (CVD) due to HT in women with VMS.
In this secondary analysis of 2 randomized clinical trials of HT, postmenopausal women aged 50 to 79 years from 40 US clinical centers were included. Data were collected from November 1993 to September 2012, and data were analyzed from December 2024 to May 2025.
INTERVENTIONS: Conjugated equine estrogens (CEE), 0.625 mg per day, or CEE with medroxyprogesterone acetate (MPA), 2.5 mg per day, vs placebo.
MAIN OUTCOMES AND MEASURES: Atherosclerotic CVD (ASCVD; defined as composite of nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral arterial disease, carotid artery disease, or CVD death).
RESULTS: Of 27 347 included postmenopausal women, the mean (SD) age was 63.4 (7.2) years; a total of 10 739 (39.3%) had a hysterectomy, and 16 608 (60.7%) had an intact uterus. The median (IQR) follow-up was 7.2 (6.4-8.1) years and 5.6 (4.8-6.5) years for those in the CEE alone trial and the CEE plus MPA trial, respectively. In the CEE alone trial, moderate or severe VMS were present at baseline in 905 (27.6%), 705 (14.7%), and 220 (8.7%) women aged 50 to 59 years, 60 to 69 years, and 70 to 79 years, respectively; in the CEE plus MPA trial, moderate or severe VMS was present in 1225 (22.4%), 649 (8.7%), and 172 (4.8%), respectively. Among women with moderate or severe VMS at enrollment, 3382 (96.7%) recalled having symptoms near menopause onset. CEE alone reduced VMS by 41% across all age groups (overall relative risk [RR], 0.59; 95% CI, 0.53-0.66). However, in the CEE plus MPA trial, VMS reduction was attenuated with age (age 50-59 years: RR, 0.41; 95% CI, 0.35-0.48; age 60-69 years: RR, 0.72; 95% CI, 0.61-0.85; age 70-79 years: RR, 1.20; 95% CI, 0.91-1.59; interaction P for trend < .001). Both CEE alone and CEE plus MPA appeared to have neutral effects on ASCVD in women with moderate or severe VMS aged 50 to 59 years (CEE alone: hazard ratio [HR], 0.85; 95% CI, 0.53-1.35; CEE plus MPA: HR, 0.84; 95% CI, 0.44-1.57). While the estimated risk was higher for CEE alone in women with VMS aged 60 to 69 years, there was no clear signal of harm (CEE alone: HR, 1.31; 95% CI, 0.90-1.90; CEE plus MPA: HR, 0.84; 95% CI, 0.51-1.39). However, women with VMS 70 years and older had increased risks of ASCVD (CEE alone: HR, 1.95; 95% CI, 1.06-3.59; 217 excess events per 10 000 person-years; interaction P for trend = .03; CEE plus MPA: HR, 3.22; 95% CI, 1.36-7.63; 382 excess events per 10 000 person-years; interaction P for trend = .02).
CONCLUSIONS AND RELEVANCE: In this secondary analysis of 2 randomized clinical trials, among younger postmenopausal women aged 50 to 59 years, both CEE alone and CEE plus MPA reduced VMS without significantly affecting ASCVD risk. In women with VMS 70 years and older, risks for ASCVD were increased in both trials. The findings support guideline recommendations for treatment of VMS with HT in women aged 50 to 59 years, caution if initiating HT in women aged 60 to 69 years, and avoidance of HT in women 70 years and older.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.}, }
@article {pmid40951524, year = {2025}, author = {Koedijk, JB and Barneh, F and Meesters-Ensing, JE and van Tuil, M and Sonneveld, E and Lambo, S and Perzolli, A and Schweighart, EK and Ferrao Blanco, MN and van der Meulen, M and Deli, A and Haasjes, E and Bang Christensen, K and de Groot-Kruseman, HA and Meshinchi, S and Hasle, H and Belderbos, ME and Luesink, M and Goemans, BF and Nierkens, S and Hehir-Kwa, J and Zwaan, CM and Heidenreich, O}, title = {Bone marrow lymphocyte dynamics during chemotherapy in pediatric acute myeloid leukemia.}, journal = {HemaSphere}, volume = {9}, number = {9}, pages = {e70212}, pmid = {40951524}, issn = {2572-9241}, }
@article {pmid40950500, year = {2025}, author = {Wang, Z and Taylor, KD and Rotter, JI and Rich, SS and Zheng, Y and Hou, L and Guo, X and Bressler, J and Raffield, LM and Liu, Y and Kaplan, R and Lloyd-Jones, DM and Morrison, AC and Fornage, M and Sofer, T}, title = {Estimating population structure using epigenome-wide methylation data.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950500}, abstract = {INTRODUCTION: In epigenome-wide association analysis (EWAS), unaddressed population stratification often leads to inflation. We aimed to compute methylation population scores (MPSs) that predict genetic principal components (GPCs) using a feature selection and regression approach.
METHODS: We used multi-ethnic methylation data (Illumina 450K/EPIC array) from unrelated MESA (n=929), CARDIA (n=1123), JHS (n=1365), ARIC (n=2338), and HCHS/SOL (n=1475) individuals, randomly assigning 85% of participants from each cohort to a training dataset and the remaining 15% to a test dataset. First, we estimated the associations of GPCs with each available CpG methylation site using linear regression within each cohort, adjusting for age, sex, smoking status, race/ethnic background (as a proxy for background information associated with lifestyle and other environmental exposures that may impact methylation), alcohol use status, body mass index, and cell type proportions. We meta-analyzed the associations across cohorts and selected CpG sites with association FDR-adjusted q-value <0.05. We next aggregated individuallevel data across the cohort-specific training datasets, and applied two-stage weighted least squares Lasso regression, with the GPCs as the outcomes and the selected CpG sites as penalized predictors, adjusting for the aforementioned covariates. The developed MPSs are the weighted sum of selected CpG sites from the Lasso. To evaluate the developed MPSs, we constructed them in the test dataset, and compared them with GPCs, and with MPSs constructed based on a previously-published paper. Comparison was based on correlation analysis and data visualization. We demonstrate the use of the MPSs in EWAS.
RESULTS: In the test dataset, the MPSs were highly correlated with GPCs, with correlation decreasing, though not monotonically, for later components. Specifically, MPS1 and GPC1 had R2= 0.99, while MPS7 and GPC7 had R2=0.27 (the lowest observed correlation). In data visualization, MPSs had similar patterns as GPCs in differentiating self-reported White, Black, and Hispanic/Latino groups, while outperforming MPC constructed using alternative published methods. MPSs showed comparable performance to GPCs in reducing some of the inflation in EWAS.
CONCLUSIONS: Methylation-based population scores provide a reliable estimate of population structure in the data and can complement GPCs when genetic data are absent. Unlike previous methods based on unsupervised methylation PCA, MPSs uses supervised learning with covariate adjustment to capture genetic structure across diverse populations. The weights for each GPCs derived in our study can be applied to generate MPSs in other studies.}, }
@article {pmid40950199, year = {2025}, author = {Chang, CH and de la Cruz, AF and Natividad, IM and Noyola, A and Malik, HS}, title = {Rapid protamine evolution suppresses meiotic drive in Drosophila.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950199}, issn = {2692-8205}, abstract = {Many animal species replace histones with protamines during spermatogenesis. Despite their importance for sperm function, protamines rapidly evolve in many species; the biological causes behind their rapid evolution remain unknown. Here, using in vivo gene replacement, we investigated the causes and consequences underlying the rapid evolution of protamine Mst77F, which is essential for male fertility in D. melanogaster. Mst77F ortholog replacements led to defects in DNA compaction of X-chromosome-bearing sperm compared to Y-chromosome-bearing sperm during spermatogenesis, resulting in fewer X-bearing mature sperm and male-biased progeny. Unlike D. melanogaster, Mst77F is not essential for male fertility in D. yakuba but is still required to suppress sex-ratio distortion. Our results suggest that relentless pressure to suppress sex chromosomal meiotic drive drives the rapid evolution of protamines.}, }
@article {pmid40950014, year = {2025}, author = {Kikawa, C and Huddleston, J and Loes, AN and Turner, SA and Lee, J and Barr, IG and Cowling, BJ and Englund, JA and Greninger, AL and Harvey, R and Hasegawa, H and Ho, F and Lacombe, K and Leung, NHL and Lewis, NS and Peck, H and Watanabe, S and Smith, DJ and Bedford, T and Bloom, JD}, title = {Near real-time data on the human neutralizing antibody landscape to influenza virus to inform vaccine-strain selection in September 2025.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950014}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI165818/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; F30 AI186284/AI/NIAID NIH HHS/United States ; }, abstract = {The hemagglutinin of human influenza virus evolves rapidly to erode neutralizing antibody immunity. Twice per year, new vaccine strains are selected with the goal of providing maximum protection against the viruses that will be circulating when the vaccine is administered ~8-12 months in the future. To help inform this selection, here we quantify how the antibodies in recently collected human sera neutralize viruses with hemagglutinins from contemporary influenza strains. Specifically, we use a high-throughput sequencing-based neutralization assay to measure how 188 human sera collected from Oct 2024 to April 2025 neutralize 140 viruses representative of the H3N2 and H1N1 strains circulating in humans as of the summer of 2025. This data set, which encompasses 26,148 neutralization titer measurements, provides a detailed portrait of the current human neutralizing antibody landscape to influenza A virus. The full data set and accompanying visualizations are available for use in vaccine development and viral forecasting.}, }
@article {pmid40949174, year = {2025}, author = {Lu, Y and Xu, H and Sun, Y and Ihejirika, SA and Chiang, CW and Darst, BF and Song, S and Shen, Y and Ye, K}, title = {Gene-Diet Interaction Analysis in UK Biobank Identified Genetic Loci That Modify the Association Between Fish Oil Supplementation and the Incidence of Dementia.}, journal = {Current developments in nutrition}, volume = {9}, number = {9}, pages = {107524}, pmid = {40949174}, issn = {2475-2991}, abstract = {BACKGROUND: Dementia is a common disease influenced by both genetic and environmental factors. APOE ε4 is well-known to increase risk of dementia, and it has been shown to attenuate the protective association of fish oil supplements (FOS) and the incidence of dementia.
OBJECTIVES: To identify additional genetic factors with modifying effects, we performed a genome-wide scan.
METHODS: We performed genome-wide association studies (GWAS) of incident all-cause dementia, Alzheimer's disease, and vascular dementia in 357,631 participants from UK Biobank and the FOS subgroups. Single-nucleotide polymorphisms (SNPs) suggestively associated with dementia (P < 1 × 10[-5]) were then evaluated for their interactions with fish oil status in Cox regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals.
RESULTS: Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (P < 5 × 10[-8]) for the incidence of all-cause dementia, Alzheimer's disease, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for Alzheimer's disease and related dementia. A total of 178 suggestive GWAS loci (P < 1 × 10[-5]) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between FOS and dementia incidence (P < 2.8 × 10[-4] with Bonferroni correction). One locus overlapped with a known Alzheimer's disease GWAS locus (EED/PICALM) and 2 with GWAS loci for circulating ω-3 fatty acids (SRSF4 and PSMG1). Candidate interacting genes exhibited cell-type-specific expression in the nervous system.
CONCLUSIONS: In total, 43 genetic loci modify the association between FOS and dementia. These findings indicate a need for genome-informed personalized nutrition of FOS for the purpose of dementia prevention.}, }
@article {pmid40947766, year = {2025}, author = {Tran, L and Nickens, R and Luu, V and Petersdorf, EW and Mack, SJ}, title = {HLAtools, Searching Shared HLA Amino Acid Residue Prevalence, and the Global Frequency Browsers: New Computational Resources for Working With HLA Data and Visualizing Global Patterns of HLA Variation.}, journal = {International journal of immunogenetics}, volume = {}, number = {}, pages = {e70013}, doi = {10.1111/iji.70013}, pmid = {40947766}, issn = {1744-313X}, support = {R01AI128775//National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01AI069197//National Institute of Allergy and Infectious Diseases (NIAID)/ ; R25HL125451/HL/NHLBI NIH HHS/United States ; }, abstract = {The highly polymorphic HLA genes inform susceptibility and resistance to infectious and autoimmune diseases and cancers and are key for successful solid-organ and stem-cell transplantation therapies. Over 41,000 HLA alleles are known and are unevenly distributed across the human population. Here, we describe HLAtools, Searching Shared HLA Amino-Acid Residue Prevalence (SSHAARP) and the Global Frequency Browser (GFB), new informatic tools developed to facilitate working with HLA data and visualizing the global distribution of HLA variants in human populations. HLAtools is an R package that consumes static resources for HLA alleles and sequences and makes these data locally computable alongside data-query, data-customization and data-analysis functions. The package further includes new reference datasets that dissect and catalogue HLA regions and HLA gene structures and provide insight into the organization of HLA pseudogenes and gene fragments. SSHAARP is an R package that describes the frequency distributions of individual HLA haplotypes, alleles and amino-acid motifs as global heatmaps. Allele frequency maps for more than 800 HLA alleles can be browsed using the GFB web and mobile applications. HLAtools and SSHAARP are available from the Comprehensive R Archive Network, and the GFB apps are available on GitHub.}, }
@article {pmid40940860, year = {2025}, author = {Nasrollahi, E and Wang, S and Yanes, R and Gonzalez Gomez, C and Magge, T and Overacre, A and Hsieh, R and Mcfarquhar, A and Tatsuoka, C and Singhi, A and Saeed, A and Sahin, IH}, title = {A Comprehensive Molecular and Clinical Study of Patients with Young-Onset Colorectal Cancer.}, journal = {Cancers}, volume = {17}, number = {17}, pages = {}, pmid = {40940860}, issn = {2072-6694}, abstract = {Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We reviewed 110 patients diagnosed with YO-CRC at our institution who underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo stage IV. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, n = 44 (40%) presented with local disease (stage 1-3), while n = 66 (60%) presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present in 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4%, respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB > 20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among 66 patients with de novo metastatic disease, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7-not reached). KRAS mutations were found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, p = 0.002), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: Patients with YO-CRC are more likely to present with de novo metastatic disease and left-sided tumors with distinct molecular characteristics. KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic interventions to improve outcomes in this high-risk group.}, }
@article {pmid40940539, year = {2025}, author = {Glasscock, CJ and Pecoraro, RJ and McHugh, R and Doyle, LA and Chen, W and Boivin, O and Lonnquist, B and Na, E and Politanska, Y and Haddox, HK and Cox, D and Norn, C and Coventry, B and Goreshnik, I and Vafeados, D and Lee, GR and Gordân, R and Stoddard, BL and DiMaio, F and Baker, D}, title = {Computational design of sequence-specific DNA-binding proteins.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40940539}, issn = {1545-9985}, abstract = {Sequence-specific DNA-binding proteins (DBPs) have critical roles in biology and biotechnology and there has been considerable interest in the engineering of DBPs with new or altered specificities for genome editing and other applications. While there has been some success in reprogramming naturally occurring DBPs using selection methods, the computational design of new DBPs that recognize arbitrary target sites remains an outstanding challenge. We describe a computational method for the design of small DBPs that recognize short specific target sequences through interactions with bases in the major groove and use this method to generate binders for five distinct DNA targets with mid-nanomolar to high-nanomolar affinities. The individual binding modules have specificity closely matching the computational models at as many as six base-pair positions and higher-order specificity can be achieved by rigidly positioning the binders along the DNA double helix using RFdiffusion. The crystal structure of a designed DBP-target site complex is in close agreement with the design model and the designed DBPs function in both Escherichia coli and mammalian cells to repress and activate transcription of neighboring genes. Our method provides a route to small and, hence, readily deliverable sequence-specific DBPs for gene regulation and editing.}, }
@article {pmid40939933, year = {2025}, author = {Wernli, KJ and Anderson, ML and Palazzo, L and Luce, C and Bezman, N and Chin, M and Gao, H and Ralston, JD and Rogers, K and Su, YR and Triplette, M and Carter-Bawa, L and Vasavada, A and Jordan, M and West, M and Boler, S and Green, BB}, title = {Effectiveness of health communication intervention to improve knowledge on timeliness to return for annual lung cancer screening: The Larch Trial.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2025.07.4111}, pmid = {40939933}, issn = {1931-3543}, abstract = {BACKGROUND: Many patients are unaware of the need to repeat lung cancer screening (LCS) annually despite shared decision-making. We tested a health communication intervention to improve patient knowledge, tobacco-related stigma, and self-efficacy in LCS.
RESEARCH QUESTION: Does additional health communication improve patient knowledge of LCS timeliness?
STUDY DESIGN AND METHODS: Trial participants aged 50-78 years with a normal LCS scan were randomized to intervention or control arm. Delivered 3 weeks after LCS scan, intervention participants received health communication (print plus video) with 3 key messages to normalize routine LCS; a reminder of when due for screening; and encouraging social connection. Interventions were primarily delivered through electronic health record patient portal. Eight weeks after scan, all participants were invited to complete an online or telephone survey about knowledge, tobacco-related stigma, and self-efficacy. We used modified Poisson and linear regression to test association of intervention on secondary trial outcomes, using weights to account for survey non-response. We tested for heterogeneity of intervention effect by tobacco and LCS histories.
RESULTS: Survey participation rate was 38.9% with 714 respondents (N=363 intervention, N=351 control). Knowledge to return in one year improved by 13% in intervention arm vs control (Relative risk (RR)=1.13, 95% confidence interval (CI) 1.05-1.22, p-value<0.001). Intervention increased the proportion by 21.9% who knew to return in one year from 62.0% to 83.9% (RR 1.35, 95% CI 1.16-1.58) in first-time screeners, but no difference in those screened 2 or more times. No other statistically significant differences in knowledge were detected. Both tobacco-related stigma (mean 13.9, 95% CI 13.6-14.2 in controls) and self-efficacy (mean 29.0, 95% CI 28.6-29.4 in controls) were high and unchanged by the intervention.
INTERPRETATION: A multiformat LCS intervention improved short-term knowledge of LCS timeliness to return, suggesting additional health communication beyond shared-decision making might encourage repeat screening, especially in first-time screeners.
CLINICAL TRIALS REGISTRATION: NCT05747443.}, }
@article {pmid40939575, year = {2025}, author = {Krishnan, M and Anwar, MY and Justice, AE and Chittoor, G and Chen, HH and Roshani, R and Scartozzi, A and Dickerson, RR and Smit, RAJ and Preuss, MH and Chami, N and Hadad, BS and Parra, EJ and Cruz, M and Hui, Q and Wilson, PWF and Sun, YV and Zhang, X and Linchangco, GV and Kardia, SLR and Faul, JD and Weir, DR and Bielak, LF and Highland, HM and Young, KL and Qi, B and Wang, Y and Fornage, M and Haiman, C and Cheng, I and Peters, U and Kooperberg, C and Buyske, S and McCormick, JB and Fisher-Hoch, SP and Lona-Durazo, F and Peralta, J and Gomez-Zamudio, J and Rich, SS and Ferrier, KR and Lange, EM and Gignoux, CR and Kenny, EE and Wojcik, GL and Cho, K and Gaziano, MJ and Djousse, L and Liu, S and Vaidya, D and de Mutsert, R and Josyula, NS and Bauer, CR and Zhao, W and Walker, RW and Smith, JA and Lange, LA and Meyer, MC and Liu, CT and Yanek, LR and Lee, M and Raffield, LM and Loos, RJF and Gordon-Larsen, P and Below, JE and North, KE and Graff, M}, title = {Genome-wide association study provides novel insight into the genetic architecture of severe obesity.}, journal = {PLoS genetics}, volume = {21}, number = {9}, pages = {e1011842}, doi = {10.1371/journal.pgen.1011842}, pmid = {40939575}, issn = {1553-7404}, abstract = {Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel signals in known loci of BMI [TENM2, PLCL2, ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.}, }
@article {pmid40938896, year = {2025}, author = {Estrella, F and Lewin, J and Schuessler, A}, title = {Establishing the clinical IDS pharmacist role in a phase 1 clinic.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251376302}, doi = {10.1177/10781552251376302}, pmid = {40938896}, issn = {1477-092X}, abstract = {BackgroundPhase 1 oncology clinical trials are complex and prioritize patient safety. Clinical pharmacists-experts in pharmacotherapy and patient-centered care-can enhance these trials by managing drug regimens and interactions. Despite demonstrated benefits, their integration into trial teams remains inconsistent. To address this, the Fred Hutch Phase 1 Clinical Trials Program embedded a clinical Investigational Drug Services (IDS) pharmacist into the clinic. This study assessed pharmacist utilization, intervention types, time spent, and inquiry sources.MethodsA retrospective review compared a pilot phase (Apr 2021-Apr 2022) and a follow-up (Apr-Sept 2023). Intervention type, frequency, duration, and communication modality were descriptively analyzed.ResultsDuring the pilot phase, 311 interventions were documented, primarily related to concomitant medication reviews (77%) and drug information (16%). In the 6-month follow-up period, 302 interventions were recorded, demonstrating an increased reliance on pharmacist services. Concomitant medication reviews remained high at 83%, indicating the pharmacist's critical role in medication management. Total intervention time was 93 h (pilot) compared to 72 h (follow-up), with a consistent median time per intervention. Over 85% of inquiries originated from study coordinators and nurses. The adoption of digital communication tools supported streamlined workflows and timely responses, aligning with broader clinic operational enhancements.ConclusionsThe integration of clinical IDS pharmacists enhanced the management of phase 1 trials while maintaining high safety and compliance standards. This study demonstrates the important contributions of pharmacists in supporting early-phase clinical trial research and highlights opportunities for expanding their role to meet growing trial complexities.}, }
@article {pmid40938106, year = {2025}, author = {Matsubara, T and Miller, CP and Min, C and Su, CY and Choi, JS and Lim, CT and Phillip, JM and Kim, JW and Kim, DH}, title = {Topographic cues regulate collective cell dynamics in curved nano/microgrooved tubular microchannels.}, journal = {Lab on a chip}, volume = {}, number = {}, pages = {}, pmid = {40938106}, issn = {1473-0189}, abstract = {Physical properties of the extracellular matrix, such as topography and curvature, regulate collective epithelial behaviors. However, the interplay between these geometric factors on collective migration is not well understood. In this study, we investigate the effects of topographic cues on a curved surface on collective epithelial migration within tubular microchannels with an inner diameter of 100 μm. These tubular microchannels feature circumferential or longitudinal micro- and nano-grooves fabricated by two-photon polymerization three-dimensional printing and micro-molding techniques. Live cell microscopy records the collective migration of GFP-labeled epithelial cells into the microchannel with each topographical design. We utilized a single-cell behavior analysis for the tracked time-dependent cell position data to visualize and quantify complex cell migration. Results show that longitudinal grooves (800 nm and 4 μm) enhanced cell migration, but circumferential grooves did not significantly enhance cell migration. This indicates that curvature rather than topography dominates migration at the microtube scale. These findings provide insights into the interplay between curvature, microscale structure, and cell behaviors and suggest the potential to control cell behaviors by manipulating the structure and topographic cues with their local microenvironments.}, }
@article {pmid40909525, year = {2025}, author = {Jena, S and Lawore, D and Briones, JM and Birse, K and Lamont, A and Mackelprang, RD and Noel-Romas, L and Perner, M and Hou, X and Irungu, E and Mugo, N and Knodel, S and Brubaker, SD and Muwonge, TR and Katabira, E and Hughes, SM and Calienes, FL and Krajci, R and Liu, R and Nemecio, D and Hladik, F and Lingappa, J and Burgener, AD and Berard, AR and Green, LN and Brubaker, DK}, title = {Identifying a Vaginal Microbiome-Derived Selective Antibiotic Metabolite via Microbiome Pharmacology Analysis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909525}, issn = {2692-8205}, abstract = {The vaginal microbiome plays a critical role in maintaining immune and epithelial homeostasis in the female reproductive tract. Bacterial Vaginosis (BV) is deleterious to female health, causing the loss of beneficial Lactobacillus species, overgrowth of anaerobic taxa, changes in vaginal pH, breakdown of protective mucins and epithelial barriers, and activation of the immune system. Treatment with gel-based antibiotics (Metronidazole or Clindamycin) resolves BV for 85% of patients, but 50% of those cases recur, indicating a need to identify strategies for overcoming antibiotic resistance and achieving a more durable response. Here, we developed a systems biology approach termed Microbiome Pharmacology Analysis to characterize the antibiotic potential of vaginal microbes, their metabolites and functions, via computational fusion of human cohort multi-omics and post-drug perturbation transcriptomic profiles. We focused on Clindamycin and Metronidazole as candidate drugs and screened 780 vaginal microbiome-drug mimicry candidates to identify candidate taxa and metabolites with antibiotic potential. We demonstrate experimentally that Lactobacillus crispatus-derived Hydroxyisocaproate (HICA) selectively kills Gardnerella vaginalis and that HICA enhances epithelial barrier integrity in a human vagina-on-a-chip system. Our work demonstrates the first use of Pharmacobiome Analysis, for discovering novel, selective antibiotic metabolites for BV with implications for charting the full pharmacologic potential of the vaginal microbiome.}, }
@article {pmid40936721, year = {2025}, author = {Parrish, AG and Holland, EC}, title = {Seq-ing answers: exploring meningioma biology utilizing bulk RNA-seq-based reference landscapes.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1631573}, pmid = {40936721}, issn = {2234-943X}, abstract = {Meningiomas are the most common primary brain tumors, accounting for 40% of all central nervous system neoplasms. While usually benign, these tumors can vary in aggressiveness. Traditional classification and grading systems, which primarily rely on histopathological features, are not always reliable in capturing tumor behavior and predicting patient outcomes. In contrast, modern systems-based on factors such as copy number alterations, DNA methylation, and gene expression-offer a more accurate framework for identifying distinct biological signatures and aggressive subtypes, as well as for predicting recurrence. Transcriptomic profiling using bulk whole-genome RNA sequencing (RNA-seq), which provides insights into alternative splicing, gene expression, fusion events, non-coding RNAs, and pathway activity, further enhances our understanding of meningioma tumorigenesis, enables the projection of new samples onto dimension-reduced reference landscapes, and helps accurately predict recurrence. As bulk RNA-seq becomes more accessible, it holds great potential for refining prognostic tools, informing personalized treatment approaches, and ultimately improving outcomes for meningioma patients.}, }
@article {pmid40935830, year = {2025}, author = {Granadier, D and Cooper, K and Acenas, D and Kousa, A and Warren, M and Hernandez, V and Iovino, L and deRoos, P and Lederer, EE and Shannon-Sevillano, S and Kinsella, S and Evandy, C and van den Brink, MRM and Lemarquis, A and Dudakov, JA}, title = {Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, pmid = {40935830}, issn = {1529-2916}, support = {R01-HL145276//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R35-HL171556//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL165673//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-AI70035//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; P01-AG052359//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30-CA015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; F30-HL165761//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4[+] T cells, cytotoxic CD8[+] T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects.}, }
@article {pmid40935610, year = {2025}, author = {Uribe, C and Iravani, A and Savir-Baruch, B and Jacene, H and Graves, SA and Dewaraja, YK and Heath, CL and Hope, TA}, title = {Summary: SNMMI/ACNM Procedure Standard for Posttreatment Imaging of [177]Lu-Based Radiopharmaceuticals.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.270979}, pmid = {40935610}, issn = {1535-5667}, }
@article {pmid40934451, year = {2025}, author = {Necchi, A and Galsky, MD and Dizman, N and Aggen, DH and Agarwal, N and Al-Ahmadie, H and Apolo, AB and Ballas, L and Bangs, R and Black, PC and Brausi, M and Brembilla, G and Cheng, L and Chiti, A and Cimadamore, A and Colecchia, M and Daneshmand, S and Di Stasi, S and Efstathiou, JA and Filicevas, A and Geynisman, DM and Grivas, P and Gupta, S and Iasonos, A and James, ND and Lerner, SP and Loriot, Y and Makaroff, LE and Maluf, F and Moschini, M and Ostrovnaya, I and Pal, SK and Plimack, ER and Prakash, G and Psutka, SP and Rosenberg, JE and Sadeghi, S and Schmidt, B and Schwartz, LH and Sonpavde, GP and St Laurent, MP and Ye, D and Spiess, PE and Kamat, AM}, title = {End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501608}, pmid = {40934451}, issn = {1527-7755}, support = {ZIA BC011351/ImNIH/Intramural NIH HHS/United States ; }, abstract = {PURPOSE: The evolving treatment landscape of muscle-invasive bladder cancer (MIBC) increasingly warrants novel trial design to evaluate perioperative strategies aimed at bladder preservation. To establish standardized outcome measures for evaluating organ preservation strategies in MIBC, the International Bladder Cancer Group (IBCG) and the Global Society of Rare Genitourinary Tumors (GSRGT) assembled an international, multidisciplinary consensus panel.
METHODS: The IBCG and GSRGT gathered global bladder cancer experts and patient advocates to establish a framework for risk-adapted bladder-sparing treatment approaches for MIBC. Working groups reviewed the literature and developed draft recommendations, which were discussed at a live meeting in December 2024 in Milan. This was followed by voting by the members using a modified Delphi process. Recommendations achieving ≥75% agreement during the meeting were further refined and presented.
RESULTS: Clinical complete response (cCR) definition should encompass the absence of high-grade malignancy on pathology and malignant cells on urine cytology and no evidence of local or metastatic disease on cross-sectional imaging. Although cCR remains immature as a primary or coprimary end point in registrational trials, it could serve as a suitable end point in early-phase studies and risk-adapted investigations. Event-free survival (EFS) remains the preferred primary end point as it could reliably capture the durability of clinically meaningful benefit after omittance of surgical consolidation or chemoradiation. Given the composite nature of EFS, events should be prespecified, evaluated in an intention-to-treat approach, and meticulously collected. Continuous assessment of individual patient preferences should begin at the outset of perioperative therapy discussions, with informed decision making prioritized throughout.
CONCLUSION: The consensus definition of cCR and the framework presented in this study can serve as a foundation for thorough testing of risk-adapted bladder-sparing treatment paradigms for MIBC.}, }
@article {pmid40934429, year = {2025}, author = {Esmaeili, S and Owens, K and Avila-Ponce de Leon, U and Standing, JF and Lowe, DM and Zhang, S and Watson, JA and Schilling, WH and Wagoner, J and Polyak, SJ and Schiffer, JT}, title = {Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI192052}, pmid = {40934429}, issn = {1558-8238}, abstract = {Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 6-7 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.4 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.}, }
@article {pmid40934225, year = {2025}, author = {Mkhize, NN and Li, SS and Hu, J and Robinson, ST and Hoosain, Z and Garrett, N and Chirenje, ZM and Fleurs, L and Kaldine, H and Modise, T and Moore, PL and Randhawa, AK and Sholukh, AM and Hutter, J and Polakowski, L and Corey, L and Gill, K and Montefiori, DC and Janes, H and Karuna, S and , }, title = {Neutralizing antibody responses over time in a demographically and clinically diverse cohort of individuals recovered from SARS-CoV-2 acquisition in Africa: A cohort study.}, journal = {PLOS global public health}, volume = {5}, number = {9}, pages = {e0005156}, pmid = {40934225}, issn = {2767-3375}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {COVID-19 has affected millions worldwide. Research characterized immune responses of individuals who acquired SARS-CoV-2 and identified co-factors, such as HIV, associated with greater likelihood of poor clinical outcomes. SARS-CoV-2-specific neutralizing antibodies (nAbs) are a strong correlate of protection but their elicitation in people living with HIV (PLWH), and particularly in southern Africa, is less well characterized. HVTN 405/HPTN 1901 was an observational cohort study of individuals recently recovered from SARS-CoV-2. We describe 323 participants enrolled early in the pandemic (June 2020 to January 2021) in Zambia (n = 12), Malawi (n = 13), Zimbabwe (n = 59), and South Africa (n = 239), profiling their SARS-CoV-2-specific nAb responses and associations with demographics, comorbidities, disease severity, and time since diagnosis based on linear and logistic regression. Participants' median age was 39 years, 63.5% were assigned female sex at birth, 71.2% were black African, and 39 (12.1%) were PLWH. Approximately one in four participants (25.7%) had asymptomatic SARS-CoV-2, 47.4% were symptomatic but not hospitalized, and 26.9% were hospitalized with COVID-19. Participants in these groups were enrolled at a median of 51.5 days, 53 days, and 60 days post-SARS-CoV-2 diagnosis, respectively. SARS-CoV-2 nAbs were measured in serum using one of two calibrated assays. Most (291/322, 90.4%) participants had positive nAb responses at enrollment. Across all participants, nAb responses generally declined in magnitude between enrollment and 2-3 months thereafter, then increased through month 12 coincident with epidemiologically observed new waves of acquisition. In a multivariate model adjusted for potentially confounding factors, PLWH had a 65% lower geometric mean (GM) nAb ID50 titer compared to people without HIV (PWOH) (GMR: 0.35, p = 0.003, q = 0.006). Greater disease severity, older age (>55 years), high BMI (≥30) and diabetes were associated with higher nAb ID50 titers (all p < 0.05, all q < 0.20).These findings are important, as nAb titers are predictive of vulnerability to COVID-19.}, }
@article {pmid40934109, year = {2025}, author = {Azhideh, A and Haseli, S and Schaub, SK and Amini, B and Hosseini, N and Mansoori, B and Chalian, H and Mirghaderi, P and Hall, ET and Chalian, M}, title = {Musculoskeletal Complications of Radiation Therapy and Immunotherapy.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {10}, pages = {e250014}, doi = {10.1148/rg.250014}, pmid = {40934109}, issn = {1527-1323}, mesh = {Humans ; *Immunotherapy/adverse effects ; *Musculoskeletal Diseases/etiology/diagnostic imaging ; *Radiation Injuries/diagnostic imaging/etiology ; *Radiotherapy/adverse effects ; }, abstract = {Radiation therapy (RT) and immunotherapy are widely used in modern oncologic care and are both associated with a broad spectrum of musculoskeletal complications. These adverse effects can be acute or delayed and include bone fragility, insufficiency fractures, osteoradionecrosis, cartilage degeneration, inflammatory arthritis, myositis, and tendinopathy. Many of these complications can closely mimic metastatic disease or infection, creating diagnostic challenges. RT-induced musculoskeletal injuries are influenced by factors such as total dose, fractionation, and technique, with newer modalities such as stereotactic body RT and proton beam therapy associated with specific imaging appearances and complication profiles. Immunotherapy, particularly immune checkpoint inhibitor medication, has introduced a distinct set of immune-related adverse events affecting the musculoskeletal system, including inflammatory arthropathy, myositis, and enthesitis, often occurring in seronegative patterns and overlapping with other systemic toxicities. The authors provide an in-depth overview of the radiobiologic principles underlying RT, the evolving landscape of immunotherapy, and the diverse musculoskeletal complications that arise from both therapies. Emphasis is placed on the clinical context and imaging features that aid in recognizing and differentiating these conditions from neoplastic or infectious processes. A thorough understanding of these complications is essential for accurate diagnosis, timely management, and improved patient outcomes. [©]RSNA, 2025 Supplemental material is available for this article.}, }
@article {pmid40909752, year = {2025}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Gruell, H and Kreer, C and Ercanoglu, MS and Gristick, HB and Schommers, P and Ahmadov, E and Radford, C and Mazzolini, A and Zhang, L and West, AP and Worczinski, J and Momot, A and Reichwein, ML and Knüfer, J and Stumpf, R and Mkhize, NN and Kaldine, H and Bhebhe, S and Deshpande, S and Giovannoni, F and Stefanutti, E and Benigni, F and Havenar-Daughton, C and Corti, D and Kroidl, A and Adhikari, A and Nanfack, AJ and Ambada, GE and Duerr, R and Maganga, L and William, W and Ntinginya, NE and Wolf, T and Geldmacher, C and Hoelscher, M and Lehmann, C and Moore, PL and Mora, T and Walczak, AM and Gilbert, PB and Doria-Rose, NA and Huang, Y and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Profiling a large HIV-1 elite neutralizer cohort reveals remarkable CD4bs bNAb for HIV-1 prevention and therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909752}, issn = {2692-8205}, support = {INV-036842/GATES/Gates Foundation/United States ; U54 AI170856/AI/NIAID NIH HHS/United States ; INV-002143/GATES/Gates Foundation/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; P01 AI100148/AI/NIAID NIH HHS/United States ; R01 AI140891/AI/NIAID NIH HHS/United States ; }, abstract = {Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape[1-9]. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04_A06, a new VH1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC50 = 0.059 μg/ml, breadth = 98.5%, 332 virus strains). Moreover, 04_A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC50 = 0.082 μg/ml, breadth = 98.4%, 191 virus strains) and in silico modeling for 04_A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.}, }
@article {pmid40909728, year = {2025}, author = {Romero, EV and Clyde, AE and Giorgi, EE and Westfall, DH and Azam, W and Taylor, ML and Caskey, M and Feder, AF and Cohn, LB}, title = {Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909728}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, abstract = {Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process: 10-1074 escape is restricted to a small number of previously documented pathways, but these escape mutations 1) pre-exist in intra-host viral populations before therapy, 2) are not all equally preferred, and 3) emerge with a high degree of genetic parallelism within and across viral populations. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different in vivo escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone.}, }
@article {pmid40909710, year = {2025}, author = {Gautier, O and Blum, JA and Nguyen, TP and Klemm, S and Yamakawa, M and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Nakayama, L and Guttenplan, KA and Chen, D and Kathira, A and Zhao, L and Rexach, JE and Greenleaf, WJ and Gitler, AD}, title = {An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909710}, issn = {2692-8205}, support = {R01 AG075802/AG/NIA NIH HHS/United States ; R01 NS128028/NS/NINDS NIH HHS/United States ; RF1 NS128800/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; S10 RR025518/RR/NCRR NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.}, }
@article {pmid40932993, year = {2025}, author = {Repele, A and Pande, D and Enstrom, MR and Perez, AM and Cui, M and Madhu, R and Nelson, V and Kiem, HP and Radtke, S}, title = {GroβT rapidly and reliably mobilizes primitive hematopoietic stem and progenitor cells in nonhuman primates.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101558}, pmid = {40932993}, issn = {2329-0501}, abstract = {Autologous hematopoietic stem cell (HSC) gene therapy has gone through remarkable advancements in recent years, especially for the treatment of sickle cell disease (SCD). However, the collection of HSCs from SCD patients requires unique considerations, as granulocyte colony-stimulating factor (G-CSF)-mediated mobilization is contraindicated, and plerixafor-only mobilization is highly variable. Consequently, alternative mobilization regimens that are safe for SCD patients and generate better cell yields are desirable for SCD HSC gene therapy. Here, we evaluated a combination of plerixafor (AMD3100, a CXCR4 antagonist) with GroβT (MGTA-145/GroβT, a CXCR2 agonist) against the current gold-standard G-CSF for HSC gene therapy in nonhuman primates (NHPs) for HSC mobilization, leukapheresis, ex vivo gene editing to reactivate fetal hemoglobin, and transplantation. AMD3100/GroβT rapidly and reliably mobilized phenotypically primitive HSCs within hours even in a G-CSF non-responder. Average CD34/CD90 frequency in the blood and yields after enrichment were comparable in both mobilization regimens. Rapid recovery and robust multilineage long-term engraftment of gene-modified HSCs was achieved in the bone marrow and blood of animals. In summary, AMD3100/GroβT allows highly efficient and reliable mobilization of HSCs, providing a G-CSF-free regimen specifically for SCD but also any other hematological disease or disorder treatable with HSC gene therapy.}, }
@article {pmid40931630, year = {2025}, author = {Ball-Burack, M and Menssen, A and Eidenschink Brodersen, L and Nalla, A and Loken, M and Pardo, L and Dahlberg, A and Hudson, C and Meshinchi, S and Tarlock, K}, title = {A Case of Blinatumomab Efficacy in RAM Immunophenotype/CBFA2T3::GLIS2 Fusion AML.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e32035}, doi = {10.1002/pbc.32035}, pmid = {40931630}, issn = {1545-5017}, }
@article {pmid40931545, year = {2025}, author = {Poh, C and Chen, X and Voutsinas, J and Naresh, K and Dizon, JJ and Shadman, M and Lynch, RC and Till, BG and Ujjani, CS and Di, M and Raghunathan, V and Warren, EH and Smith, SD and Wu, QV and Cherian, S and Gopal, AK}, title = {Impact of immunophenotype on clinical disease characteristics and outcomes in T-cell prolymphocytic leukaemia.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.70113}, pmid = {40931545}, issn = {1365-2141}, }
@article {pmid40931081, year = {2025}, author = {Wen, L and Miyagi, H and Spiess, PE and Yu, A and Mendelsohn, CL and Tan, WS and Psutka, SP and Lerner, SP and Cheng, L and Dyrskjøt, L and Meeks, JJ and Shariat, SF and Gontero, P and Pradere, B and Steinberg, GD and Kamat, AM and Li, R}, title = {Low-grade non-muscle-invasive bladder cancer: molecular landscape, treatment strategies and emerging therapies.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {40931081}, issn = {1759-4820}, abstract = {Low-grade non-muscle invasive bladder cancer is a specific category of bladder cancer with a favourable prognosis; however, its management presents several challenges. The risk of stage progression is very low, but approximately half of patients will experience recurrence within the first 5 years after diagnosis. This high propensity for recurrence, coupled with the threat of progression, mandates ongoing surveillance. However, the optimal frequency and duration of follow-up monitoring remain undefined. Current management strategies for low-grade non-muscle invasive bladder cancer rely heavily on routine office cystoscopy, with few advances in diagnostic and treatment options over the past 25 years. Our basic understanding of disease biology has substantially advanced. However, at present, considerable variations in clinical practice exist, with implications for increased financial and treatment burden for patients and health care systems. Molecular signatures and biomarker discoveries are crucial to understand disease behaviour and inform novel treatment strategies. Emerging therapies, such as advanced drug-delivery systems, immunomodulatory agents and targeted therapies, offer the potential to improve patient outcomes, streamline management and reduce the need for surveillance cystoscopies. Actionable avenues for future research in the field include prospective validation of novel biomarkers and therapies with the ultimate aim of optimizing patient care and reducing health care costs.}, }
@article {pmid40930249, year = {2025}, author = {Newsom, OJ and Zheng, E and Sullivan, LB}, title = {Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {110693}, doi = {10.1016/j.jbc.2025.110693}, pmid = {40930249}, issn = {1083-351X}, abstract = {Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.}, }
@article {pmid40930223, year = {2025}, author = {Portuguese, AJ and Tuazon, SA and Pont, MJ and Cole, GO and Sather, BD and Song, X and Thomas, S and Wood, BL and Blake, M and Works, MG and Shadman, M and Liang, EC and Wu, VQ and Voutsinas, JM and Gooley, TA and Turtle, CJ and Till, BG and Coffey, DG and Maloney, DG and Libby, EN and Chapuis, AG and Milano, F and Riddell, SR and Green, DJ and Cowan, AJ}, title = {Impact of Gamma-Secretase Inhibition on Outcomes Following BCMA CAR-T Therapy in Multiple Myeloma: A Comparison of Two Phase 1 Trials.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.09.003}, pmid = {40930223}, issn = {2666-6367}, abstract = {BACKGROUND: BCMA-directed chimeric antigen receptor (CAR)-T cell therapy represents a major therapeutic breakthrough for relapsed/refractory multiple myeloma (RRMM), offering deep and durable responses in heavily pretreated patients. However, a subset of patients experience early relapse or fail to respond, highlighting the need for strategies to enhance efficacy. Gamma-secretase inhibitors (GSIs) have been shown to increase surface BCMA expression on malignant plasma cells and may potentiate the activity of BCMA CAR-T cells, particularly in patients with low baseline BCMA antigen density. Two contemporaneous phase 1 trials (FH9952 and FH9762) evaluated the fully human BCMA-targeted CAR-T product FCARH143, with FH9952 incorporating GSI co-administration.
OBJECTIVE: To determine whether GSI use improves clinical outcomes following FCARH143 CAR-T therapy in RRMM, with particular focus on overall survival (OS), progression-free survival (PFS), and subgroup differences based on prior BCMA-targeted therapy and baseline tumor BCMA levels.
STUDY DESIGN: This retrospective analysis compared outcomes from two single-arm, single-center phase 1 trials of the fully human BCMA-targeted CAR-T cell product FCARH143 in RRMM: FH9952 (n=18), which incorporated the GSI crenigacestat, and FH9762 (n=25), which did not. Both studies had extended follow-up beyond previously published reports. Eligible patients had measurable RRMM with ≥10% bone marrow plasma cell involvement and confirmed BCMA expression. BCMA-naïve patients were defined as those without prior exposure to BCMA-targeted therapies (e.g., BCMA CAR-T, bispecific antibodies, or antibody-drug conjugates); BCMA-exposed patients had received at least one such therapy. All participants received lymphodepletion with fludarabine and cyclophosphamide followed by infusion of FCARH143. In FH9952, crenigacestat (25 mg orally, three times weekly) was administered from day 0 through day +18. Outcomes included response rates, adverse events, OS, and PFS. Cox proportional hazards models were used for survival analysis.
RESULTS: With extended follow-up (median 5.8 years), the overall cohort (n=43) had a median OS of 2.7 years (95% CI 1.9-4.8) and median PFS of 1.1 years (95% CI 0.72-2.2). Baseline characteristics were generally similar, though BCMA-exposed status was more frequent in FH9952 (39% vs. 8%). Rates of cytokine release syndrome, immune effector cell-associated neurotoxicity, and early immune effector cell-associated hematotoxicity were comparable between trials. Among BCMA-naïve patients (n=34), GSI use was associated with improved OS (not reached vs. 2.3 years; adjusted HR 0.30, 95% CI 0.10-0.88, p=0.028) and a trend toward improved PFS (2.6 vs. 1.3 years; adjusted HR 0.47, 95% CI 0.22-1.04, p=0.062). No benefit was observed among BCMA-exposed patients. Exploratory spline modeling suggested GSI mitigated the adverse impact of low tumor BCMA levels, with inferior outcomes at low BCMA expression observed only in the non-GSI cohort.
CONCLUSIONS: Co-administration of a GSI with BCMA CAR-T therapy was associated with improved survival in BCMA-naïve RRMM patients, particularly those with low baseline tumor BCMA levels. These findings suggest GSI modulation of BCMA surface expression may enhance CAR-T efficacy in select patients and support further prospective investigation.}, }
@article {pmid40930044, year = {2025}, author = {Diemert, DJ and Graciaa, DS and Zhang, B and Rouphael, NG and Branche, AR and Martin, TCS and Jackson, LA and Presti, RM and Kamidani, S and Mahgoub, SM and Babu, TM and Magaret, CA and Simon, V and van Bakel, H and Roberts, PC and Beigel, JH and Gilbert, PB and Follmann, D and , }, title = {Effect of Omicron BA.1-based compared to prototype booster mRNA vaccination on incidence of COVID-19 in the COVAIL trial.}, journal = {Vaccine}, volume = {64}, number = {}, pages = {127718}, doi = {10.1016/j.vaccine.2025.127718}, pmid = {40930044}, issn = {1873-2518}, abstract = {BACKGROUND: Covid-19 vaccines are updated to match circulating strains based on reasoning that better strain-matched immunogenicity should provide better protection. Randomized evidence with disease endpoints to support strain matching is lacking. We evaluated COVID-19 incidence among adults randomized to a second booster of Prototype or Omicron-based vaccines.
METHODS: COVAIL was a four-stage Phase 2 clinical trial; results from Stages 1 (mRNA-1273 [Moderna]) and 2 (BNT162b2 [Pfizer/BioNTech]) are described here. Adults who had received a primary series and one booster of an authorized COVID-19 vaccine were eligible. Participants received one dose of either Prototype vaccine or a monovalent or bivalent Omicron BA.1 vaccine. SARS-CoV-2 neutralization titers (ID50) were measured pre- and post-vaccination. Covariate-adjusted cumulative COVID-19 incidence and Cox regression analyses were conducted separately for each stage.
RESULTS: 706 participants with pre- and day 15 post-vaccination ID50 titers (n = 503 in Stage 1, n = 203 in Stage 2) were included. Within stages, participant characteristics and baseline ID50 titers were similar between Prototype and Omicron-based arms. There was no difference in cumulative COVID-19 incidence for Prototype vs. Omicron-based vaccine in Stage 1 (RR 1.04, 95 % CI 0.73-1.48), while incidence was higher among Prototype recipients in Stage 2 (RR 2.56, 1.44-4.52). Cox regression analysis showed no difference in Stage 1 (HR 1.04, 0.68-1.58), but higher incidence for Prototype recipients in Stage 2 (HR 2.95, 1.52-5.72).
CONCLUSIONS: Omicron-based vaccines as second boosters were more protective against COVID-19 relative to Prototype among those receiving BNT162b2 but not mRNA-1273. Differences between stages such as force of infection, antigen matching, and vaccine differences may explain this finding.
CLINICALTRIALS: govRegistry Number: NCT05289037.}, }
@article {pmid40929366, year = {2025}, author = {Goya, S and Greninger, AL}, title = {Distinct Evolutionary Signatures of Human Parainfluenza Viruses 2 and 4 Reveal Host Antagonism Divergence and Phylogenetic Discordance.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msaf217}, pmid = {40929366}, issn = {1537-1719}, abstract = {Human parainfluenza virus 2 (HPIV-2) and human parainfluenza virus 4 (HPIV-4) are significant but underappreciated respiratory pathogens, particularly among high-risk populations including children, the elderly, and immunocompromised individuals. In this study, we sequenced 101 HPIV-2 and HPIV-4 genomes from respiratory samples collected in western Washington State and performed comprehensive evolutionary analyses using both new and publicly available sequences. Phylogenetic and phylodynamic analyses revealed that both HPIV-2 and HPIV-4 evolve at significantly faster rates compared to mumps virus, a reference human orthorubulavirus. Notably, while HPIV-2 demonstrated the highest evolutionary rates in the surface glycoprotein HN, consistent with humoral immune-driven selection, the innate immune antagonist V/P gene evolved fastest in HPIV-4. We identified a hypervariable region within the HPIV-4 V/P protein (residues 35-75), which structural modeling placed in a loop overlapping a known interferon antagonism domain in other paramyxovirus V proteins, though HPIV-4 is functionally incompetent in this activity. Expanded phylogenetic analysis across the Paramyxoviridae family uncovered a striking evolutionary discordance: while the HN glycoprotein and L polymerase of HPIV-4 and its two closest bat-derived viruses clustered within the Orthorubulavirus genus, their nucleoprotein (N), phosphoprotein (P), matrix (M), and fusion (F) proteins formed a distinct lineage outside the Rubulavirinae subfamily. Together, these findings highlight the distinct evolutionary trajectories of HPIV-2 and HPIV-4, raise hypotheses around complex Paramyxoviridae zoonotic events including recombination-like patterns, and demonstrate limitations of current L protein-based taxonomic classification schemes.}, }
@article {pmid40929264, year = {2025}, author = {Hollis, JA and Chan, MC and Malik, HS and Campbell, MG}, title = {Molecular exaptation by the integrin αI domain.}, journal = {Science advances}, volume = {11}, number = {37}, pages = {eadx9567}, pmid = {40929264}, issn = {2375-2548}, mesh = {Cryoelectron Microscopy ; Protein Domains ; Animals ; Humans ; Protein Binding ; Ligands ; Evolution, Molecular ; Models, Molecular ; *Integrin alpha Chains/chemistry/metabolism ; Binding Sites ; }, abstract = {Integrins bind ligands between their alpha (α) and beta (β) subunits and transmit signals through conformational changes. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain that expanded integrin's ligand-binding repertoire but obstructed the ancestral ligand pocket, seemingly blocking conventional integrin activation. Here, we compare cryo-electron microscopy structures of apo and ligand-bound states of the I domain-containing αEβ7 integrin and the I domain-lacking α4β7 integrin to illuminate how the I domain intrinsically mimics an extrinsic ligand to preserve integrin function. We trace the I domain's evolutionary origin to an ancestral collagen-collagen interaction domain, identifying an ancient molecular exaptation that facilitated integrin activation immediately upon I domain insertion. Our analyses reveal the evolutionary and biochemical basis of expanded cellular communication in vertebrates.}, }
@article {pmid40929164, year = {2025}, author = {Colegrove, HL and Monnat, RJ and Feder, AF}, title = {Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.}, journal = {PLoS computational biology}, volume = {21}, number = {9}, pages = {e1012915}, doi = {10.1371/journal.pcbi.1012915}, pmid = {40929164}, issn = {1553-7358}, abstract = {Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.}, }
@article {pmid40929058, year = {2025}, author = {Haas, JS and Todd, KW and Mclerran, D and Tiro, JA and Vachani, A and Kobrin, S and Saia, C and Sugg Skinner, C and Zheng, Y and Chubak, J and Corley, DA and Greenlee, RT and Halm, EA and Li, CI}, title = {Gaps in care across the cancer screening continuum for cervical, colorectal and lung cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf248}, pmid = {40929058}, issn = {1460-2105}, abstract = {BACKGROUND: While screening for cervical, colorectal, and lung cancers reduce cancer-specific mortality, the full benefits of screening are only realized when coupled with timely care across the subsequent "screening continuum" steps, including surveillance (results warranting frequent monitoring), diagnostic evaluation (results that require additional testing), and treatment (detected cancers). Our goal was to describe the proportion of individuals receiving timely cervical, colorectal, and lung cancer care at each step in the screening continuum.
METHODS: This retrospective cohort study used data from the 10 health care settings that participate in the Population-based Research to Optimize the Screening Process (PROSPR II) consortium and included individuals who were eligible for a step along the cancer screening continuum in 2018. Proportions of individuals who received timely testing were calculated for screening, surveillance, and diagnostic tests for each of the three cancers and treatment (colorectal only), and the association of these outcomes with patient characteristics was evaluated using multivariate logistic regression.
RESULTS: The overall proportions of timely screening, surveillance, and diagnostic testing were 41.8%, 37.3%, and 61.2%, for cervical cancer; 82.4%, 45.5%, and 73.5% for colorectal (94.1% for timely treatment); and 73.8%, 80.5%, and 80.7% for lung cancer. Across all three cancers, there were differences across the screening continuum by insurance status, race/ethnicity, and socioeconomic status.
CONCLUSIONS: There are important gaps in care across the screening continuum beyond common metrics for screening uptake. Comparison across organ types may facilitate the identification of interventions and policies that could broadly improve cancer prevention and promote health equity.}, }
@article {pmid40928768, year = {2025}, author = {Gunnell, L and Hippe, DS and Park, SY and Fu, A and Akaike, T and Lachance, K and Cahill, K and Doolittle-Amieva, C and Nghiem, P}, title = {Polyomavirus Antibodies for Merkel Cell Carcinoma Recurrence Detection.}, journal = {JAMA dermatology}, volume = {}, number = {}, pages = {}, pmid = {40928768}, issn = {2168-6084}, abstract = {IMPORTANCE: Merkel cell carcinoma (MCC) is typically caused by the Merkel cell polyomavirus (MCPyV) and recurs in 40% of patients. Half of patients with MCC produce antibodies to MCPyV oncoproteins, the titers of which rise with disease recurrence and fall after successful treatment.
OBJECTIVE: To assess the utility of MCPyV oncoprotein antibodies for early detection of first recurrence of MCC in a real-world clinical setting.
This prospective cohort study used a data and specimen repository from 2008 to 2020 in Seattle, Washington. Patients with MCC with locoregional disease underwent serum antibody testing at diagnosis. Statistical analysis was conducted between 2020 and 2025.
MAIN OUTCOMES AND MEASURES: The first posttreatment titer was necessary to establish a trend and was not used to assess risk (deferred). Subsequent titers were defined as (1) falling or negative, (2) rising, or (3) stable compared with the preceding titer.
RESULTS: Among the 503 patients in the cohort (median [IQR] age at diagnosis, 70 [62-77] years; 40% female), 1402 tests were performed; 247 (49%) were seropositive. A total of 877 were falling or negative, 62 were rising, 317 were stable, and 146 were deferred. Median (IQR) follow-up was 4.2 (1.8-7.4) years. On average, antibody titers fell by half every 3 months among patients not experiencing a recurrence. After a falling or negative titer, the likelihood that a given patient would remain recurrence-free for 3 months was 99.3% (95% CI, 98.6%-99.8%). In contrast, after a single rising titer, the risk of recurrence over the next 3 months was 36% (95% CI, 22%-52%), increasing to 58% (95% CI, 40%-78%) by 12 months and 68% (95% CI, 48%-86%) by 24 months. A rising titer preceded clinical or radiographic evidence of recurrence in 57% of cases (20/35). The median (IQR) interval between a rising titer and clinical disease detection was 3.7 (1.1-7.5) months, with 90% of recurrences (18/20) occurring within 14 months of the rising titer. Recurrences and antibody titers were analyzed in 196 patients with multiple blood draws.
CONCLUSIONS AND RELEVANCE: In this prospective cohort study, given a negative predictive value of 99.3%, a falling or negative titer may obviate the need for imaging, reducing radiation and contrast dye exposure. Conversely, a rising antibody titer should trigger closer follow-up, as it may lead to earlier detection of clinical recurrence and initiation of therapy.}, }
@article {pmid40927245, year = {2025}, author = {Wilson, MH and Krantz, EM and Pergam, SA and Mielcarek, M and Elgar, S and Rosen, E and Swetky, M and Liu, C and Hill, JA and Cohen, S and McCulloch, DJ}, title = {Limited yield of SARS-CoV-2 screening in asymptomatic hematopoietic cell transplant and chimeric antigen receptor T-cell therapy patients.}, journal = {Antimicrobial stewardship & healthcare epidemiology : ASHE}, volume = {5}, number = {1}, pages = {e195}, pmid = {40927245}, issn = {2732-494X}, abstract = {Early in the COVID-19 pandemic, screening was initiated in several settings to mitigate asymptomatic transmission of SARS-CoV-2. However, this practice was later discouraged by the Society for Healthcare Epidemiology of America. This single-center retrospective study demonstrates limited utility of SARS-CoV-2 screening tests in asymptomatic HCT and CAR T-cell patients.}, }
@article {pmid40926591, year = {2025}, author = {Shaik, F and Uldrick, TS and Mazinu, M and Gwebushe, N and Mosam, A}, title = {Cytokine biomarkers and their relationship to symptoms and quality of life in people with HIV-associated Kaposi sarcoma.}, journal = {HIV medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/hiv.70107}, pmid = {40926591}, issn = {1468-1293}, support = {//South African Medical Research Council/ ; }, abstract = {INTRODUCTION: Quality of life (QOL) is an essential component of care in people with HIV-associated Kaposi sarcoma (HIV-KS). Kaposi sarcoma herpes virus (KSHV) promotes cytokine expression and a dysfunctional inflammatory environment, contributing to KS pathogenesis and progression. However, disease-related inflammatory factors influencing QOL and symptoms remain underexplored. This study examines the relationship between baseline QOL parameters and inflammatory cytokine biomarkers in treatment-naïve Africans with HIV-KS participating in the randomized controlled KAART study. We hypothesized that inflammatory cytokines are linked with reduced QOL and symptom burden.
METHODS: Twenty-eight cytokines were measured from stored baseline serum using the Milliplex® multiplex assay. QOL was assessed using the validated EORTC QLQ-C30. Spearman Rho-Rank correlation was used to assess relationships between cytokine levels and QOL parameters, with p ≤ 0.01 considered statistically significant.
RESULTS: Paired cytokine and QOL data were available for 68 participants. IL-8 showed significant negative correlations with summary scores, a reliable indicator of overall QOL (rs = -0.35, p = 0.005). Increased IL-8 also correlated significantly with reduced emotional functioning scales (rs = -0.33, p = 0.01) and increased pain (rs = 0.32, p = 0.01). By contrast, increased IL-10 correlated significantly with reduced pain (rs = -0.31, p = 0.01). VEGF and MCP-1 levels correlated negatively with role functioning (rs = -0.32, p = 0.01; rs = -0.30, p = 0.01).
CONCLUSION: IL-8 is a key cytokine affecting QOL in HIV-KS. Elevations have a negative impact on pain, emotional functioning and overall QOL. IL-10, VEGF and MCP-1 perturbations also impact QOL. These findings enhance understanding of cytokine involvement in KS pathogenesis.}, }
@article {pmid40926209, year = {2025}, author = {Selvaraj, MS and Li, X and Li, Z and Van Buren, E and Haidermota, S and Postupaka, D and Hornsby, W and Bis, JC and Brody, JA and Cade, BE and Chung, RH and Curran, JE and Damrauer, SM and de Las Fuentes, L and de Vries, PS and Duggirala, R and Freedman, BI and Graff, M and Guo, X and Hidalgo, BA and Hou, L and Irvin, R and Judy, R and Kalyani, RR and Kelly, TN and Konigsberg, IR and Kral, BG and Kwee, LC and Levy, D and Li, C and Manichaikul, AW and Martin, LW and Montasser, ME and Morrison, AC and Naseri, T and North, KE and O'Connell, JR and Palmer, ND and Peyser, PA and Reiner, AP and Shah, SH and Smit, RAJ and Smith, JA and Taylor, KD and Tiwari, H and Tsai, MY and Viali, S and Wang, Z and Wang, Y and Zhao, W and Arnett, DK and Blangero, J and Boerwinkle, E and Bowden, DW and Carlson, JC and Chen, YI and Ellinor, PT and Fornage, M and He, J and Heard-Costa, N and Kaplan, RC and Kardia, SLR and Kooperberg, C and Kraus, WE and Lange, LA and Loos, RJF and Mitchell, BD and Psaty, BM and Rader, DJ and Redline, S and Rich, SS and Yanek, LR and Gibbs, R and Gabriel, S and Viaud-Martinez, KA and Dutcher, SK and Germer, S and Kim, R and Rotter, JI and Lin, X and Peloso, GM and , and Natarajan, P}, title = {Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {273}, pmid = {40926209}, issn = {1474-760X}, support = {75N92021F00229//NHLBI TOPMed fellowship/ ; R01HL142711//National Institutes of Health (NIH)/ ; R01HL142711//National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Cholesterol, LDL/genetics/blood ; *Whole Genome Sequencing ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Genome, Human ; Genetic Variation ; }, abstract = {BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.
RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate.
CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.}, }
@article {pmid40925936, year = {2025}, author = {Lawrenson, K and Kar, S and McCue, K and Kuchenbaeker, K and Michailidou, K and Tyrer, J and Beesley, J and Ramus, SJ and Li, Q and Delgado, MK and Lee, JM and Aittomäki, K and Andrulis, IL and Anton-Culver, H and Arndt, V and Arun, BK and Arver, B and Bandera, EV and Barile, M and Barkardottir, RB and Barrowdale, D and Beckmann, MW and Benitez, J and Berchuck, A and Bisogna, M and Bjorge, L and Blomqvist, C and Blot, W and Bogdanova, N and Bojesen, A and Bojesen, SE and Bolla, MK and Bonanni, B and Børresen-Dale, AL and Brauch, H and Brennan, P and Brenner, H and Bruinsma, F and Brunet, J and Buhari, SA and Burwinkel, B and Butzow, R and Buys, SS and Cai, Q and Caldes, T and Campbell, I and Cannioto, R and Chang-Claude, J and Chiquette, J and Choi, JY and Claes, KBM and , and Cook, LS and Cox, A and Cramer, DW and Cross, SS and Cybulski, C and Czene, K and Daly, MB and Damiola, F and Dansonka-Mieszkowska, A and Darabi, H and Dennis, J and Devilee, P and Diez, O and Doherty, JA and Domchek, SM and Dorfling, CM and Dörk, T and Dumont, M and Ehrencrona, H and Ejlertsen, B and Ellis, S and , and Engel, C and Lee, E and Evans, DG and Fasching, PA and Feliubadalo, L and Figueroa, J and Flesch-Janys, D and Fletcher, O and Flyger, H and Foretova, L and Fostira, F and Foulkes, WD and Fridley, BL and Friedman, E and Frost, D and Gambino, G and Ganz, PA and Garber, J and García-Closas, M and Gentry-Maharaj, A and Ghoussaini, M and Giles, GG and Glasspool, R and Godwin, AK and Goldberg, MS and Goldgar, DE and González-Neira, A and Goode, EL and Goodman, MT and Greene, MH and Gronwald, J and Guénel, P and Haiman, CA and Hall, P and Hallberg, E and Hamann, U and Hansen, TVO and Harrington, PA and Hartman, M and Hassan, N and Healey, S and , and Heitz, F and Herzog, J and Høgdall, E and Høgdall, CK and Hogervorst, FBL and Hollestelle, A and Hopper, JL and Hulick, PJ and Huzarski, T and Imyanitov, EN and , and , and Isaacs, C and Ito, H and Jakubowska, A and Janavicius, R and Jensen, A and John, EM and Johnson, N and Kabisch, M and Kang, D and Kapuscinski, M and Karlan, BY and Khan, S and Kiemeney, LA and Kjaer, SK and Knight, JA and Konstantopoulou, I and Kosma, VM and Kristensen, V and Kupryjanczyk, J and Kwong, A and de la Hoya, M and Laitman, Y and Lambrechts, D and Le, N and De Leeneer, K and Lester, J and Levine, DA and Li, J and Lindblom, A and Long, J and Lophatananon, A and Loud, JT and Lu, K and Lubinski, J and Mannermaa, A and Manoukian, S and Le Marchand, L and Margolin, S and Marme, F and Massuger, LFAG and Matsuo, K and Mazoyer, S and McGuffog, L and McLean, C and McNeish, I and Meindl, A and Menon, U and Mensenkamp, AR and Milne, RL and Montagna, M and Moysich, KB and Muir, K and Mulligan, AM and Nathanson, KL and Ness, RB and Neuhausen, SL and Nevanlinna, H and Nord, S and Nussbaum, RL and Odunsi, K and Offit, K and Olah, E and Olopade, OI and Olson, JE and Olswold, C and O'Malley, D and Orlow, I and Orr, N and Osorio, A and Park, SK and Pearce, CL and Pejovic, T and Peterlongo, P and Pfeiler, G and Phelan, CM and Poole, EM and Pylkäs, K and Radice, P and Rantala, J and Rashid, MU and Rennert, G and Rhenius, V and Rhiem, K and Risch, HA and Rodriguez, G and Rossing, MA and Rudolph, A and Salvesen, HB and Sangrajrang, S and Sawyer, EJ and Schildkraut, JM and Schmidt, MK and Schmutzler, RK and Sellers, TA and Seynaeve, C and Shah, M and Shen, CY and Shu, XO and Sieh, W and Singer, CF and Sinilnikova, OM and Slager, S and Song, H and Soucy, P and Southey, MC and Stenmark-Askmalm, M and Stoppa-Lyonnet, D and Sutter, C and Swerdlow, A and Tchatchou, S and Teixeira, MR and Teo, SH and Terry, KL and Terry, MB and Thomassen, M and Tibiletti, MG and Tihomirova, L and Tognazzo, S and Toland, AE and Tomlinson, I and Torres, D and Truong, T and Tseng, CC and Tung, N and Tworoger, SS and Vachon, C and van den Ouweland, AMW and van Doorn, HC and van Rensburg, EJ and Van't Veer, LJ and Vanderstichele, A and Vergote, I and Vijai, J and Wang, Q and Wang-Gohrke, S and Weitzel, JN and Wentzensen, N and Whittemore, AS and Wildiers, H and Winqvist, R and Wu, AH and Yannoukakos, D and Yoon, SY and Yu, JC and Zheng, W and Zheng, Y and Khanna, KK and Simard, J and Monteiro, AN and French, JD and Couch, FJ and Freedman, ML and Easton, DF and Dunning, AM and Pharoah, PD and Edwards, SL and Chenevix-Trench, G and Antoniou, AC and Gayther, SA}, title = {Author Correction: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8237}, doi = {10.1038/s41467-025-63507-x}, pmid = {40925936}, issn = {2041-1723}, }
@article {pmid40909820, year = {2025}, author = {Lim, R and O'Connor, C and Pan, J and Tang, TT and Castelo, AH and He, Y and Titt, U and Mohan, R and Liao, Z and Brock, KK}, title = {Weekly changes in ventilation response for photon and proton lung cancer patients during radiotherapy.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40909820}, abstract = {PURPOSE: Conformal dose distributions in proton radiotherapy promise to reduce normal tissue toxicity such as radiation-induced pneumonitis, but this has not been fully realized in clinical trials. To further investigate dose and toxicity, we employ voxel-based normal tissue evaluation techniques such as ventilation maps throughout treatment. We hypothesize that ventilation change after 1 week of treatment (WK1) predicts for ventilation change at the end of treatment (EOT).
METHODS: For 48 photon and 23 proton lung cancer patients, 4DCT-based ventilation maps were generated using stress-based methods at planning, WK1, and EOT. Voxel-wise ventilation change from planning to WK1 and EOT was calculated and binned by planned dose, and median ventilation change at WK1 and EOT was calculated across all patients in each dose bin. Patients were stratified into 6 groups based on modality and increased, decreased, or stable ventilation at WK1. Mann-Whitney U tests were performed to determine if median ventilation change at WK1 and EOT in each dose bin was significantly different from zero. Univariate analysis was performed to correlate ventilation change at EOT with change at WK1 and other clinical factors. A linear regression model was developed to predict ventilation at EOT using a variety of input features including ventilation at planning, ventilation at WK1, tumor response information, and tumor location. Accuracy of the model was assessed through R[2].
RESULTS: For patients that decreased in ventilation at WK1, 90% of photon patients and 92% of proton patients were stratified similarly at EOT. Patients that were stratified as increased ventilation at WK1 were stratified similarly (72% for photon, 80% for proton) at EOT. These patients were more likely to develop Grade 2+ pneumonitis though the difference was not significant when computing a Fisher's exact test. Univariate analysis indicated that only ventilation change at WK1 was correlated with ventilation change at EOT. The linear regression model achieved R[2] of 0.65.
CONCLUSION: Ventilation changes at EOT can be predicted using ventilation information from planning and WK1. Patients that increased in ventilation at WK1 were more likely to develop pneumonitis. Further work is needed to characterize the relationship between ventilation change with pneumonitis development.}, }
@article {pmid40924774, year = {2025}, author = {Mugwany, KK and Saina, M and Mugo, NR and MaWhinney, S and Morrow, M and Schaafsma, TT and Donnell, D and Glidden, DV and Ngure, K and Brown, CE and Rechkina, EA and Chohan, BH and Wu, L and Hill, E and Koome, E and Akelo, N and Mbaire, S and Morrison, SA and Kibatha, M and Njeru, I and Muriithi, M and Coppinger, C and Bushman, L and Baeten, JM and Anderson, PL and , }, title = {Adherence thresholds for emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis against HIV acquisition in cisgender women: A randomized directly observed dosing study.}, journal = {PLoS medicine}, volume = {22}, number = {9}, pages = {e1004732}, doi = {10.1371/journal.pmed.1004732}, pmid = {40924774}, issn = {1549-1676}, abstract = {BACKGROUND: Oral emtricitabine/tenofovir disoproxil fumarate (F/TDF) preexposure prophylaxis (PrEP) effectiveness against HIV acquisition highly depends on adherence. For men who have sex with men, a dosing study in the United States (US) population defined clinically meaningful tenofovir diphosphate (TFV-DP) thresholds in dried blood spots (DBS) based on the rounded 25th percentile for 2, 4, and 7 doses/week as 350, 700, and 1,250 fmol/punch. However, divergent efficacy results in the first generation randomized clinical trials of F/TDF PrEP among African women led to several hypotheses to question whether the pharmacology and adherence requirement for oral F/TDF PrEP may be different in cisgender women compared to what is already established for men.
METHODS AND FINDINGS: We conducted an open-label, parallel, randomized study of directly observed oral F/TDF PrEP among women without HIV who were not pregnant or breastfeeding in Kenya. Participants were randomly assigned to 2, 4, or 7 DOD doses/week for 8 weeks. Blood was collected weekly, and TFV-DP and emtricitabine triphosphate (FTC-TP) concentrations in DBS and peripheral blood mononuclear cells (PBMCs) were quantified using validated liquid chromatography-tandem mass spectrometry. For DBS, concentrations were quantified from a 3-mm punch using the 70% methanol/30% water (70:30) extraction method as the primary process-the same method used for the original TFV-DP benchmarks derived in US adults, and additionally with 50% methanol/50% water (50:50) extraction using punches from the same DBS spot to compare the extraction performance of 70:30 versus 50:50 methods. The primary outcome was the steady-state fitted concentrations of TFV-DP and dose proportionality in DBS and the observed PBMC TFV-DP levels by study dosing groups. Secondary outcomes included the quantitative concentrations of FTC-TP in DBS, TFV-DP half-life in DBS, and the relative TFV-DP recovery from DBS using the 70:30 versus 50:50 extraction method. One-compartment population pharmacokinetic models were fit to estimate steady-state DBS concentrations. Descriptive statistics were summarized as range, means, and medians with interquartile range (IQR) for continuous outcomes and proportions for categorical variables. Fifty-four women were enrolled and randomized. Median age was 22 (IQR, 20-25) years. The observed median (IQR) week 8 TFV-DP concentrations in DBS were 359 (266-464), 749 (596-923), and 1,389 (1,151-1,551) fmol/punch after 2, 4, and 7 doses/week, respectively. At week 8, FTC-TP was quantifiable in 71%, 19%, and 0% DBS samples for 7, 4, and 2 doses/week groups, respectively. Fitted median (IQR) steady-state DBS TFV-DP concentrations were 416 (316, 516), 832 (631, 1,033), and 1,457 (1,106, 1,808) fmol/punch for 2, 4, and 7 doses/week, respectively, similar to previous estimates in US adults. TFV-DP exhibited a mean half-life of 17.5 days (95%CI: 16.7, 18.4) in DBS and steady-state TFV-DP concentrations varied in direct proportion to the dosing frequency [slope: 1.02 90% confidence interval 0.84, 1.20]. The 50:50 DBS extraction method yielded 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared to the 70:30 method. When the 1.27 conversion factor was applied to the original 70:30 method-derived TFV-DP thresholds, the updated TFV-DP adherence interpretation benchmarks based on the 50:50 extraction were: <450 for <2 dose/week, 450-899 for 2-3 doses/week, 900-1,599 for 4-6 doses/week, and ≥1,600 fmol/punch for 7 doses/week. The observed mean (standard deviation) steady-state PBMC TFV-DP concentrations was 11.99 ± 8.47, 31.81 ± 15.66, and 63.1 ± 28.97 fmol/106 cells after 2, 4, and 7 doses/week, respectively. Overall, oral F/TDF PrEP was well tolerated. No grade 3 or higher adverse events were observed during the dosing phase. The primary study limitation was dosing for 8 weeks, but population pharmacokinetic modeling enabled steady-state estimates.
CONCLUSIONS: Steady-state DBS TFV-DP concentrations from directly observed F/TDF PrEP dosing in African cisgender women participants are similar to previous estimates defined from US-based participants. These data demonstrate that cisgender women achieve similar DBS and PBMC TFV-DP concentrations as men for the same adherence level and validate the original TFV-DP benchmarks to interpret F/TDF adherence in HIV prevention studies and PrEP programs among cisgender women.
TRIAL REGISTRATION: Clinicaltrials.gov: NCT05057858.}, }
@article {pmid40924642, year = {2025}, author = {Blinka, S and Yu, EY}, title = {Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-2546}, pmid = {40924642}, issn = {1557-3265}, abstract = {Human Kallikrein 2 (KLK2) is a prostate cancer tissue specific protein that is regulated by androgen receptor (AR) signaling. KLK2 was not previously recognized as a therapeutic target as it is secreted. It has now been demonstrated that KLK2 is expressed on the cell surface and targetable by various methodologies.}, }
@article {pmid40923785, year = {2025}, author = {Rossenkhan, R and Giorgi, EE and Shao, D and Ludwig, J and Labuschagne, P and Magaret, CA and Ndung'u, T and Muema, D and Gounder, K and Dong, KL and Walker, BD and Rolland, M and Robb, ML and Eller, LA and Sawe, F and Nitayaphan, S and Grebe, E and Busch, MP and Delaney, KP and Facente, S and Carpp, LN and deCamp, AC and Huang, Y and Korber, B and Juraska, M and Rudnicki, E and Kosmider, E and Reeves, DB and Mayer, BT and Hural, J and Deng, W and Westfall, DH and Yssel, A and Matten, D and Bhattacharya, T and Corey, L and Gilbert, PB and Williamson, C and Mullins, JI and Edlefsen, PT}, title = {Bayesian estimation of HIV acquisition dates for prevention trials.}, journal = {mBio}, volume = {}, number = {}, pages = {e0188125}, doi = {10.1128/mbio.01881-25}, pmid = {40923785}, issn = {2150-7511}, abstract = {Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, "true DDA" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.}, }
@article {pmid40923321, year = {2025}, author = {Song, Q and Zheng, M and Li, Q and Wu, X and Lin, B and Kang, TH and Qin, H and Kujawski, M and Pillai, RK and Lin, JL and Nakamura, R and Shively, J and Martin, PJ and Zeng, D}, title = {Intestinal epithelial Ceacam1 deficiency prevents steroid-refractory acute gut graft-versus-host disease.}, journal = {JCI insight}, volume = {10}, number = {17}, pages = {}, doi = {10.1172/jci.insight.186984}, pmid = {40923321}, issn = {2379-3708}, mesh = {*Graft vs Host Disease/immunology/prevention & control/genetics ; Animals ; Mice ; Humans ; *Intestinal Mucosa/immunology/metabolism/pathology ; Disease Models, Animal ; *Cell Adhesion Molecules/genetics ; Hematopoietic Stem Cell Transplantation/adverse effects ; *Antigens, CD/genetics/metabolism ; Interleukin-22 ; Male ; Mice, Inbred C57BL ; Interleukins/metabolism ; Female ; Epithelial Cells/metabolism/immunology ; Mice, Knockout ; Steroids ; T-Lymphocytes, Regulatory/immunology ; CEACAM1 Protein ; Carcinoembryonic Antigen ; }, abstract = {Steroid-refractory gut acute graft-versus-host disease (SR-Gut-aGVHD) is the major cause of nonrelapse death after allogeneic hematopoietic cell transplantation. High numbers of donor-type IL-22+ T cells, IL-22-dependent dysbiosis, and loss of antiinflammatory CX3CR1hi mononuclear phagocytes (MNPs) play critical roles in SR-Gut-aGVHD pathogenesis. CEACAM1 on intestinal epithelial cells (IECs) is proposed to regulate bacterial translocation and subsequent immune responses in the intestine. Here, with imaging mass cytometry (IMC), combined scRNA-Seq with ATAC-Seq, and high-dimensional flow cytometry analysis, we show that CEACAM1 expression was enhanced on IECs in murine and human SR-Gut-aGVHD. Ceacam1 deficiency on host IECs effectively prevented SR-Gut-aGVHD in murine models. Ceacam1 deficiency on IECs resulted in (i) higher numbers of IL-22+IL-10+Foxp3+CD4+ peripheral Tregs (pTregs) and lower numbers of conventional IL-22+CD4+ T (Tcon), Th/Tc1, and Th17 cells in the intestine; (ii) higher prevalence of beneficial commensal bacteria that augment colonic pTreg expansion, with lower prevalence of pathogenic bacteria; and (iii) higher numbers of antiinflammatory CD103-CX3CR1hi MNPs that produce indoleamine 2,3-dioxygenase (IDO) and IL-10, with lower numbers of proinflammatory CD103+CX3CR1lo MNPs that produce IL-6. Thus, specifically targeting IEC CEACAM1 represents a promising approach for prevention of SR-Gut-aGVHD.}, }
@article {pmid40923286, year = {2025}, author = {Malik, H}, title = {The viral arms race: an interview with Harmit Malik.}, journal = {Disease models & mechanisms}, volume = {18}, number = {9}, pages = {}, doi = {10.1242/dmm.052591}, pmid = {40923286}, issn = {1754-8411}, }
@article {pmid40920995, year = {2025}, author = {Thakur, R and Al Hadidi, S}, title = {From Physician-Driven to Patient-Centered: Transforming Multiple Myeloma Care Decisions.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500712}, doi = {10.1200/OP-25-00712}, pmid = {40920995}, issn = {2688-1535}, }
@article {pmid40920992, year = {2025}, author = {Bashore, L and Peterson, RK and Li, C and Liu, W and Wang, M and Jiwani, ZM and McDonald, AJ and Lupo, PJ and King, A and Srivastava, D and Leisenring, WM and Howell, RM and Gibson, TM and Oeffinger, K and Armstrong, GT and Bowman, WP and Krull, KR and Edelstein, K}, title = {Chronic Health Conditions and Academic Achievement: A Childhood Cancer Survivor Study Report.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500414}, pmid = {40920992}, issn = {2688-1535}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: To examine associations between special education, chronic health conditions (CHCs), and college graduation in survivors of childhood cancer and their siblings.
METHODS: Childhood Cancer Survivor Study participants included 23,082 5-year survivors (53.7% male; median [IQR] age at diagnosis, 6 [3-13] years; age at evaluation, 31.0 [24-39] years; treated between 1970 and 1999) and 5,037 siblings (47.7% male; 36.0 [28-44] years at evaluation). Special education use, reasons for special education, CHCs, and college graduation were self-reported. Primary cancer diagnosis and treatment exposures were abstracted from medical records. Comparisons between survivors and siblings were made using chi-square statistics; demographic and treatment factors associated with outcomes were examined using modified Poisson regression models.
RESULTS: More survivors reported special education use than siblings (26.5% v 8.6%; relative risk [RR], 2.55 [95% CI, 2.32 to 2.80]). Of those survivors and siblings who had special education services, use was highest between kindergarten and fifth grade (64.4% of survivors and 71.9% of siblings in kindergarten-fifth grade, 14.4% of survivors and 12.5% of siblings in sixth-eighth grade, and 9.2% of survivors and 9.0% of siblings in ninth-12th grade), and primarily attributable to learning and concentration problems. Despite receiving special education, survivors were less likely to graduate college compared with siblings requiring special education (RR, 0.76 [95% CI, 0.66 to 0.88]). Risk for not graduating college included history of CNS tumor (RR, 1.47 [95% CI, 1.40 to 1.55]), cranial irradiation (20-29 Gy, RR, 1.16 [95% CI, 1.09 to 1.25]; 30-49 Gy, RR, 1.37 [95% CI, 1.26 to 1.49]; ≥50 Gy, RR, 1.35 [95% CI, 1.28 to 1.42]), or the presence of a severe, disabling or life-threatening CHC (Common Terminology Criteria for Adverse Events grade 3-4, RR, 1.15 [95% CI, 1.07 to 1.24]).
CONCLUSION: Cognitive problems and CHCs increase risk for not graduating college; these problems are not alleviated by special education.}, }
@article {pmid40920378, year = {2025}, author = {Lee, JR and Morehead, D and Young, B and Tolbert, V and Masembe, J and Britt, G and Neuenschwander, L and Schuppe, K and Pelman, R and Johnson, D and Henderson, V and Darst, BF and Egwuatu, P and Kim, SM and Wolff, EM and Gore, JL and Nyame, YA}, title = {Patient and Physician Perceptions of Prostate-Specific Antigen Testing Among Black Individuals.}, journal = {JAMA network open}, volume = {8}, number = {9}, pages = {e2530946}, pmid = {40920378}, issn = {2574-3805}, mesh = {Adult ; Aged ; Humans ; Male ; Middle Aged ; *Attitude of Health Personnel ; *Black or African American/psychology/statistics & numerical data ; *Early Detection of Cancer/psychology ; *Health Knowledge, Attitudes, Practice ; *Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/diagnosis/ethnology ; Qualitative Research ; United States ; }, abstract = {IMPORTANCE: Black individuals have a twofold higher rate of prostate cancer death in the US compared with the average population with prostate cancer. Few guidelines support race-conscious screening practices among at-risk Black individuals.
OBJECTIVE: To examine structural factors that facilitate or impede access to prostate cancer screening among Black individuals in the US.
This qualitative, mixed-methods study was conducted between September 1, 2021, and December 31, 2023, in clinical and community settings across Washington, Wyoming, Alaska, Montana, Idaho, and Oregon. It included semistructured interviews with Black adults (aged ≥18 years) at risk for prostate cancer with or without a history of prostate-specific antigen (PSA) testing and a survey of primary care practitioners (PCPs) and urologists.
MAIN OUTCOMES AND MEASURES: Patient and physician experiences, knowledge, attitudes, and practices of PSA testing and prostate cancer screening were evaluated. Consensus coding and thematic analysis were used to analyze interviews; surveys were analyzed using descriptive statistics.
RESULTS: A total of 29 Black men (median [range] age, 59 [32-72] years) participated in the interviews, and 31 PCPs (including 30 phyicians and 1 physician assistant) and 32 urologists (45 of 63 aged 30-59 years [71.4%]; 40 male [63.5%]) participated in the survey. Interview participants perceived that PCPs function as gatekeepers in accessing PSA testing but may lack knowledge specific to Black men's risk for prostate cancer and hold attitudes about PSA testing that do not support its use. Interview participants also reported a lack of trusted relationships with PCPs to support shared decision-making. While both urologists and PCPs were highly aware of US Preventive Services Task Force guidelines, PCPs were much less likely than urologists to believe in the value of PSA testing or the role of early detection to prevent prostate cancer-related mortality (2 [6.5%] vs 24 [75.0%], respectively).
CONCLUSIONS AND RELEVANCE: In this qualitative study examining structural factors associated with access to prostate cancer screening among Black individuals, findings from the survey supported participants' perceptions that PCPs do not value PSA testing for prostate cancer early detection or appreciate its role in reducing the risk of prostate cancer-related mortality. Primary care practitioner reliance on USPSTF guidelines, which currently do not provide guideline recommendations for screening high-risk groups, including Black individuals, suggests that incorporating evidence-driven guidance for PSA screening among Black individuals into these guidelines may substantially improve prostate cancer early detection among this high-risk population.}, }
@article {pmid40920226, year = {2025}, author = {Wang, LH and Sonbas Cobb, B and Riem, L and DuCharme, O and Shaw, DW and Walker, M and Eichinger, K and Lewis, L and Tawil, R and Hamel, JI and Mul, K and Blemker, SS and Tapscott, SJ and Friedman, SD and Rutkove, SB and Statland, JM}, title = {Electrical impedance myography captures features of muscle structure measured by MRI and transcriptomic analysis in facioscapulohumeral muscular dystrophy.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251369246}, doi = {10.1177/22143602251369246}, pmid = {40920226}, issn = {2214-3602}, abstract = {BACKGROUND: Electrical impedance myography (EIM) has been proposed as an efficient, non-invasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD).
OBJECTIVE: We investigate whether EIM parameters are associated with muscle structure measured by magnetic resonance imaging (MRI), muscle histology, and transcriptomic analysis as well as strength at the individual leg muscle level.
METHODS: We performed a multi-center cross-sectional study enrolling 33 patients with FSHD. EIM measurements were recorded from bilateral vastus lateralis, tibialis anterior (TA), and medial gastrocnemius muscles and compared to quantitative muscle volume measures by MRI as well as knee extension and ankle dorsiflexion strength by quantitative muscle testing. EIM measurements of the bilateral TA were further compared to histology and transcriptomic analysis (RNAseq) of muscle and fat content.
RESULTS: EIM phase at multiple frequencies was positively associated to the amount of muscle measured by MRI (ρ = 0.48 to 0.70, p ≤ 0.001) and negatively associated to the amount of fat replacement of muscle (ρ = -0.53 to -0.73, p ≤ 0.001). EIM phase of the vastus lateralis and TA was positively associated with knee extension and ankle dorsiflexion strength normalized to age and sex (ρ = 0.45 to 0.60, p < 0.0001). The bilateral TA muscles were analyzed at the histopathological and molecular (transcriptomic) levels and showed that EIM phase was positively associated with amount of muscle (ρ = 0.33 to 0.35, p < .01) and negatively associated with amount of fat (ρ = -0.36 to -0.56, p < .001) by transcriptomic analysis.
CONCLUSIONS: This study supports the hypothesis that the amount and quality of muscle tissue as assessed by EIM is associated with the amount and quality of muscle tissues as assessed by MRI and muscle biopsy, with all measures ultimately being strongly associated with muscle strength. These data provide further convergent validity for the use of EIM as a potential non-invasive biomarker to assess muscle health in FSHD.}, }
@article {pmid40919994, year = {2025}, author = {Choe, M and Kirkey, D and Lira, I and Hawkins, G and Blankenfeld, M and Menashe, S and Ries, R and Wrightson, B and Root, C and McKay, CN and Peplinski, JH and Glabman, R and Davis, LE and Malhotra, SV and Gorlick, R and Loggers, ET and Meshinchi, S}, title = {Preclinical evaluation of folate receptor-alpha chimeric antigen receptor T cells (FOLR1-CART) exhibit highly efficient anti-tumor activity against osteosarcoma.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-25-0086}, pmid = {40919994}, issn = {2767-9764}, abstract = {Metastatic and relapsed osteosarcoma (OS) remains difficult to treat despite advanced surgical techniques, intensified chemotherapy, and targeted therapies. Adoptive immunotherapies such as chimeric antigen receptor (CAR) T cells, are in their nascent stage, but remain a viable therapeutic strategy for patients with aggressive solid tumors such as OS. Folate receptor-(?) (FOLR1) has been functionally implicated in OS pathophysiology, providing rationale as a potential therapeutic target. We recently advanced a FOLR1-specific CAR T cell product (FH FOLR1-CART) into a trial in infant AML (NCT06609928) and now evaluate this CAR construct against OS. We provide comprehensive FOLR1 transcript and protein expression profile in OS patients, cell lines and patient-derived xenografts, substantiating its significance as a therapeutic target. We further evaluate in vitro and in vivo efficacy of FH FOLR1-CART in both standard and patient-derived OS cell lines and xenograft models. FOLR1 transcript is expressed in the overwhelming majority of OS primary patient specimens, in OS cell lines, and patient-derived models. FH FOLR1-CART exhibit robust in vitro activation and potent cytotoxicity against FOLR1-expressing OS cell lines and primary OS patient samples. More importantly, FH FOLR1-CART demonstrates potent anti-tumor activity in both localized and metastatic in vivo cell-derived and patient-derived xenograft models, with complete tumor eradication. These results demonstrate a potential therapeutic option for patients with advanced OS. FH FOLR1 CART is advancing to an early phase trial in relapsed/refractory OS at Fred Hutch Cancer Center and Seattle Children's Hospital.}, }
@article {pmid40919233, year = {2025}, author = {Wallace, M and Mathey, B and Yeung, CCS and Appelbaum, JS and Wallace, M}, title = {Coexistence of Essential Thrombocythemia and Waldenström Macroglobulinemia: A Case Report.}, journal = {Case reports in hematology}, volume = {2025}, number = {}, pages = {3390770}, pmid = {40919233}, issn = {2090-6560}, abstract = {Waldenström macroglobulinemia (WM) and essential thrombocythemia (ET) are distinct hematologic malignancies that have only been reported to co-occur in one previous patient. We present a 64-year-old man with a significant family history for WM who was found to have both ET and WM. He had symptomatic ET, diagnosed by elevated platelets and a positive JAK2 V617F mutation, and asymptomatic WM was found on serum electrophoresis done for screening due to family history. Genomic evaluation of the myeloid and lymphoid cells suggested independent neoplastic transformation. This is the second reported case of a patient with both WM and ET. There was no evidence for a shared mechanism in these dual malignancies.}, }
@article {pmid40918924, year = {2025}, author = {Nriagu, BN and Rosario, KF and Hansen, S and Luciano, PD and Joshi, P and Mehta, A and Khera, AV and Kaplan, R and Sofer, T and McClelland, RL and Rodriguez, CJ}, title = {Hispanic/Latino ethnic background and genetic ancestry in relation to atherosclerotic cardiovascular disease risk estimation: Findings from the Multi-Ethnic Study of Atherosclerosis (MESA).}, journal = {American journal of preventive cardiology}, volume = {23}, number = {}, pages = {101268}, pmid = {40918924}, issn = {2666-6677}, abstract = {BACKGROUND: Hispanics/Latinos are a heterogenous population with no validated atherosclerotic cardiovascular disease (ASCVD) risk estimation tool. We examined performance of the pooled cohort equation (PCE) across Hispanic/Latino background groups and quantiles of African, Amerindian, and European genetic ancestry.
METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) was used to evaluate the performance of the non-Hispanic Black (NHB) and non-Hispanic White (NHW) PCE defined by predicted to observed (P/O) ratios of 10-year ASCVD events. Risk calibration was expressed as P/O ratios and risk discrimination was assessed with Harrell's C-statistic based on Cox models.
RESULTS: Our study included 966 Hispanics/Latinos [age 58 years at baseline (SD=9); 52 % females], comprising 504 Hispanics/Latinos of Mexican descent (MX), 284 Hispanics/Latinos of Caribbean descent (CA) and 178 Other Hispanics (O). At 10-years, there were 54 ASCVD events: MX (33); CA (13) and O (8). The PCE overestimated ASCVD risk across disaggregated Hispanic/Latino background groups. Both NHW and NHB PCE models performed best with increasing European genetic ancestry (NHW PCE: P/O ratio decreasing from 1.5 to 1.0; NHB PCE: from 2.4 to 1.5 between the 20th and 80th quantile threshold of European genetic ancestry). In contrast, PCE performance worsened with increasing African genetic ancestry (NHW PCE: P/O ratio increasing from 1.5 to 2.6; NHB PCE: from 1.5 to 2.9 between the 20th and 80th quantile threshold of African genetic ancestry).
CONCLUSIONS: Disaggregating Hispanics/Latinos by background and ancestry led to variability in PCE performance with greater overestimation of ASCVD risk for those of Caribbean background and those with increasing quantiles of African genetic ancestry.}, }
@article {pmid40917113, year = {2025}, author = {Chakraborty, H and Sun, Q and Bhupathiraju, SN and Schenk, JM and Mishchuk, DO and Bain, JR and He, X and Sun, J and Harnly, J and Simmons, W and Raftery, D and Liang, L and Newman, JW and Fiehn, O and Clish, CB and Lampe, JW and Bennett, BJ and Navarro, SL and Wang, Y and Zheng, C and Mossavar-Rahmani, Y and McCullough, ML and Huang, Y and Shojaie, A and Zhu, W and Djukovic, D and Sacks, F and Williams, J and Steinberg, FM and Adams, SH and Hu, FB and Neuhouser, ML and Slupsky, CM and Maruvada, P}, title = {Corrigendum to "The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition. [Current Developments in Nutrition, Volume 9, Issue 5, May 2025, 107435]".}, journal = {Current developments in nutrition}, volume = {9}, number = {8}, pages = {107517}, doi = {10.1016/j.cdnut.2025.107517}, pmid = {40917113}, issn = {2475-2991}, abstract = {[This corrects the article DOI: 10.1016/j.cdnut.2025.107435.].}, }
@article {pmid40916416, year = {2025}, author = {Giorgi, EE and Abrahams, MR and Fouda, G and John-Stewart, G and Goga, A and Mullins, JI and Permar, SR and Janes, HE and Martin, TM}, title = {Characterization of Early Viral Populations in Infants Acquiring HIV Through Perinatal and Breastmilk Transmission: A Review of what is Currently Known and the Gaps that Need to be Addressed to Guide Passive HIV Immunization of Breastfeeding Infants.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570162X357975250902104402}, pmid = {40916416}, issn = {1873-4251}, abstract = {Newborns represent only 1% of the population. Yet, HIV vertical transmissions represent 10% of all new infections globally, even though antiretroviral therapy (ART) has been shown to reduce the risk of vertical transmission to less than 2%. While vaccines still represent the most efficient and cost-effective intervention to eradicate new infections, HIV immunogens that can effectively elicit broad-spectrum protection are still at least a decade away. In contrast, passive immunization with broadly neutralizing antibody (bnAb) combinations has the potential to provide a more immediate pathway to HIV prophylaxis. Early-phase infant trials are underway to establish the safety and pharmacokinetics of bnAb combinations selected for their potency against viruses acquired via adult transmissions. However, the specific characteristics and phenotypic differences of vertically transmitted viruses in infants compared to those in adults remain uncertain, including their susceptibility to known broadly neutralizing antibodies (bnAbs). We review the current knowledge of vertically transmitted HIV viruses, including their genetics and phenotypic features. Differences in immunity between adults and infants lead us to hypothesize that distinct selection and evolutionary pressures act on the virus at the time of transmission and during the early phases of infection, and these may in turn affect the choice of bnAb combinations needed for protection against vertical transmission of HIV.}, }
@article {pmid40915872, year = {2025}, author = {MacKay, EJ and Zhang, B and Beaty, JM and Devine, KA and O'Reilly-Shah, V and Mathis, MR and Szeto, WY and Groeneveld, PW and Augoustides, JG}, title = {Practice Pattern Variability in the Use of Pulmonary Arterial Catheters in Cardiac Surgery.}, journal = {Journal of cardiothoracic and vascular anesthesia}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.jvca.2025.08.013}, pmid = {40915872}, issn = {1532-8422}, abstract = {OBJECTIVES: To quantify intraoperative pulmonary arterial catheter (PAC) use during cardiac surgery and identify hospital-, anesthesiologist-, and patient-level factors associated with PAC utilization.
DESIGN: A cross-sectional, observational study using generalized logistic mixed models to examine variations in PAC use.
SETTING: Fifty-three US academic hospitals participating in the Multicenter Perioperative Outcomes Group (MPOG) national registry PARTICIPANTS: 145,343 adult patients undergoing cardiac surgery between January 1, 2016, and December 31, 2022.
INTERVENTION(S): Receipt of intraoperative PAC, defined by ≥60 minutes of physiologically plausible pulmonary arterial pressures.
The primary outcome was PAC utilization. Mixed-effects logistic regression quantified fixed-effect predictors, and variation attributable to anesthesiologists and then to anesthesiologists nested within a hospital was characterized using median odds ratio (MOR). Of the 145,343 cardiac surgeries performed across 53 hospitals, 104,626 (72%) included PAC monitoring. PAC use varied widely across hospitals (0-98%) and across anesthesiologists (0-100%). PAC was used most frequently in heart transplants (94%) and lung transplants (87%) and least frequently in pulmonic valve procedures (30%). A patient's likelihood of receiving a PAC was influenced most strongly by hospital (MOR, 15.00; 95% confidence interval [CI], 8.98-28.32), with substantially less variation attributable to an anesthesiologist within the same hospital (MOR, 1.70; 95% CI, 1.61-1.81).
CONCLUSIONS: Intraoperative PAC monitoring is used in nearly three-quarters of cardiac surgeries at US academic centers, with hospital practice pattern the factor most closely associated with PAC utilization.}, }
@article {pmid40914769, year = {2025}, author = {Upreti, M and Petrosyan, A and Thornton, ME and Hovsepyan, A and Fernandez, GE and Koos, DS and Byrum, SD and Mackintosh, SG and Al-Husseini, JK and Porras, T and Ha, J and Tackett, AJ and Zhang, M and Johal, MS and Erdreich-Epstein, A and Durham, S and Krieger, MD and Margol, AS and Grubbs, BH and Chambers, TC and Asgharzadeh, S and Moats, RA and Chiarelli, PA}, title = {Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, pmid = {40914769}, issn = {1476-5594}, support = {CDMRP RA210290//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; CDMRP RA210290//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; CDMRP RA210290//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; K08NS125175-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K08NS125175-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R24GM137786//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R24GM137786//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R24GM137786//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {It has become evident from decades of clinical trials that multimodal therapeutic approaches with focus on cell intrinsic and microenvironmental cues are needed to improve understanding and treat the rare, inoperable, and ultimately fatal diffuse intrinsic pontine glioma (DIPG), now categorized as a diffuse midline glioma. In this study we report the development and characterization of an in vitro system utilizing 3D Tumor Tissue Analogs (TTA), designed to replicate the intricate DIPG microenvironment. The innate ability of fluorescently labeled human brain endothelial cells, microglia, and patient-derived DIPG cell lines to self-assemble has been exploited to generate multicellular 3D TTAs that mimic tissue-like microstructures, enabling an in- depth exploration of the spatio-temporal dynamics between neoplastic and stromal cells. The 3D-TTA model recapitulates clinical patterns of DIPG growth, evidenced by resistance to chemotherapy, HDAC and proteasome inhibitors, as well as sensitization to the antibody-activated innate immune microenvironment including complement proteins and surrounding microglia. Multimodal fluorescence imaging platforms integrated with high-throughput omics revealed that alterations in tumor cell motility and growth in the 3D-TTA model compared to tumor cell only spheroids correlated with specific transcriptomic and proteomic changes. STAT3, ITGA5, LGALS1, SOD2, MVP, and CLIC1, associated with microenvironment signaling, DNA replication, and immune regulation, were identified as potential novel targets in the 3D model. The results indicate that the 3D TTA platform developed here represents a powerful tool for preclinical studies, paving the way for identification/validation of tissue specific biomarkers and novel drug targets, thus advancing disease management strategies for DIPG in children.}, }
@article {pmid40914661, year = {2025}, author = {de la Calle, CM and Jing, Y and Fountain, J and Fletcher, SA and Mamawala, MM and Landis, P and Macura, KJ and Lotan, TL and Trock, BJ and Isaacs, WB and Pavlovich, CP}, title = {Family History of Prostate, Breast, Ovarian, and/or Pancreatic Cancer and Associations with Grade Reclassification in a Large Prostate Cancer Active Surveillance Cohort.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.07.008}, pmid = {40914661}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: The effect of family history (FH) on prostate cancer active surveillance outcomes is unknown. Our objective is to evaluate FH of prostate, breast, ovarian, and/or pancreatic cancer in a large prospective active surveillance cohort.
METHODS: Patients with recorded FH data (N = 1421) were selected. Association between grade reclassification to Gleason grade (GG) ≥2 and GG ≥3, and FH of prostate cancer (FH-Pr); FH of breast, ovarian, and/or pancreatic cancer (FH-BOPa); and FH-Pr and/or FH-BOPa in first-degree relatives was evaluated by a competing risk analysis. Association with adverse pathologic features (APFs; GG ≥3, seminal vesicle, and/or lymph node involvement) at radical prostatectomy was assessed with multivariable logistic regression.
KEY FINDINGS AND LIMITATIONS: Of the 1421 patients, 41/362 (11.3%) with FH-Pr, 37/336 (11.0%) with FH-BOPa, and 67/600 (11.2%) with FH-Pr and/or FH-BOPa were reclassified to GG ≥3. FH-Pr was associated with reclassification to GG ≥2 and GG ≥3 (adjusted hazard ratio [HR] 1.49 for GG ≥3 [95% confidence interval {CI} 1.02-2.17], p = 0.039), as was FH-Pr and/or FH-BOPa (HR 1.52 for GG ≥3 [95% CI 1.07-2.17], p = 0.020). FH-BOPa however was not associated with any grade reclassification (HR 1.30 for GG ≥3 [95% CI 0.88-1.94], p = 0.190). In the 349 patients who underwent radical prostatectomy, no FH status was associated with APFs. Our study is limited by having information on first-degree relatives only.
Patients with FH-Pr had a higher risk of grade reclassification, including extreme grade reclassification (GG ≥3), but no FH status led to more APFs at radical prostatectomy. Patients with FH can safely be managed on surveillance, but might benefit from closer monitoring.}, }
@article {pmid40909667, year = {2025}, author = {Ju, X and Hannon, WW and Kaszuba, T and Radford, CE and Larsen, BB and Nelson, SS and Nelson, CA and Baltazar-Perez, I and Zimmerman, O and Fremont, DH and Diamond, MS and Bloom, JD}, title = {Determinants of human versus mosquito cell entry by the Chikungunya virus envelope proteins.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909667}, issn = {2692-8205}, abstract = {Chikungunya virus (CHIKV) infects both humans and mosquitoes during its transmission cycle. How the virus's envelope proteins mediate entry in cells from such different species is unclear. MXRA8 is a receptor for CHIKV in mammalian cells, but the receptor(s) in mosquito cells remains unknown. Here we use pseudovirus deep mutational scanning to measure how nearly all amino-acid mutations to the CHIKV envelope proteins affect entry in MXRA8-expressing human and mosquito cells. Most mutations similarly affect entry in both types of cells, and our comprehensive measurements of these effects define functional constraints related to protein folding and fusion activity. However, some mutations differentially affect entry in MXRA8-expressing human cells versus mosquito cells. Sites where mutations specifically impair entry in MXRA8-expressing human cells are often involved in MXRA8 binding, and we hypothesize sites where mutations specifically impair entry in mosquito cells are involved in binding the unknown mosquito receptor(s). We use the deep mutational scanning data to design loss-of-tropism mutant viruses that are impaired in their ability to infect either mosquito cells or MXRA8-expressing human cells. Our findings provide insights into the species-specific determinants of CHIKV cell entry that can help guide receptor identification and vaccine development.}, }
@article {pmid40291665, year = {2025}, author = {Bakker, RA and Nicholson, OB and Park, H and Xiao, YL and Tang, W and Subramaniam, AR and Lapointe, CP}, title = {Deaminase-based RNA recording enables high throughput mutational profiling of protein-RNA interactions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40291665}, issn = {2692-8205}, abstract = {Protein-RNA interactions govern nearly every aspect of RNA metabolism and are frequently dysregulated in disease. While individual protein residues and RNA nucleotides critical for these interactions have been characterized, scalable methods that jointly map protein- and RNA-level determinants remain limited. RNA deaminase fusions have emerged as a powerful strategy to identify transcriptome-wide targets of RNA-binding proteins by converting binding events into site-specific nucleotide edits. Here, we demonstrate that this 'RNA recording' approach enables high-throughput mutational scanning of protein-RNA interfaces. Using the λN-boxB system as a model, we show that editing by a fused TadA adenosine deaminase directly correlates with binding affinity between protein and RNA variants in vitro. Systematic variation of RNA sequence context reveals a strong bias for editing at UA dinucleotides by the engineered TadA8.20, mirroring wild-type TadA preferences. We further demonstrate that stepwise recruitment of the deaminase using nanobody and protein A/G fusions maintains both sequence and binding specificity. Stable expression of the TadA fusion in human cells reproduces in vitro editing patterns across a library of RNA variants. Finally, comprehensive single amino acid mutagenesis of λN in human cells reveals critical residues mediating RNA binding. Together, our results establish RNA recording as a versatile and scalable tool for dissecting protein-RNA interactions at nucleotide and residue resolution, both in vitro and in cells.}, }
@article {pmid40914571, year = {2025}, author = {Vuong, W and Lo, SS}, title = {A Case for Widening the Window of Opportunity.}, journal = {International journal of radiation oncology, biology, physics}, volume = {123}, number = {2}, pages = {331-332}, doi = {10.1016/j.ijrobp.2025.03.089}, pmid = {40914571}, issn = {1879-355X}, }
@article {pmid40910475, year = {2025}, author = {Moore, A and Kane, E and Teras, LR and Machiela, MJ and Arias, J and Panagiotou, OA and Monnereau, A and Doo, NW and Wang, Z and Slager, SL and Vermeulen, RCH and Vajdic, CM and Smedby, KE and Spinelli, JJ and Vijai, J and Giles, GG and Link, BK and Arslan, AA and Nieters, A and Bracci, PM and Camp, NJ and Salles, G and Cozen, W and Hjalgrim, H and De Vivo, I and Adami, HO and Albanes, D and Becker, N and Benavente, Y and Bisanzi, S and Boffetta, P and Brennan, P and Brooks-Wilson, AR and Canzian, F and Clavel, J and Conde, L and Cox, DG and Curtin, K and Foretova, L and Ghesquières, H and Glimelius, B and Habermann, TM and Hofmann, JN and Lan, Q and Liebow, M and Lincoln, A and Maynadie, M and McKay, J and Melbye, M and Miligi, L and Milne, RL and Molina, TJ and Morton, LM and North, KE and Offit, K and Padoan, M and Piro, S and Patel, AV and Purdue, MP and Ravichandran, V and Riboli, E and Severson, RK and Southey, MC and Staines, A and Tinker, LF and Travis, RC and Wang, SS and Weiderpass, E and Weinstein, S and Zheng, T and Chanock, SJ and Rothman, N and Birmann, BM and Cerhan, JR and Berndt, SI}, title = {Genetically determined body mass index is associated with diffuse large B-cell lymphoma in polygenic and Mendelian randomization analyses.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70039}, pmid = {40910475}, issn = {1097-0215}, support = {/CP/NCI NIH HHS/United States ; }, abstract = {Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05-1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (ORper SD = 1.12, 95% CI: 1.02-1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.}, }
@article {pmid40909725, year = {2025}, author = {Hong, A and Liu, M and Truta, A and Talaie, A and Smith, GR and Bondy-Denomy, J}, title = {Gabija restricts phages that antagonize a conserved host DNA repair complex.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909725}, issn = {2692-8205}, abstract = {Anti-bacteriophage systems like restriction-modification and CRISPR-Cas have DNA substrate specificity mechanisms that enable identification of invaders. How Gabija, a highly prevalent nuclease-helicase anti-phage system, executes self- vs. non-self-discrimination remains unknown. Here, we propose that phage-encoded DNA end-binding proteins that antagonize host RecBCD sensitize phages to Gabija. When targeting a temperate Lambda-like phage in Pseudomonas aeruginosa, Gabija protects the cell by preventing phage genome circularization and subsequent replication. Phage and plasmid sensitivity to Gabija is licensed by DNA end-binding complexes such as a phage exonuclease together with a ssDNA-annealing protein or GamMu dimers, which prevent loading of host repair complex RecBCD. Escape phages lacking these end-binding proteins become protected from Gabija by RecBCD translocation activities. RecBCD activity on the bacterial genome also prevents Gabija from targeting self-DNA. Therefore, we propose that Gabija antagonizes circularization of linear DNA devoid of RecBCD as a mechanism to identify foreign invaders.}, }
@article {pmid40909540, year = {2025}, author = {Ockerman, F and Chen, B and Sun, Q and Kharitonova, EV and Chen, W and Zhou, LY and Loos, RJF and Kooperberg, C and Peters, U and Haessler, J and Reiner, A and Jung, SY and Manson, JE and Nassir, R and North, KE and Buyske, S and Haiman, CA and Conti, DV and Wilkens, LR and Lange, EM and Cox, NJ and Cao, H and Raffield, LM and Li, Y and Tao, R}, title = {An Efficient Lasso Framework for Admixture-Aware Polygenic Scores.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909540}, issn = {2692-8205}, abstract = {Polygenic scores (PGS) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGS are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGS methods have demonstrated greater generalizability than single-ancestry PGS, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI is a recently proposed PGS method which overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI re-parameterizes the GAUDI model as a standard LASSO problem, allowing for extension to multi-way admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly out-performs GAUDI across 18 clinical phenotypes, including total triglycerides (TG), C-reactive protein (CRP), and mean corpuscular hemoglobin concentration (MCHC), and shows substantial benefits over an ancestry-agnostic PGS for white blood cell count (WBC) and chronic kidney disease (CKD).}, }
@article {pmid40908355, year = {2025}, author = {Chu, HY and Janes, H and Carone, M and Gilbert, PB and Plotkin, S}, title = {Improving the evidence base for COVID-19 vaccines.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40908355}, issn = {1546-170X}, }
@article {pmid40907772, year = {2025}, author = {Ali, M and Correa, RJM and Pryor, D and Higgs, B and Sridharan, S and Sidhom, M and Muacevic, A and Onishi, H and Swaminath, A and Grubb, W and Yang, DX and Grant, A and Morgan, SC and Ponsky, L and Cury, FL and Teh, BS and Lo, SS and Mahadevan, A and Kaplan, ID and Chu, W and Hannan, R and Staehler, M and Zaorsky, NG and Warner, A and Louie, AV and Siva, S}, title = {Efficacy of Stereotactic Ablative Body Radiotherapy (SABR) in uncommon subtypes of primary kidney cancer: An analysis from the International Radiosurgery Oncology Consortium of the Kidney.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.08.043}, pmid = {40907772}, issn = {1879-355X}, abstract = {BACKGROUND: While stereotactic ablative body radiotherapy (SABR) is associated with excellent local control for primary renal cell carcinoma (RCC), outcomes based on clear-cell (ccRCC) and non-clear cell (nccRCC) histologies are not well defined.
METHODS AND MATERIALS: Individual data of adult patient with biopsy confirmed primary RCC receiving SABR between 2007 and 2021 from 16 institutions in Australia, Canda, Germany, Japan and USA pooled. Patients with metastatic disease or upper tract urothelial carcinoma were excluded. The primary outcome was local failure (LF), based on the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Distant failure (DF), cancer-specific survival (CSS), treatment related toxicity and renal function changes following SABR were defined as secondary outcomes. Kaplan-Meier estimates were generated for LF, DF and CSS stratified by clear cell vs. non-clear cell histology, compared using the log-rank test (CSS) or Gray's test (LF and DF).
RESULTS: Two hundred and eleven patients with a biopsy confirmed ccRCC (n=167) or nccRCC (n=44) were included. In the nccRCC group, 59% (n=26/44) and 11% (n=5/44) were papillary and chromophobe histologies, respectively. Patients with nccRCC were more likely to be older (median age at SABR 77.2 years vs. 71.5, p=0.009) and to be treated with multifraction SABR (82% [n=36/44] vs. 38% [n=63/167]; p < 0.001) than the ccRCC group. The median follow-up was 4.02 years (IQR: 3.43-4.94) and 4.25 years (IQR: 3.02-5.00) for ccRCC and nccRCC groups, respectively. The 5-year cumulative incidence of LF was 1.5% (95% confidence interval [CI]: 0.3-4.8%) in ccRCC group vs. 2.4% (95% CI: 0.2-11.0%) in nccRCC group (hazard ratio [HR]: 0.90, 95% CI: 0.10-8.31, p=0.922). The corresponding cumulative incidence of DF at 5-years was 6.0% in ccRCC group vs. 2.9% in nccRCC group (HR: 0.34, 95% CI: 0.04-2.68, p=0.304). The 5-year estimated CSS was 96.4% in ccRCC group vs. 96.4% in nccRCC group (HR: 2.04, p=0.561). From baseline, eGFR reduced by 11.4 ± 13.4 mL/min at 3 years and by 12.2 ± 14.0 mL/min at 5 years. Sixteen patients (7.6%) experienced grade-2 or higher toxicities, with grade-2 fatigue (5.7%) being the most common.
CONCLUSION: SABR provides excellent oncologic outcomes, irrespective of ccRCC or nccRCC histology.}, }
@article {pmid40907516, year = {2025}, author = {Gui, C and Wang, JZ and Patil, V and Landry, AP and Singh, O and Castelo-Branco, P and Tabori, U and Aldape, K and Behling, F and Barnholtz-Sloan, JS and Horbinski, C and Tabatabai, G and Ajisebutu, A and Liu, J and Patel, Z and Yakubov, R and Kaloti, R and Ellenbogen, Y and Wilson, C and Cohen-Gadol, A and Tatagiba, M and Holland, EC and Sloan, AE and Chotai, S and Chambless, LB and Gao, A and Makarenko, S and Yip, S and Nassiri, F and Zadeh, G and , }, title = {Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study.}, journal = {The Lancet. Oncology}, volume = {26}, number = {9}, pages = {1191-1203}, doi = {10.1016/S1470-2045(25)00267-0}, pmid = {40907516}, issn = {1474-5488}, mesh = {Humans ; *Telomerase/genetics ; *Meningioma/genetics/pathology/mortality/surgery ; Male ; Female ; Middle Aged ; Promoter Regions, Genetic ; Mutation ; Retrospective Studies ; *Meningeal Neoplasms/genetics/pathology/mortality/surgery ; Aged ; Adult ; Prognosis ; Progression-Free Survival ; *Biomarkers, Tumor/genetics ; Canada ; Cohort Studies ; }, abstract = {BACKGROUND: TERT promoter mutation is a rare biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival. Although high TERT expression is characteristic of tumours with TERT promoter mutations, it has also been observed in tumours with wildtype TERT promoters. This study aimed to investigate the prevalence and prognostic association of TERT expression in meningiomas.
METHODS: This multi-institutional cohort study retrospectively collected clinical and molecular data from 1241 meningiomas surgically resected between Jan 1, 2000, and Dec 31, 2024, at Toronto Western Hospital, Canada (n=380; discovery cohort) and external institutions in Canada, Germany, and the USA (n=861; validation cohort). All patients were aged 18 years and older. TERT promoter mutation and TERT expression were determined by Sanger and bulk RNA sequencing. The primary outcomes were TERT expression (presence or absence) in meningiomas with and without TERT promoter mutations, and the difference in progression-free survival between tumours expressing TERT and those not expressing TERT. Survival analysis was assessed using Cox regression and Kaplan-Meier analysis.
FINDINGS: Between Jan 1, 2000, and Dec 31, 2024, clinical demographics and tumour characteristics were collected. Median follow-up was 6·2 years (IQR 1·7-12·5) in the discovery cohort and 3·3 years (1·3-3·8) in the validation cohort. 777 (65·8%) of 1181 patients with sex data in the overall cohort were female; 404 (34·2%) were male. TERT was expressed in 157 (28·7%) of 547 wildtype TERT promoter meningiomas and in 193 (32·0%) of 604 overall with RNA data. TERT expression overall conferred an intermediate progression-free survival, shorter than that in patients with TERT-negative tumours but longer than in those with TERT promoter mutations. In the discovery cohort, median progression-free survival was 3·2 years (95% CI 1·7-6·5) in patients with wildtype TERT promoter tumours expressing TERT, 16·0 years (7·1 to not reached; p=0·0021) in patients with TERT-negative wildtype TERT promoter tumours, and 1·6 years (0·9 to not reached; p=0·039) in patients with TERT promoter mutations. These findings were replicated in the validation cohort. Within each WHO grade, TERT expression conferred a progression-free survival equivalent to TERT-negative meningiomas of one grade higher. Grade 1 tumours with TERT expression had a progression-free survival similar to TERT-negative grade 2 tumours (median not reached [95% CI 16·0 to not reached] vs 8·2 years [95% CI 4·5 to not reached]; p=0·59). Grade 2 tumours with TERT expression had a similar progression-free survival to TERT-negative grade 3 tumours (median 3·6 years [2·4 to 5·3] vs 3·8 years [2·3 to not reached]; p=0·42). Multivariable regression showed that TERT expression remained associated with shorter progression-free survival even after adjusting for TERT promoter mutations, CDKN2A/B loss, chromosome 1p/22q status, and WHO grade (hazard ratio 1·85 [95% CI 1·33-2·57]; p=0·0002).
INTERPRETATION: TERT expression in meningiomas predicted earlier disease progression, independent of TERT promoter mutation and other markers, and might warrant reclassification of meningiomas that express TERT to a higher WHO grade.
FUNDING: Canadian Institutes of Health Research, Brain Tumour Charity UK, University Health Network Foundation, Mary Hunter Meningioma Research Fund, V Foundation, and National Institutes of Health.}, }
@article {pmid40907068, year = {2025}, author = {Beckers, F and Karkada, N and Yang, Y and Scott, J and Huang, L and Klinglmüller, F and Fay, MP and Englert, S and Spiessens, B and Van Dromme, I and Shekar, T and Zhou, H and Deng, Q and Casula, D and Janes, H and Moulton, LH}, title = {Adopting the estimand framework in prophylactic vaccine trials.}, journal = {Vaccine}, volume = {64}, number = {}, pages = {127645}, doi = {10.1016/j.vaccine.2025.127645}, pmid = {40907068}, issn = {1873-2518}, abstract = {The estimand framework as outlined in ICH E9(R1) has been extensively discussed and implemented in clinical trials of therapeutic products. However, there is limited literature on the application of the framework in preventive vaccine trials, which has many unique characteristics, including emphasis on estimating the per-protocol or "biological" effect. We provide a comprehensive review of the application of the framework to preventive vaccine trials evaluating clinical outcome and immunogenicity, focusing on commonly encountered intercurrent events including but not limited to: noncompliance with vaccination schedule and blood sampling window, infection not meeting protocol definition, death, and use of prohibited products. We discuss various considerations in choosing strategies to handle intercurrent events in terms of their utility in addressing the scientific questions. Finally, we provide considerations and examples for summarizing study estimands and data handling which may be incorporated into the protocol and statistical analysis plan.}, }
@article {pmid40906481, year = {2025}, author = {Osazuwa-Peters, N and Gao, MZ and Kahmke, RR and Ramkumar, SP and Bates, NE and Scherrer, JF}, title = {Preexisting Psychiatric Risk Factors and Any and Long-Term Opioid Use in Head and Neck Cancer.}, journal = {JAMA otolaryngology-- head & neck surgery}, volume = {}, number = {}, pages = {}, pmid = {40906481}, issn = {2168-619X}, abstract = {INTRODUCTION: Head and neck cancer (HNC), one of the most emotionally distressing cancers, carries a significant burden of psychiatric comorbidities. While opioids are commonly prescribed in cancer care, the association between preexisting psychiatric risk factors and prescription opioid use in HNC remains unclear.
OBJECTIVE: To test the hypothesis that preexisting psychiatric risk factors are associated with any opioid prescription and long-term opioid therapy in patients with HNC.
This retrospective longitudinal cohort study used deidentified data from the Optum electronic health record database, comprising a random sample of 5 million patients across the US between January 2010 and December 2018. Eligible patients were adults diagnosed with HNC. Using a 2-year look-back prior to the index date of HNC diagnosis, patients who used prescription opioids prior to HNC diagnosis were excluded. The data analysis was conducted between July 2022 and July 2023.
MAIN OUTCOMES AND MEASURES: Outcomes of interest were receipt of any prescription opioid within 12 months of index HNC and long-term opioid therapy (LTOT), defined as 10 or more opioid prescriptions within 12 months of index HNC. Psychiatric risk factors included anxiety disorders, depression, smoking/nicotine dependence, substance use disorders, and benzodiazepine prescription. Multivariate logistic regression estimated the odds of opioid use based on preexisting psychiatric factors.
RESULTS: Of 20 286 patients with an HNC diagnosis, 11 335 met all eligibility criteria. Patients in the analytic cohort had a mean (SD) age of 57.1 (15.5) years, and 55.4% were female. Within 12 months of HNC diagnosis, 23.4% received an opioid prescription, and 4.9% received LTOT. In fully adjusted models, depression (adjusted odds ratio [aOR], 1.21; 95% CI, 1.01-1.45), nicotine dependence (aOR, 1.56; 95% CI, 1.40-1.73), and benzodiazepine comedication (aOR, 1.44; 95% CI, 1.22-1.70) were associated with increased odds of receiving any opioid prescription. Furthermore, male patients had 49% greater odds of receiving opioid prescriptions (aOR, 1.49; 95% CI, 1.36-1.64). Only smoking/nicotine dependence was associated with increased odds of LTOT (aOR, 1.77; 95% CI, 1.21-2.61).
CONCLUSIONS AND RELEVANCE: Preexisting psychiatric comorbidities, especially depression and smoking/nicotine dependence, were associated with increased odds of prescription opioid use and LTOT in patients with HNC in this longitudinal cohort study. Screening for these comorbidities during the management of patients with HNC can be impactful in informing clinical decisions that contribute to safer opioid prescribing.}, }
@article {pmid40906475, year = {2025}, author = {Issaka, RB and Matrajt, L and de Lima, PN and Rutter, CM}, title = {Modeled Cost-Effectiveness of a Rideshare Program to Facilitate Colonoscopy Completion.}, journal = {JAMA network open}, volume = {8}, number = {9}, pages = {e2530515}, pmid = {40906475}, issn = {2574-3805}, mesh = {Humans ; *Colonoscopy/economics/statistics & numerical data ; *Cost-Benefit Analysis ; *Colorectal Neoplasms/diagnosis/economics/prevention & control ; Male ; Female ; Middle Aged ; *Early Detection of Cancer/economics/methods/statistics & numerical data ; Aged ; Occult Blood ; *Mass Screening/economics ; }, abstract = {IMPORTANCE: In colorectal cancer (CRC) screening, too many patients fail to receive follow-up colonoscopy after an abnormal fecal immunochemical test (FIT), and transportation is a frequently reported barrier.
OBJECTIVE: To determine the outcomes and cost-effectiveness of providing a rideshare intervention to patients with abnormal FIT results.
The CRC-Simulated Population Model for Incidence and Natural History microsimulation model was used to simulate the outcomes and cost-effectiveness of a rideshare intervention to improve colonoscopy completion in a population-based CRC screening program. Cohorts were adherent to annual FIT-based screening; baseline analyses assumed that 35% would complete a follow-up colonoscopy. Data were analyzed from November 14, 2023, to July 8, 2025.
INTERVENTION: A $40 or $100 rideshare to increase completion of follow-up colonoscopy.
MAIN OUTCOMES AND MEASURES: Lifetime outcomes included the number of CRC cases, deaths, and life-years gained (LYG) per 1000 people screened and costs associated with improved completion of a colonoscopy after an abnormal FIT result.
RESULTS: Four single-age cohorts (ages 45, 55, 65, and 70 years on January 1, 2024) of 10 million people each were simulated. In cohorts with similar sex distribution as the US population (aged 45 years, 50.0% male; aged 55 years, 49.4% male); aged 65 years, 48.0% male; and aged 70 years, 46.9% male), compared with no intervention, using a rideshare intervention starting at age 45 years that costs $100 per ride to increase colonoscopy completion from 35% to 70% was associated with a reduction in CRC cases per 1000 by 26.3% (30.7 vs 41.6 cases per 1000), CRC deaths per 1000 by 32.5% (9.8 vs 14.6 cases per 1000), 24.9 LYG per 1000, and at $100 per ride cost $43 308 per 1000 people screened and saved $330 587 per 1000 people screened.
CONCLUSIONS AND RELEVANCE: In a microsimulation model, increasing colonoscopy completion in a population with abnormal FIT results via a rideshare intervention was cost saving up to $100 per ride due to the combined outcome of cancer prevention and early detection.}, }
@article {pmid40906320, year = {2025}, author = {Ilozumba, MN and Gomez, MF and Lin, T and Himbert, C and Round, JL and Zac Stephens, W and Warby, CA and Hardikar, S and Li, CI and Figueiredo, JC and Damerell, V and Fillmore, GC and Pickron, B and Toriola, AT and Shibata, D and Holowatyj, AN and Kahlert, C and Sankar, K and Siegel, EM and Jedrzkiewicz, J and Gigic, B and Byrd, DA and Ose, J and Ulrich, CM}, title = {Pre-surgery gut microbial diversity and abundance are associated with post-surgery onset of cachexia in colorectal cancer patients: the ColoCare Study.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40906320}, issn = {1573-7225}, support = {U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; 01KD2101D//the German Ministry of Education and Research project PerMiCCion/ ; 01KD2101D//the German Ministry of Education and Research project PerMiCCion/ ; }, abstract = {BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and it is indicative of poor prognosis and progressive functional impairment. The role of the gut microbiome in the development of cachexia in colorectal cancer (CRC) patients has not been established.
METHODS: Pre-surgical stool samples from n = 103 stage I-III CRC patients in the ColoCare Study were analyzed using 16S rRNA gene sequencing (Illumina) to characterize fecal bacteria. We calculated estimates of alpha- and beta-diversity and a priori- and exploratory-selected bacterial relative abundance. Using Fearon criteria, cachexia onset at 6 months post-surgery was defined as > 5% weight loss over the past 6 months and/or body mass index (BMI) of < 20 kg/m[2] and weight loss of > 2%. Associations of microbial metrics with cachexia onset were estimated using multivariable logistic regression models.
RESULTS: Higher alpha-diversity was positively associated with cachexia onset, with stronger associations in females, patients < 65 years, those receiving adjuvant treatment, consuming high fiber, or with energy intake outside USDA recommendations (p < 0.05). Porphyromonas (OR = 0.51, 95% CI 0.26-0.89, p = 0.03) and Actinomyces (OR = 0.72, 95% CI 0.48-1.03, p = 0.08) were inversely associated with cachexia, although the association for Actinomyces did not reach statistical significance. Stratified analyses revealed a stronger inverse association between Porphyromonas and cachexia onset in males, patients with rectal or stage III tumors, those receiving neoadjuvant treatment, physically inactive individuals, and those consuming low fiber. However, these associations did not reach statistical significance (0.05 ≤ p < 0.10).
CONCLUSION: Higher gut microbial alpha-diversity and lower relative abundances of the genera Porphyromonas and Actinomyces in pre-surgery stool samples were associated with onset of cachexia in CRC patients six months post-surgery. This is the first study to explore a link between the gut microbiome and cachexia in CRC patients, providing novel insights into the biology of cachexia and potential clinical interventions.}, }
@article {pmid39651144, year = {2024}, author = {Swan, DA and Krantz, EM and Byrne, C and Okuku, F and Nankoma, J and Mutyaba, I and Phipps, W and Schiffer, JT}, title = {Human Herpes Virus-8 Oral Shedding Heterogeneity is Due to Varying Rates of Reactivation from Latency and Immune Containment.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39651144}, issn = {2692-8205}, abstract = {Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or positive as well as KS-negative or positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, episodic low viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation, and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection.}, }
@article {pmid40905821, year = {2025}, author = {Lawson-Michod, KA and Johnson, CE and Barnard, ME and Davidson, NR and Collin, LJ and Nix, DA and Huff, CD and Berchuck, A and Salas, LA and Greene, CS and Marks, JR and Peres, LC and Doherty, JA and Schildkraut, JM}, title = {Homologous recombination deficiency and survival in ovarian high-grade serous carcinoma by self-reported race.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0762}, pmid = {40905821}, issn = {1538-7755}, abstract = {BACKGROUND: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well-characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race.
METHODS: HRD features were identified using matched tumor-normal whole-exome and RNA sequencing in a HGSC cohort. We calculated age and stage-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for survival, comparing individuals with a feature to those without, separately by self-reported race.
RESULTS: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR=0.68, 95%CI 0.43-1.09; White HR=0.38, 95%CI 0.14-1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% versus 45%; somatic 62% versus 50%, respectively). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% versus 49.6%; family history 68.4% versus 34.6%).
CONCLUSIONS: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals.
IMPACT: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.}, }
@article {pmid40905566, year = {2025}, author = {Merli, P and Masetti, R and Pigazzi, M and Girardi, K and Miele, E and Bresolin, S and Baccelli, F and Peplinski, JH and Becilli, M and Paganelli, V and Strocchio, L and Buldini, B and Pagliara, D and Meshinchi, S and Locatelli, F}, title = {Sensitivity of Pediatric Myelodysplastic Syndromes With Excess of Blasts With UBTF-TD to Venetoclax/Azacitidine.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70056}, pmid = {40905566}, issn = {1096-8652}, support = {//Fondazione Umberto Veronesi (F.L.)/ ; AIRCIG26039//Fondazione AIRC/ ; }, abstract = {UBTF-TD has been reported in a significant percentage of childhood MDS-EB and has been associated with inferior survival compared to that of patients with the wild-type gene. We treated three consecutive pediatric patients affected by UBTF-TD MDS-EB with venetoclax and azacitidine (ven/aza) in combination as 28-day cycles on a compassionate use basis three consecutive pediatric patients affected by UBTF-TD MDS-EB as a bridge to allogeneic HSCT. Treatment with ven/aza was well-tolerated, and all patients responded to the ven/aza course, achieving CR with flow-cytometry negativity. All three patients were bridged to myeloablative HSCT. All patients are disease-free and graft-versus-host disease-free at last follow-up. Comprehensive biological characterization of the disease showed (i) high expression of the BCL2 gene, paralleled by a low expression of BCL2A1 and MCL1; (ii) overexpression of both HOXA and HOXB; and (iii) a distinct methylation signature of patients with UBTF-TD myeloid neoplasms.}, }
@article {pmid40905099, year = {2025}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Minot, SS and Dean, DR and Rashidi, A}, title = {Dental plaque microbiota following allogeneic hematopoietic cell transplantation and risk of chronic graft-versus-host disease.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288279}, pmid = {40905099}, issn = {1592-8721}, abstract = {Microbiota disruptions have been associated with short-term complications after allogeneic hematopoietic cell transplantation (alloHCT). However, only a few studies have examined the relationship between dysbiosis and chronic graft-versus-host disease (cGVHD), the main long-term immunologic toxicity of alloHCT. Considering the role of oral microbiota in systemic inflammatory diseases, we evaluated whether oral microbiota at day 28 post-HCT corresponding to clinical recovery from the acute events after transplantation is associated with subsequent cGVHD. Shotgun metagenomic sequencing of 207 saliva and supragingival plaque samples collected longitudinally at baseline (pre-conditioning), day +28, and day +84 from 37 patients (11 with subsequent moderate/severe cGVHD) revealed a significant association between day +28 plaque microbiota composition and cGVHD. Two orthogonal statistical approaches demonstrated Streptococcus sanguinis and Prevotella loescheii in day +28 plaque to be associated with cGVHD. Metagenome-based functional analysis identified 4 microbial metabolic pathways associated with future cGVHD, two of which were highly attributed to S. sanguinis. These pathways - ethanolamine utilization and glycerol metabolism - increase bacterial fitness by providing an alternative carbon/nitrogen source and improving survival in inflamed tissues. Our findings propose a novel mechanism by which the early post-transplant dental biofilm may contribute to cGVHD months later, offering a potential target for early prophylactic intervention.}, }
@article {pmid40904946, year = {2025}, author = {Cho, Y and Zheng, C and Qi, L and Prentice, RL and Zhang, MJ}, title = {Causal effect estimation for competing risk data in randomized trial: adjusting covariates to gain efficiency.}, journal = {Journal of applied statistics}, volume = {52}, number = {11}, pages = {2094-2112}, pmid = {40904946}, issn = {0266-4763}, abstract = {The double-blinded randomized trial is considered the gold standard to estimate the average causal effect (ACE). The naive estimator without adjusting any covariate is consistent. However, incorporating the covariates that are strong predictors of the outcome could reduce the issue of unbalanced covariate distribution between the treated and controlled groups and can improve efficiency. Recent work has shown that thanks to randomization, for linear regression, an estimator under risk consistency (e.g. Random Forest) for the regression coefficients could maintain the convergence rate even when a nonparametric model is assumed for the effect of covariates. Also, such an adjusted estimator will always lead to efficiency gain compared to the naive unadjusted estimator. In this paper, we extend this result to the competing risk data setting and show that under similar assumptions, the augmented inverse probability censoring weighting (AIPCW) based adjusted estimator has the same convergence rate and efficiency gain. Extensive simulations were performed to show the efficiency gain in the finite sample setting. To illustrate our proposed method, we apply it to the Women's Health Initiative (WHI) dietary modification trial studying the effect of a low-fat diet on cardiovascular disease (CVD) related mortality among those who have prior CVD.}, }
@article {pmid40903320, year = {2025}, author = {Bakaloudi, DR and Koehne, EL and Voutsinas, JM and Diamantopoulos, LΝ and Makrakis, D and Grivas, P and True, LD and Tretiakova, MS and Vakar-Lopez, F and Psutka, SP and Holt, SK and Gore, JL and Lin, DW and Schade, GR and Nyame, YA and Hsieh, AC and Yezefski, T and Hawley, JE and Schweizer, MT and Cheng, HH and Yu, EY and Montgomery, RB and Wu, QV and Wright, JL}, title = {Agreement between transurethral resection of bladder tumor and radical cystectomy pathology in patients with bladder cancer subtype histology: A retrospective cohort study.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.07.024}, pmid = {40903320}, issn = {1873-2496}, abstract = {INTRODUCTION AND OBJECTIVES: Transurethral Resection of Bladder Tumor (TURBT) is a diagnostic staging procedure for bladder cancer (BC). Its pathologic interpretation may be limited by cautery artifact, lack of spatial orientation of tumor specimens, inter-pathologist variance in identifying subtypes, and sampling bias. Accurately identifying subtype histology (SH) on TURBT is critical for clinical decisions. We compared the agreement between TURBT and radical cystectomy (RC) pathology in patients with SH BC.
METHODS: We examined TURBT and RC pathology of patients who underwent RC at our institution. We included patients with pure SH and mixed histologies in either TURBT or RC specimens. Cohen's kappa coefficient was used to determine the degree of agreement between TURBT and RC.
RESULTS: From 1135 RC performed, 650 (57%) patients had SH in either TURBT or RC; 225 patients were (y)pT0 at the time of RC and 36 patients had rare histologies, leaving 389 patients for analysis. 172 (44%) patients had an exact match between TURBT and RC. We found a high level of agreement between TURBT and RC in pure non-UC histology (kappa range: 0.82-0.98). In contrast, we found substantial (sarcomatoid; kappa 0.70), moderate (squamous, glandular, plasmacytoid, small cell/neuroendocrine; kappa range: 0.42-0.55) and fair (micropapillary; kappa 0.38) concordance between TURBT and RC in patients with UC mixed with SH.
CONCLUSIONS: We found variable levels of agreement of SH detection between TURBT and RC. Agreement was high in pure non-UC histology. Further, we found that NAT, completeness of TURBT, and >50% SH at TURBT are associated with the persistence of SH at RC. Future efforts are needed to develop reproducible diagnostic tools for accurate characterization of SH in UC.}, }
@article {pmid40902330, year = {2025}, author = {Colbert, CM and Kruse, E and Jacqmin, D and Pichardo, JC and Wang, C and Schubert, LK and Bennett, S and Lin, MH and Olsen, L and Li, B and Kim, M}, title = {Virtual radiotherapy plan quality education: Perspectives from a global setting.}, journal = {Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)}, volume = {137}, number = {}, pages = {105069}, doi = {10.1016/j.ejmp.2025.105069}, pmid = {40902330}, issn = {1724-191X}, abstract = {PURPOSE: Evaluation of treatment plan quality is a critical element of training for radiotherapy professionals. With the increased adoption of intensity modulated radiotherapy internationally, this training is crucial to address patient care inequity. We aim to evaluate learning outcomes from a 14-session remote training course targeting critical elements of plan quality with advanced modalities.
METHODS: The virtual training course was delivered to over 500 radiotherapy professionals in North Africa. Attendees completed online pre- and post-course knowledge assessments, and surveys of their confidence in core competencies. Paired t-tests, general linear regression, and ANOVA were used to evaluate learning outcomes.
RESULTS: On the pre-course knowledge assessment, attendees scored a mean of 3.97 ± 1.54 out of 10. After the course, remaining attendees' scores increased to a mean of 4.88 ± 1.86 (p < 0.001). Mean confidence scores increased from 2.28 ± 1.22 to 3.70 ± 0.76 out of 5. Confidence scores varied significantly with enrollees' years of experience, clinical role, and involvement in treatment planning (p < 0.05). However, pre-course knowledge scores only varied based on clinicians' current involvement in advanced treatment planning (p < 0.01). The improvement in knowledge score from baseline increased significantly with course attendance (p = 0.02).
CONCLUSIONS: This course produced positive overall learning outcomes, particularly with advanced treatment planning modalities. Attendees gained practical experience applying rigorous plan quality criteria. The study results support the crucial importance of continuing education and hands-on experience in the rapidly advancing technological environment of radiation oncology.}, }
@article {pmid40899409, year = {2025}, author = {Johnson, T and Spieler, BO and Toskich, BB and Wang, DS and Folkert, MR and Russo, S and Sharma, NK and Kim, CY and Wright, CL and Kappadath, SC and Farsad, K and Muzahir, S and Chundury, A and Parent, EE and Sio, TT and Mercier, GA and Ghesani, MV and Subramaniam, RM and Caplin, D and Small, W and Schechter, NR}, title = {ACR-ABS-ACNM-ARS-SIR-SNMMI Practice Parameter for Radioembolization of Liver Malignancies.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000001234}, pmid = {40899409}, issn = {1537-453X}, abstract = {OBJECTIVES: The practice parameter was revised collaboratively by the American College of Radiology (ACR), the American Brachytherapy Society (ABS), the American College of Nuclear Medicine (ACNM), the American Radium Society (ARS), the Society of Interventional Radiology (SIR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This document summarizes current evidence-based guidelines for the administration of Yttrium radioembolic therapy to the liver, including training requirements, evidence-based guidelines for administration, and safe practice for administration.
METHODS: This practice parameter was revised according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards-Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ABS, the ACNM, the ARS, the SIR, and the SNMMI.
RESULTS: This review seeks not to be a comprehensive discussion of radiotherapy to the liver, but rather, seeks to provide a parameter for safe and effective therapy. We discuss the qualifications of physicians involved in this therapy, basic indications, contraindications, procedural work-up, safe-handling, and regulatory requirement for the administration of selective internal radiation therapy to patients that are likely to benefit. The goal of this document is not to define which patients are best treated by these therapies, as this is best determined for individual patients after multidisciplinary review. A consistent and evidence-based approach to therapy, however, would benefit all patients who are offered this therapy. This document seeks to provide a framework for current best practices for the administration of the 2 currently available radioembolization devices.
CONCLUSIONS: As Yttrium-90 radiotherapy to the liver occupies a growing role in the treatment of primary and metastatic liver cancer, this review seeks to assist clinicians of all involved specialties to optimize the efficacy and safety of these procedures.}, }
@article {pmid40895774, year = {2025}, author = {Malik, NH and Plastaras, JP and Corradini, S and Dawson, LA and Hawkins, MA and Salerno, KE and Mayo, CS and Dunne, EM and Gabryś, D and Grassberger, C and Lawrence, TS and Sharma, M and Bergman, AM and Owen, D and Zaila, A and Rudra, S and Velec, M and Murrell, DH}, title = {Reirradiation clinical practice in gastrointestinal abdominal malignancies: an international reirradiation collaborative group (ReCOG) systematic review.}, journal = {Clinical and translational radiation oncology}, volume = {55}, number = {}, pages = {101033}, pmid = {40895774}, issn = {2405-6308}, abstract = {PURPOSE: Reirradiation in abdominal malignancies has grown more common with advanced radiotherapy techniques. However, clinical use and implementation varies, and there remains limited consensus on best practices for reirradiation. In this systematic review, a multidisciplinary team treating gastrointestinal and hepatobiliary malignancies within the Reirradiation Collaborative Group (ReCOG) convened to review published literature on reirradiation in the abdomen to offer insights into patient selection, radiotherapy planning, risk management, and assessing knowledge gaps for future development of guidelines.
METHODS AND MATERIALS: A systematic search of Cochrane Central, CINAHL Plus, EMBASE, and PubMed up to August 30, 2024, was conducted as per Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) framework. Data on patient characteristics, radiation doses, dose constraints, treatment outcomes, and toxicities were extracted. Where feasible, pooled weighted analyses were performed.
RESULTS: Thirty-three studies involving 1,264 patients met inclusion criteria: 30 were retrospective and 3 prospective. The median number of patients reported per study was 26 (range 2-245). Of the reported tumor sites, 718 patients had liver tumors and 277 pancreas, with smaller numbers of mixed/lymph node targets. Reirradiation doses, fractionation schemes, and dose constraints varied widely; only half of the studies provided explicit organ-at-risk constraints. Three studies included patients treated with palliative intent. Median overall survival ranged from 5.9 to 44 months, with a pooled weighted median OS of 19.6 months across 20 studies that reported it. One-year local control rates ranged from 19 % to 93 %, with severe (grade ≥ 3) toxicities typically reported in 5-15 % of patients, although one study reported 25 % lethal RILD in liver reirradiation.
CONCLUSION: Reirradiation in abdominal malignancies appears to be able to achieve meaningful local control and survival in select patients, though heterogeneity in planning, dosing, and toxicity reporting remains a major challenge for establishing best practices. Standardized reporting of doses, constraints, and dose-volume relationships are needed to guide safe and effective reirradiation in this setting.}, }
@article {pmid40894770, year = {2025}, author = {Dadonaite, B and Harari, S and Larsen, BB and Kampman, L and Harteloo, A and Elias-Warren, A and Chu, HY and Bloom, JD}, title = {Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40894770}, issn = {2692-8205}, abstract = {SARS-CoV-2 is under strong evolutionary selection to acquire mutations in its spike protein that reduce neutralization by human polyclonal antibodies. Here we use pseudovirus-based deep mutational scanning to measure how mutations to the spike from the recent KP.3.1.1 SARS-CoV-2 strain affect cell entry, binding to ACE2 receptor, RBD up/down motion, and neutralization by human sera and clinically relevant antibodies. The spike mutations that most affect serum antibody neutralization sometimes differ between sera collected before versus after recent vaccination or infection, indicating these exposures shift the neutralization immunodominance hierarchy. The sites where mutations cause the greatest reduction in neutralization by post-vaccination or infection sera include receptor-binding domain (RBD) sites 475, 478 and 487, all of which have mutated in recent SARS-CoV-2 variants. Multiple mutations outside the RBD affect sera neutralization as strongly as any RBD mutations by modulating RBD up/down movement. Some sites that affect RBD up/down movement have mutated in recent SARS-CoV-2 variants. Finally, we measure how spike mutations affect neutralization by three clinically relevant SARS-CoV-2 antibodies: VYD222, BD55-1205, and SA55. Overall, these results illuminate the current constraints and pressures shaping SARS-CoV-2 evolution, and can help with efforts to forecast possible future antigenic changes that may impact vaccines or clinical antibodies.}, }
@article {pmid40892926, year = {2025}, author = {Willcox, AC and Gobillot, TA and Kikawa, C and Baumgarten, NE and Stoddard, CI and Sung, K and Bhattacharya, T and Freeman, TS and Marceau, J and Humes, D and Overbaugh, J}, title = {Identification of AMOTL2 as an antiviral factor that enhances the human type I interferon response against Zika virus.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {36}, pages = {e2507955122}, doi = {10.1073/pnas.2507955122}, pmid = {40892926}, issn = {1091-6490}, support = {T32 AI083203/AI/NIAID NIH HHS/United States ; F30 AI181359/AI/NIAID NIH HHS/United States ; F30 AI142870/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Zika Virus/immunology/physiology ; *Interferon Type I/metabolism/immunology ; *Zika Virus Infection/immunology/virology/genetics ; Virus Replication ; Signal Transduction ; Angiomotins ; STAT1 Transcription Factor/metabolism/genetics ; HEK293 Cells ; Animals ; Immunity, Innate ; Antigens, Differentiation ; }, abstract = {Zika virus (ZIKV) has caused multiple human outbreaks, with more recent epidemics associated with severe outcomes in infants. Today, ZIKV is endemic to many countries and presents a persistent threat for future epidemics. The host innate immune proteins that regulate ZIKV replication are incompletely defined. We developed a CRISPR knockout screen to identify host factors that impact ZIKV replication, resulting in the finding of angiomotin-like protein 2 (AMOTL2), a protein that inhibits ZIKV by regulating the host type I interferon (IFN) response. AMOTL2 affects IFN signaling by modulating STAT1 levels and activation in response to type I IFN. Thus, AMOTL2, which has largely been studied for its role in cancer, represents an antiviral protein that interacts with the IFN signaling pathway to promote downstream expression of IFN stimulated genes, resulting in restriction of ZIKV.}, }
@article {pmid40892436, year = {2025}, author = {Nguyen, E and Korolkova, A and Ahmed, A and Meanley, S and Dee, L and Hussain, M and Wan, F and Hoh, R and Rodriguez, A and Figueroa, T and Cohn, LB and Deeks, SG and Peluso, MJ and Eskaf, S and Sugarman, J and Sauceda, JA and Dubé, K}, title = {Participant Perspectives in an HIV Treatment Interruption Study in San Francisco, United States.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1177/08892229251375470}, pmid = {40892436}, issn = {1931-8405}, support = {R01 MH126768/MH/NIMH NIH HHS/United States ; }, abstract = {HIV cure-related clinical research studies often include analytical treatment interruptions (ATIs), in which participants pause antiretroviral treatment (ART). During ATIs, researchers closely monitor laboratory values and adverse events. We assessed and compared the perspectives of two distinct groups of participants: HIV noncontrollers and controllers in a San Francisco-based ATI study focused on identifying biomarkers predicting HIV viral rebound. Data were collected from 2021 to 2024 over five study time points to assess motivations, understanding of the study, decisional regret, and partner protections. All participants (n = 16) endorsed the goal of helping advance HIV research as a motivator, about half were also driven by interest in their body's response to the ATI, and some indicated monetary compensation as a key motivator. Most participants (6 of 10 noncontrollers and 4 of 6 controllers) did not view personal health benefit as a primary study goal. All understood the option for an extended ATI if they had not met ART restart criteria after 28 days. At the study's onset, all sexually active participants (n = 14) were informed about the risk of transmission to sex partners and the need for partner protections during ATIs. Among noncontrollers, 2 of 5 reported using condoms, being abstinent or partner use of pre-exposure prophylaxis (PrEP) during sexual activity. Among controllers, 3 of 5 reported sexual activity: one with a partner on PrEP, one with a partner on ART, and one using other protection methods. Decisional regret about study participation, measured on a scale of 0-100, was low among both noncontrollers (range 1.67-13.57), and controllers (range 8.33-10) during the ATI, and remained low following it (noncontroller M = 5.07, SD = 4.52; controller M = 10.00, SD = 11.31). Participants generally understood the study, highlighted the need for partner protection support during ATI, and reported low decisional regret.}, }
@article {pmid40891586, year = {2025}, author = {Velloza, J and Ortblad, KF and Kemp, CG}, title = {"Measuring the gap": advances and practical considerations in assessment of adoption, penetration, and sustainment of HIV prevention services.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000979}, pmid = {40891586}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: Prior reviews have documented lack of consistency around implementation outcome measurement and gaps in assessing adoption, penetration or reach, and sustainment in HIV research. Our review sought to summarize approaches to measuring adoption, penetration, and sustainment in the HIV research literature, with a focus on the preexposure prophylaxis (PrEP) field which is ripe for exploration as long-acting PrEP formulations become available and oral PrEP programs become increasingly sustained.
RECENT FINDINGS: Our literature search of adoption, penetration, and sustainment measurement in HIV research identified 250 manuscripts. We developed a conceptual heuristic of latent and manifest measures for HIV implementation research. Few PrEP studies measured adoption according to our heuristic and latent adoption measurements were often conflated with acceptability, while manifest measurements were conflated with penetration. Most PrEP studies measuring penetration focused on the client level, with fewer measuring penetration among organizations or providers. Sustainment measurement across studies was diverse and included mixed methods assessment at organization, provider, and client levels.
SUMMARY: Heterogeneity persists in operationalizing adoption, penetration, and sustainment. Future work is needed to develop and validate pragmatic and robust measures of these constructs that can be used in evolving HIV implementation contexts.}, }
@article {pmid40890722, year = {2025}, author = {Henderson, V and Carnahan, L and Cohn, EB and Waite, AW and Mersha, T and Block, R and Kolpack, M and Sommers, J and Salum, K and Hoskins, KF and Nguyen, R}, title = {"The more I know, the more you know" Using culturally responsive marketing strategies to develop tools that increase awareness about clinical trials among Black communities.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {3003}, pmid = {40890722}, issn = {1471-2458}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Black or African American/psychology/statistics & numerical data ; *Clinical Trials as Topic ; *Cultural Competency ; Focus Groups ; *Marketing/methods ; Neoplasms/ethnology/therapy ; }, abstract = {BACKGROUND: Ineffective dissemination of cancer research and information among the public contributes to cancer inequities. Dissemination rarely involves efforts to engage non-research audiences and end-users in developing effective messaging. Efforts to promote equity in clinical trial participation may benefit from marketing strategies traditionally applied in the business sector. Black Americans suffer the highest death rates from most cancers than any other race/ethnicity, yet only 5% of patients enrolled in cancer clinical trials are Black. Our team used a marketing strategy framework to create a culturally responsive public service announcement (PSA) video to increase awareness of clinical trials among Black audiences.
METHODS: We partnered with a marketing recruitment firm and a marketing agency to conduct six focus groups (n = 54) with social support networks of Black cancer survivors and Black community members. Maximum variation sampling was used to recruit a national sample of eligible participants that varied in age, education, geographic region, and gender. Focus groups were conducted over three phases that informed script development, script and storyline testing, and sought feedback on the PSA video post-production. We used the Marketing and Clinical Trials Reference Model to guide marketing strategies, data collection, video content development and production. We used rapid qualitative data analysis techniques to identify themes for each phase to guide PSA development.
RESULTS: Partnered with a film production company, we produced a 2-min PSA video that uses professional actors and storytelling and marketing techniques to describe clinical trials, provide relevant statistics, address barriers to participation expressed by participants, and provide credible resources to seek further information. We also produced 30 s and 60 s versions of the PSA to accommodate different marketing media outlets. Participants felt the videos were engaging and relatable and that the messaging was clear. The videos ignited meaningful discussions about clinical trial participation and motivated participants to share the information learned.
CONCLUSIONS: Using marketing communication strategies is a low-tech, pragmatic approach to effectively produce health information that is meaningful, can be tailored for specific audiences, and disseminated to broader audiences.}, }
@article {pmid40887511, year = {2025}, author = {Cimino, PJ and Keiser, DJ and Parrish, AG and Holland, EC and Szulzewsky, F}, title = {C-terminal fusion partner activity contributes to the oncogenic functions of YAP1::TFE3.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {32013}, pmid = {40887511}, issn = {2045-2322}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; R35 CA253119-01A1//National Institutes of Health,United States/ ; U54 CA243125/NH/NIH HHS/United States ; U54 CA243125/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; Start-up funds//University of Utah Department of Neurosurgery and Huntsman Cancer Institute/ ; }, mesh = {*Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism/chemistry ; YAP-Signaling Proteins ; Humans ; Animals ; Mice ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; *Oncogene Proteins, Fusion/genetics/metabolism ; Cell Line, Tumor ; Carcinogenesis/genetics ; Protein Domains ; *Phosphoproteins/genetics/metabolism ; }, abstract = {YAP1 gene fusions are found in a multitude of human tumors and are the likely tumor-initiating events in these tumors. We have previously shown that YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we expressed eight different YAP1 gene fusions in vivo. Tumors induced by YAP1::TFE3 displayed a significantly different histomorphology compared to tumors induced by other YAP1 fusions or activated non-fusion YAP1. To assess the extent to which TFE3 activity and the functional TFE3 domains (DNA binding: leucine zipper (LZ) and basic-helix-loop-helix (bHLH); activation domain (AD)) contribute to the oncogenic functions of YAP1::TFE3, we generated several mutant variants and performed functional in vitro and in vivo assays. In vitro, mutation or deletion of the TFE3 DNA binding domains (LZ, bHLH) resulted in reduced TFE3 activity but increased YAP1 activity of YAP1::TFE3. In vivo, deletion of the LZ and bHLH domains did not result in a decrease in tumor incidence but induced the formation of more YAP1-like tumors that lacked prominent features of YAP1::TFE3-driven tumors. By contrast, loss of the TFE3 AD almost completely abrogated tumor formation. Our results suggest that the TFE3 domains significantly contribute to the oncogenic activity of YAP1::TFE3.}, }
@article {pmid40889272, year = {2025}, author = {Kazemian, E and Mo, Q and Matejcic, M and Tsai, YY and Sobieski, D and Li, X and Hoogland, AI and Crowder, SL and Gonzalez, BD and Oswald, LB and Sleight, AG and Nguyen, N and Loroña, NC and Damerell, V and Komrokji, KR and Mooney, K and Playdon, MC and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Ose, J and Peoples, AR and Hardikar, S and Kahlert, C and Siegel, EM and Bower, JE and Schmit, SL and Gigic, B and Jim, HSL and Figueiredo, JC}, title = {Genetic predisposition to persistent fatigue after a diagnosis of colorectal cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf140}, pmid = {40889272}, issn = {1460-2105}, abstract = {BACKGROUND: Cancer-related fatigue (fatigue) is a common and persistent symptom after cancer treatment, yet the role of genetic susceptibility remains unclear.
METHODS: We leveraged data from a prospective cohort study, ColoCare Study (ie, five U.S. sites and Germany). Fatigue was assessed at five timepoints using the EORTC QLQ-C30 fatigue subscale and analyzed as (1) a binary summary measure of the trajectory from diagnosis into survivorship (defined as severe: yes, no), (2) a mean score across all time points, and (3) the highest (ie, worst) score across all time points. We genotyped samples using Infinium Global Diversity Array with imputation using the TOPMed reference panel to conduct a genome-wide analysis (GWAS). SuSiE was used to identify independent secondary signals. Transcriptome-wide association studies (TWAS) using S-PrediXcan and MultiXcan were conducted to examine genetic regulation of gene expression. COLOC assessed whether variants identified in the GWAS influence gene expression through colocalization analysis.
RESULTS: Among 1,219 participants, 31.0% experienced severe fatigue over the course of their diagnosis. A locus near LINC02505 on chromosome 4 was associated with severe fatigue (rs6531463, OR = 3.25, p = 3.88 × 10-8). When modeling mean fatigue levels, significantly associated variants were identified in or near NEK10 and SLC4A7. Integrative analyses linked the predicted expression of NEK10 in liver tissue to risk of fatigue (p < 4.36 × 10-6). Colocalization analysis identified genetic loci and gene expression near NEK10 (posterior probabilities > 0.9).
CONCLUSIONS: This study identified novel genetic loci associated with fatigue in CRC patients and may be useful for identifying high-risk individuals for preventative strategies.}, }
@article {pmid40888442, year = {2025}, author = {Grivas, P and Tagawa, ST and Jain, RK and Bupathi, M and Balar, A and Rezazadeh Kalebasty, A and George, S and Palmbos, P and Nordquist, L and Petrylak, DP and Davis, N and Sternberg, CN and Agarwal, N and Park, C and Tonelli, J and Zhou, H and Bangs, R and Loriot, Y}, title = {A plain language summary of the TROPHY-U-01 study (Cohort 2): use of sacituzumab govitecan after immunotherapy in people with metastatic urothelial cancer who cannot take cisplatin-based chemotherapy.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/14796694.2025.2548757}, pmid = {40888442}, issn = {1744-8301}, }
@article {pmid40886051, year = {2025}, author = {Li, R and Gagliano Taliun, SA and Liao, K and Flickinger, M and Sobell, JL and Genovese, G and Locke, AE and Chiu, RR and LeFaive, J and Wang, J and Martins, T and Chapman, S and Neumann, A and Handsaker, RE and Arnett, DK and Barnes, KC and Boerwinkle, E and Braff, D and Cade, BE and Fornage, M and Gibbs, RA and Hoth, KF and Hou, L and Kooperberg, C and Loos, RJF and Metcalf, GA and Montgomery, CG and Morrison, AC and Qin, ZS and Redline, S and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Viaud-Martinez, KA and , and , and Bigdeli, TB and Gabriel, S and Zollner, S and Smith, AV and Abecasis, G and McCarroll, S and Pato, MT and Pato, CN and Boehnke, M and Knowles, J and Kang, HM and Ophoff, RA and Ernst, J and Scott, LJ}, title = {Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100499}, doi = {10.1016/j.xhgg.2025.100499}, pmid = {40886051}, issn = {2666-2477}, abstract = {In studies of individuals of primarily European genetic ancestry, common and low- frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls (∼37X). To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.}, }
@article {pmid40885199, year = {2025}, author = {Necchi, A and Guerrero-Ramos, F and Crispen, PL and Herrera-Imbroda, B and Garje, R and Powles, T and Peyton, CC and Pradere, B and Ku, JH and Shore, N and Bögemann, M and Preston, MA and Xylinas, E and Sanchez de Llano, C and Hasan, M and Stitou, H and Bhanvadia, S and Sweiti, H and Psutka, SP}, title = {TAR-200 plus cetrelimab versus cetrelimab monotherapy as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or decline neoadjuvant cisplatin-based chemotherapy (SunRISe-4): interim analysis of a randomised, open-label phase 2 trial.}, journal = {The Lancet. Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1470-2045(25)00358-4}, pmid = {40885199}, issn = {1474-5488}, abstract = {BACKGROUND: Effective treatments are needed for patients with muscle-invasive bladder cancer scheduled for radical cystectomy who are ineligible for or decline to receive neoadjuvant cisplatin-based chemotherapy. We aimed to evaluate neoadjuvant TAR-200 plus cetrelimab (anti-PD-1) versus cetrelimab monotherapy in this setting.
METHODS: SunRISe-4 is a randomised, open-label, phase 2 trial being conducted at 109 investigative centres in ten countries worldwide. Eligible patients were aged 18 years or older, were newly diagnosed with histologically confirmed muscle-invasive bladder cancer (stage cT2-cT4 N0M0), had an Eastern Cooperative Oncology Group performance status of 0-1, were scheduled to undergo radical cystectomy, and were deemed ineligible for or declined platinum-based neoadjuvant chemotherapy. Patients were randomly assigned (5:3) in blocks of eight using an interactive web response system to receive four cycles of intravesical TAR-200 (225 mg gemcitabine) plus intravenous cetrelimab (360 mg) every 21 days or four cycles of intravenous cetrelimab (360 mg) monotherapy every 21 days. Randomisation was stratified by results of transurethral resection of bladder tumour (visibly complete vs incomplete and ≤3 cm) and tumour stage (cT2 vs cT3-4a at initial diagnosis). The primary endpoint was centrally confirmed pathological complete response in the efficacy-evaluable set. As this was a prespecified interim analysis and all patients had not completed treatment, efficacy-evaluable set was defined as all patients who had radical cystectomy or progressive disease or death before radical cystectomy. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04919512, and is ongoing.
FINDINGS: From July 7, 2022, to May 31, 2024, 196 patients were assessed for eligibility and 122 were randomly assigned (TAR-200 plus cetrelimab n=80, cetrelimab monotherapy n=42). 120 patients received at least one dose of study drug. Mean age was 70·7 years (SD 7·9); 102 (85%) participants were male, 18 (15%) were female, 81 (68%) were White, 28 (23%) were Asian, and 11 (9%) were other races. In the efficacy-evaluable set (TAR-200 plus cetrelimab n=53, cetrelimab monotherapy n=31), at a median follow up of 23·5 weeks (IQR 8·6-42·0), pathological complete response rates were 42% (22 of 53 patients; 95% CI 28-56) in the TAR-200 plus cetrelimab cohort and 23% (seven of 31 patients; 10-41) in the cetrelimab monotherapy cohort. In the safety set, at a median follow-up of 10·2 weeks (IQR 1·1-36·9), treatment-related adverse events occurred in 57 (72%) of 79 patients in the TAR-200 plus cetrelimab cohort and in 18 (44%) of 41 patients in the cetrelimab monotherapy cohort. Grade 3 or worse treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and two (5%) in the cetrelimab monotherapy cohort, the most common being haematuria (two [3%] in the TAR-200 plus cetrelimab cohort). Serious treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and one (2%) patient in the cetrelimab monotherapy cohort. In the TAR-200 plus cetrelimab cohort, seven (9%) patients had treatment-related adverse events leading to discontinuation of TAR-200 and six (8%) had treatment-related adverse events leading to discontinuation of cetrelimab; there were no treatment related deaths. In the cetrelimab monotherapy cohort, no patients discontinued due to treatment-related adverse events; there was one death from a treatment-related adverse event due to hyperglycaemic, hyperosmolar, non-ketotic syndrome.
INTERPRETATION: Neoadjuvant TAR-200 plus cetrelimab showed a high pathological complete response rate with a manageable safety profile. These results support continued investigation of TAR-200 in patients with muscle-invasive bladder cancer planned for radical cystectomy.
FUNDING: Johnson & Johnson.}, }
@article {pmid40885198, year = {2025}, author = {von Lilienfeld-Toal, M and Khawaja, F and Compagno, F and Robin, C and Piñana, JL and Cesaro, S and Einsele, H and Ljungman, P and Navarro, D and Boeckh, M and Chemaly, RF and Hirsch, HH}, title = {Community-acquired respiratory virus infections in patients with haematological malignancies or undergoing haematopoietic cell transplantation: updated recommendations from the 10th European Conference on Infections in Leukaemia.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00365-2}, pmid = {40885198}, issn = {1474-4457}, abstract = {To update recommendations of the 4th European Conference on Infections in Leukaemia (ECIL-4) on community-acquired respiratory virus (CARV) infections published in 2013, we reviewed publications from between Jan 1, 2014, and June 30, 2024 on adenovirus, bocavirus, coronavirus, influenzavirus, metapneumovirus, parainfluenzavirus, respiratory syncytial virus (RSV), and rhinovirus in patients with haematological malignancies or undergoing haematopoietic cell transplantation (HCT), or both. In the current ECIL recommendations (ECIL-10), we outline a common approach to infection control, laboratory testing, and diagnosis for all CARVs (including SARS-CoV-2) and specific management and deferral strategies for CARVs other than SARS-CoV-2. For influenzavirus, seasonal inactivated-vaccines and early antivirals are recommended, whereas routine antiviral prophylaxis is discouraged for immunocompromised patients. For RSV, licensed vaccines can be considered according to local approval, despite scarce evidence for patients with haematological malignancies and those undergoing HCT. Passive immunisation with palivizumab or nirsevimab is recommended for children younger than 2 years, but data are insufficient for pre-exposure or post-exposure prophylaxis, or treatment of older children and adults. Oral ribavirin or intravenous immunoglobulins, or a combination of the two, are recommended for patients undergoing HCT with severe immunodeficiency scores. For other CARVs, recommendations include only supportive care, improving immune functions, correcting hypogammaglobulinaemia, and judicious lowering of corticosteroids. We highlight unmet needs in immunisation and antivirals for reducing CARV-associated morbidity and mortality in patients with haematological malignancies and those undergoing HCT.}, }
@article {pmid40884510, year = {2025}, author = {Bhole, S and Grimm, LJ and Parikh, JR and Dontchos, BN and Reig, B and Jacobs, SA and Coffey, K and Dashevsky, BZ and Mullen, LA and Daly, C and Dodelzon, K}, title = {Breast Imaging Staffing Shortages: Defining the Problem and Addressing Root Causes.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbaf031}, pmid = {40884510}, issn = {2631-6129}, abstract = {OBJECTIVE: To assess the current perceptions of breast imaging staffing shortages and contributing factors among breast imaging radiologists.
METHODS: A survey assessing current perception of breast radiologists regarding breast imaging-specific staffing shortages and contributing factors was developed by the Patient Care and Delivery Committee of the Society of Breast Imaging (SBI) and emailed to SBI active physician members. Bivariable analysis (chi-squared, t test) was performed between the survey demographics and survey response questions of interest.
RESULTS: There were 309 responses (response rate of 15.7%). Most respondents perceived their practices to be short-staffed for breast radiologists (79%, 239/302), US technologists (74%, 216/290), mammography technologists (70%, 211/301), and support staff (66%, 201/302). Of the respondents who indicated they were short-staffed for breast imaging radiologists, 92% (226/246) believed it was due to insufficient number of radiologists, 67% (164/246) thought it was due to increase in volume, and 63% (154/246) attributed it to both increase in volume and insufficient number of breast imaging radiologists. Practices were more likely to be short-staffed if they had more practice sites (mean, 8.2 ± 7.1 vs 6.4 ± 8.4; P = .002), had fewer breast imaging radiologists (mean, 10.1 ± 9.6 vs 11.3 ± 11.5; P = .009), and were academic practices (35.1% vs 25.7%; P = .028).
CONCLUSIONS: Most breast imaging radiologists perceive their current breast imaging practices to be short-staffed for radiologists, mammography technologists, US technologists, and support staff. Understanding contributing factors is crucial to addressing root causes and mitigating impact on patient care and burnout across breast imaging team members.}, }
@article {pmid40884418, year = {2025}, author = {Yu, N and Panch, S and Mepani, K and Stanworth, S and Bonet-Bub, C and Gragert, L and Menard, V and Mangiola, M and Maiers, M and Berka, N}, title = {"Epitope-based matching for platelet transfusion overview: Is it time?"-Insights and future directions from the 2024 American Red Cross symposium on platelet component selection.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18392}, pmid = {40884418}, issn = {1537-2995}, }
@article {pmid40883483, year = {2025}, author = {Urgessa, F and Jenkins, I and Tsegaye, A and Nigussie, H and Kuru, T and Gebremedhin, A and Abdela, F and Tadesse, F and Radich, J}, title = {MicroRNAs as prognostic and predictive biomarkers among chronic myeloid leukemia patients in Addis Ababa, Ethiopia.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31844}, pmid = {40883483}, issn = {2045-2322}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/drug therapy/diagnosis/blood ; *MicroRNAs/genetics/blood ; Male ; Female ; Ethiopia ; *Biomarkers, Tumor/genetics/blood ; Adult ; Middle Aged ; Prognosis ; Imatinib Mesylate/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Young Adult ; Aged ; Gene Expression Regulation, Leukemic ; Adolescent ; }, abstract = {Approximately 1.5 million people worldwide suffer from chronic myeloid leukemia (CML). MicroRNAs (miRs) are important regulators of gene expression and offer an attractive option as biomarkers for cancer detection, diagnosis, and prognosis assessment in solid and liquid tumors. To assess miRs as prognostic and predictive biomarkers among CML patients at the Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia from April 2021 to May 2023. Blood samples were collected from newly diagnosed CML patients before initiation of tyrosine kinase inhibitor (TKI), imatinib treatment, and while on therapy. The expression level of miRs were determined using the NanoString platform. LIMMA analysis was used to identify differentially expressed miR between TKI response groups and disease phases. Fifty-two study participants were enrolled in the study. From each sample, 798 hsa-miRs included on the Nanostring assay were measured. Comparing TKI naive new CML patients (n = 14) with those progressed or had blast crisis (BC) on TKI therapy (n = 12), 97 miRs were differentially expressed (|log2FC|, FDR, and P-value at > 1, < 0.001, and < 0.0001, respectively). Most miRs showed upregulation in BC CML patients compared to new CML cases except miR-223-3p, miR-4454, miR-7975, and miR-630 which were downregulated in patients with BC. In addition, eight miRs were differentially expressed comparing poor molecular responder (n = 12) with good molecular responder (n = 28) patients (P < 0.05). MiR-223-3p, miR-4454, miR-7975, and miR-630 were commonly deregulated in BC and poor molecular response groups. MiRs have significant potential as prognostic and predictive biomarkers for CML patients. MiR-223-3p, miR-4454, miR-7975 and miR-630 could be considered as prognostic and predictive biomarkers for disease progression and treatment response if validated by other large studies.}, }
@article {pmid40879331, year = {2025}, author = {Sung, K and Johnson, MM and Dumm, W and Simon, N and Haddox, H and Fukuyama, J and Matsen, FA}, title = {Thrifty wide-context models of B cell receptor somatic hypermutation.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40879331}, issn = {2050-084X}, support = {2919.02//Gordon and Betty Moore Foundation/ ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; PHY-2309135//National Science Foundation/ ; R01-AI146028/NH/NIH HHS/United States ; }, mesh = {*Somatic Hypermutation, Immunoglobulin ; *Receptors, Antigen, B-Cell/genetics ; Humans ; }, abstract = {Somatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, understanding the selective forces guiding affinity maturation, and understanding the underlying biochemical process. High-throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this article, we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM; however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop 'thrifty' models of SHM of various sizes; these can have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model, and other modern model elaborations worsen performance. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model-on out-of-frame sequence data and on synonymous mutations-produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.}, }
@article {pmid40880210, year = {2025}, author = {Dahlberg, A and Milano, F}, title = {Targeted GVL through HLA mismatch in double cord blood transplant.}, journal = {Blood advances}, volume = {9}, number = {17}, pages = {4470-4471}, doi = {10.1182/bloodadvances.2025016876}, pmid = {40880210}, issn = {2473-9537}, }
@article {pmid40832168, year = {2025}, author = {Mout, L and Moreno-Rodriguez, T and Grillo, G and Nand, A and Keshavarzian, T and Bahl, S and Kang, K and Bootsma, M and Minnee, E and Zhou, S and Burns, KH and Corey, E and Nelson, P and Dehm, SM and Zhao, SG and Zwart, W and Feng, F and Quigley, D and Lupien, M}, title = {Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832168}, issn = {2692-8205}, support = {P50 CA275741/CA/NCI NIH HHS/United States ; R01 CA174777/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA276112/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; UG3 NS132127/NS/NINDS NIH HHS/United States ; R01 CA289390/CA/NCI NIH HHS/United States ; R01 CA240816/CA/NCI NIH HHS/United States ; }, abstract = {Extrachromosomal DNAs (ecDNAs), which replicate and segregate in a non-Mendelian manner, serve as vectors for accelerated tumor evolution. By integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from a cohort of metastatic Castration-Resistant Prostate Cancer (mCRPC) cases, we show that epigenetically activated repeat DNA, amplified in ecDNAs, drive oncogene overexpression. Specifically, we identify a subgroup of mCRPCs (20%) characterized by clusters of accessible LINE1 repeat DNA elements flanking the androgen receptor (AR) gene. These LINE1 elements are co-amplified with AR and provide binding sites for prostate-lineage transcription factors, including AR, FOXA1 and HOXB13. Accessible LINE1 elements establish novel 3D chromatin interactions with the AR gene, forging a new regulatory plexus driving AR overexpression and confers resistance to androgen signaling inhibitors. Our findings indicate how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA, activating and amplifying them to allow oncogene overexpression.}, }
@article {pmid40832049, year = {2025}, author = {Ralph, DK and Bakis, AG and Galloway, J and Vora, AA and Araki, T and Victora, GD and Song, YS and DeWitt, WS and Matsen, FA}, title = {Inference of germinal center evolutionary dynamics via simulation-based deep learning.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40832049}, issn = {2331-8422}, support = {U01 AI150747/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However the exact form of this relationship between affinity and fecundity, which we call the "affinity-fitness response function", is not known. Here we use deep learning and simulation-based inference to learn this function from a unique experiment that replays a particular combination of GC conditions many times. All code is freely available at https://github.com/matsengrp/gcdyn, while datasets and inference results can be found at https://doi.org/10.5281/zenodo.15022130.}, }
@article {pmid40879300, year = {2025}, author = {Nieto, C and Kadan-Lottick, NS and Ross, WL and Santiago-Rivera, Y and Sandbo, C and Hild, M and Bryant, S and Barnhorst, M and Appel, B and Mendoza, JA}, title = {Increasing Physical Activity in Children During Cancer Treatment: A Qualitative Study of Parents' Perspectives.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e31961}, doi = {10.1002/pbc.31961}, pmid = {40879300}, issn = {1545-5017}, support = {//Georgetown Lombardi Comprehensive Cancer Center/ ; //Fred Hutchinson Cancer Research Center/ ; }, abstract = {This qualitative study explored barriers, facilitators, and preferences for promoting physical activity (PA) in children undergoing cancer therapy by interviewing 36 parents of children aged 4-15 years, on-therapy or less than 1 year post-therapy at three hospitals. Key barriers included safety concerns, risk of infection, and treatment side effects. Facilitators included social support and oncologist recommendations for PA. Parents preferred interventions that were flexible, varied, gamified, low-burden, and tailored to the child. Parents also expressed a desire for family involvement, connection to other parents, online social media groups, and activity trackers. These findings can inform PA interventions for children undergoing cancer therapy.}, }
@article {pmid40876913, year = {2025}, author = {Sandmaier, BM}, title = {Profile of a Pioneer: Rainer F. Storb.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {599-604}, doi = {10.1016/j.jtct.2025.08.001}, pmid = {40876913}, issn = {2666-6367}, }
@article {pmid40875889, year = {2025}, author = {Boothby, AB and Ruiz Lopez, JN and Hegerova, L and Manogna, D and Chintapatla, R and Harris, S and Teramura, G and Tirschwell, DL and Taylor, B and Keel, SB}, title = {Addition of ADAMTS13 Testing to Cryptogenic Stroke Evaluation: Index Case and Single-Center Screening Initial Experience.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017702}, pmid = {40875889}, issn = {2473-9537}, }
@article {pmid40875887, year = {2025}, author = {Galarza Fortuna, GM and Peres, LC and Nazarenko, E and De Menezes Silva Corraes, A and Hovanky, V and Shune, L and McGuirk, JP and de Avila, G and Khouri, J and Dima, D and Gaballa, MR and Dhakal, B and Forsberg, PA and Godara, A and Afrough, A and Anderson, LD and Herr, MM and Davis, JA and Mann, H and Purvey, S and Clark, WB and Htut, MM and Beitinjaneh, AM and Pereira, DL and Kocoglu, M and Ferreri, CJ and Atrash, S and Voorhees, PM and Rossi, AC and Richard, S and Hashmi, H and Patel, KK and Sidana, S and Lin, Y and Hansen, DK and Sborov, DW}, title = {Safety and Efficacy of BCMA directed Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Plasma Cell Leukemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016966}, pmid = {40875887}, issn = {2473-9537}, abstract = {Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL treated with the B-cell Maturation Antigen (BCMA)-directed Chimeric Antigen Receptor T-Cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients, 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression free survival (mPFS) was 9.0 months (95% CI 4-15 months) and the median overall survival (mOS) was 13.0 months (95% CI 8-not estimable (NE) months). The 1-year cumulative incidence of progression or death was 72% and the 1-year cumulative incidence of death was 47%. Patients receiving cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (>23 months (NE) vs 9.0 months) compared to those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI 17.4%-68.5%) with cilta-cel, while all patients treated with ide-cel progressed or died within 12 months of infusion. Rates of hematological and non-hematological toxicities were similar between those patients treated with cilta-cel and ide-cel and consistent with those reported in patients with MM. In this first multicenter study evaluating patients with PCL treated with standard of care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes compared to historical standards.}, }
@article {pmid40875591, year = {2025}, author = {Hall, K and Lazaryan, A and Der Laan, MV and Lee, CJ and Logan, AC and Gruber, S and Kabadi, S and Khan, I and Nicholls, C and Rota, LM and Nikai, E and Ponomareva, E and Koumas, A and Waller, EK}, title = {Efficacy and Safety of Belumosudil as Compared with Best Available Therapy for the Treatment of cGVHD in the US.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025015832}, pmid = {40875591}, issn = {2473-9537}, abstract = {Belumosudil was FDA-approved in the United States (US) for the treatment of relapsed/refractory chronic graft-versus-host disease (cGVHD) based on a randomized phase II trial comparing two belumosudil doses. The efficacy and safety of belumosudil versus the best available therapy (BAT) have not been studied. Applying rigorous statistical methodology to real-world data, this study estimated the efficacy of belumosudil versus BAT in cGVHD patients whose disease failed to respond to 2-5 prior lines of therapy (LOTs). Retrospective data between March 2015 and 2024 was collected across 8 US sites on 196 patients contributing 113 belumosudil and 245 BAT LOTs. The primary outcome was 6-month overall response rate (ORR), defined as the proportion of complete or partial responses based on 2014 NIH consensus criteria, physician assessment, or corticosteroid dose taper of ≥ 50% without cGVHD progression. Death, relapse, and beginning a new LOT were considered a lack of response. Targeted maximum likelihood estimation (TMLE) was used to estimate the 6-month ORR following belumosudil versus BAT (38.7% versus 26.8%, respectively, or 44.2% improvement with belumosudil (one-sided 95% confidence interval (CI): [4.4%, ∞); p: 0.031)). TMLE was also used to estimate 1-year failure-free survival (FFS) when treated with belumosudil (61.2%) or BAT (47.8%), a 13.5% difference (95% CI: [1.5%, 100.0%), p: 0.032). Descriptive assessment of safety showed adverse events recorded in 27% of belumosudil and 36% of BAT LOTs. Findings demonstrated that belumosudil improved clinical outcomes versus BAT in cGVHD patients with 2-5 prior LOTs, and safety was consistent with belumosudil's established profile.}, }
@article {pmid40875480, year = {2025}, author = {Friedland, BA and Browne, EN and Roberts, ST and Ngure, K and Nakalega, R and Macdonald, P and Mpongo, CN and Tenza, S and Mhlanga, N and Szydlo, D and Johnson, S and McClure, T and Nair, G and Celum, C and Hillier, S and van der Straten, A and , }, title = {Higher acceptability of the monthly dapivirine ring versus daily oral pre-exposure prophylaxis among adolescent girls and young women in sub-Saharan Africa in the REACH trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000003756}, pmid = {40875480}, issn = {1944-7884}, abstract = {BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is effective for HIV prevention, yet use has been inconsistent in adolescent girls and young women (AGYW). We compared PrEP to the dapivirine vaginal ring (ring) among AGYW in MTN-034 (REACH).
METHODS: We randomized 247 16-21-yr-old AGYW (South Africa, Uganda, Zimbabwe) to the sequence of using the ring and oral PrEP for 6m each (February 2019-September 2021). Participants rated overall product acceptability (1, dislike very much to 5, like very much) after 3m and 6m, and product characteristics/use attributes after 3m. We compared proportions of participants rating each product a "5" (binomial model with generalized estimating equations). We assessed associations between product characteristics/use attribute ratings at 3m and overall acceptability after 6m (Chi-square).
RESULTS: 65% and 41% of participants rated the ring versus PrEP a "5" (adjusted risk difference [aRD] 24%, 95% CI: 15%, 32%; p<0.001). For both products, high overall acceptability was associated with "excellent" self-rated adherence (ring, p< 0.001; PrEP, p = 0.03), product appearance (ring, p = 0.005; PrEP, p < 0.001), and ease of use (ring, p = 0.001; PrEP, p = 0.003). Not worrying about/or experiencing side effects were also associated with high acceptability of oral PREP.
CONCLUSIONS: The dapivirine ring was highly acceptable to substantially more individuals than oral PrEP, although a significant minority rated oral PrEP highly, even after using the ring. As has been found in the contraceptive field, offering AGYW a choice of PrEP products is likely to increase the use of any HIV prevention method in this vulnerable population.}, }
@article {pmid40873297, year = {2025}, author = {Duong, VA and Pan, E and Dabral, P and Utzschneider, KM and Lampe, JW and Chen, R and A J Hullar, M}, title = {Metaproteomic Analysis to Assess the Impact of Storage Media on Human Gut Microbiome in Fecal Samples.}, journal = {Proteomics}, volume = {}, number = {}, pages = {e70035}, doi = {10.1002/pmic.70035}, pmid = {40873297}, issn = {1615-9861}, support = {R01CA211892//National Institutes of Health (NIH)/ ; R01CA276173//National Institutes of Health (NIH)/ ; }, abstract = {The human gut microbiome is a diverse community of microorganisms residing in the gastrointestinal tract. The storage condition of fecal samples may impact the taxonomic and protein compositions of microbiomes in these samples. Here, we performed a mass spectrometry-based metaproteomic study to assess the impact of storage media on human gut microbiome in fecal samples. We evaluated FDA-authorized OMNIgene·GUT (OG), phosphate-buffered saline (PBS), and RNALater (RNAL) buffers and identified 38,185 microbial peptides corresponding to 7348 microbial proteins, which matched 16 phyla, 20 classes, 50 orders, 104 families, 332 genera, and 453 species. We found a high similarity among the fecal microbiomes preserved in OG, PBS, and RNAL in terms of the identification of proteins, taxa, and functional annotations. Both alpha and beta diversity suggested the high similarity among samples stored in the three media. Nonetheless, we also found some notable differences among buffers regarding the abundances of a few taxon groups. A partial human proteome (over 400 proteins) was identified in the fecal samples, with most of these proteins associated with the membrane and extracellular regions. The findings indicate the similarity among microbiomes in the fecal samples stored in OG, PBS, and RNAL regarding proteome profile, taxa, and functional capacity. SUMMARY: This study thoroughly analyzed and compared the metaproteomes of fecal samples preserved at -80°C in PBS, RNALater, and OMNIgene·GUT Dx buffers, offering novel insights into the effectiveness of these buffers in maintaining the stability and composition of the human gut microbiome. We found a high similarity in the identification and quantification of proteins, taxa, and functional annotations across the three buffers, with notable quantitative differences highlighting subtle yet important variations in preservation efficacy. The unique datasets and findings could offer valuable revelations into the impact of fecal sample preservation on translational and clinical analyses of the human gut microbiome.}, }
@article {pmid40870354, year = {2025}, author = {Han, Z and Li, T and You, J and Balakrishnan, N}, title = {Varying-Coefficient Additive Models with Density Responses and Functional Auto-Regressive Error Process.}, journal = {Entropy (Basel, Switzerland)}, volume = {27}, number = {8}, pages = {}, pmid = {40870354}, issn = {1099-4300}, support = {21YJA910001//Humanities and Social Science Fund of Ministry of Education of China/ ; 11971291//National Natural Science Foundation of China (NSFC)/ ; }, abstract = {In many practical applications, data collected over time often exhibit autocorrelation, which, if unaccounted for, can lead to biased or misleading statistical inferences. To address this issue, we propose a varying-coefficient additive model for density-valued responses, incorporating a functional auto-regressive (FAR) error process to capture serial dependence. Our estimation procedure consists of three main steps, utilizing spline-based methods after mapping density functions into a linear space via the log-quantile density transformation. First, we obtain initial estimates of the bivariate varying-coefficient functions using a B-spline series approximation. Second, we estimate the error process from the residuals using spline smoothing techniques. Finally, we refine the estimates of the additive components by adjusting for the estimated error process. We establish theoretical properties of the proposed method, including convergence rates and asymptotic behavior. The effectiveness of our approach is further demonstrated through simulation studies and applications to real-world data.}, }
@article {pmid40867077, year = {2025}, author = {Ebadi, M and Reddi, S and Senyshyn, L and Minot, SS and Gooley, T and Kabage, AJ and Lee, SJ and Hill, GR and Khoruts, A and Rashidi, A}, title = {Effect of fecal microbiota transplantation on gut microbiota functional profile in recipients of allogeneic hematopoietic cell transplantation.}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2551882}, pmid = {40867077}, issn = {1949-0984}, mesh = {Humans ; *Fecal Microbiota Transplantation ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Gastrointestinal Microbiome ; Male ; Middle Aged ; Female ; Adult ; Bacteria/classification/genetics/isolation & purification/metabolism ; *Dysbiosis/therapy/microbiology ; Transplantation, Homologous ; Feces/microbiology ; Aged ; }, abstract = {Intestinal dysbiosis has been associated with both the effectiveness and toxicity of immunotherapy in cancer patients, inspiring multiple trials investigating fecal microbiota transplantation (FMT) in these patients. FMT restores microbial community structures damaged by antibiotics and enriches the microbiota with beneficial bacteria. However, the precise mechanism through which FMT exerts its effects and provides clinical benefits remains incompletely understood. Efforts to date have primarily focused on characterizing taxonomic changes following FMT. We hypothesized that FMT may also modify the functional pathways and metabolic capabilities of the gut microbiota, with possible clinical impact. To investigate this, we conducted a study involving 17 patients with blood disorders who received prophylactic FMT from one of the three healthy donors shortly after hematopoietic cell transplantation (HCT). By analyzing shotgun metagenomic profiles of the baseline, pre-FMT, and post-FMT gut microbiota, we demonstrate that FMT effectively restored pathways that had been depleted following HCT. However, it did not significantly reduce pathways that had expanded, indicating that FMT operates primarily through a restorative mechanism, reestablishing lost functional capabilities in the microbiota rather than suppressing overactive pathways. These findings highlight the potential for optimizing FMT protocols and identifying patient populations where FMT may be particularly beneficial.}, }
@article {pmid40864714, year = {2025}, author = {Craig, E and Keyes, TJ and Sarno, J and D'Silva, JP and Domizi, P and Zaslavsky, M and Tsai, A and Glass, D and Nolan, GP and Hastie, T and Tibshirani, R and Davis, KL}, title = {Annotation-free discovery of disease-relevant cells in single-cell datasets.}, journal = {Science advances}, volume = {11}, number = {35}, pages = {eadv5019}, pmid = {40864714}, issn = {2375-2548}, mesh = {Humans ; *Single-Cell Analysis/methods ; *Leukemia/pathology ; Neoplasm, Residual/pathology ; Algorithms ; }, abstract = {In single-cell datasets, patient labels indicating disease status (e.g., "sick" or "not sick") are typically available, but individual cell labels indicating which of a patient's cells are associated with their disease state are generally unknown. To address this, we introduce mixture modeling for multiple-instance learning (MMIL), an expectation-maximization approach that trains cell-level binary classifiers using only patient-level labels. Applied to primary samples from patients with acute leukemia, MMIL accurately separates leukemia from nonleukemia baseline cells, including rare minimal residual disease (MRD) cells; generalizes across tissues and treatment time points; and identifies biologically relevant features with accuracy approaching that of a hematopathologist. MMIL can also incorporate cell labels when they are available, creating a robust framework for leveraging both labeled and unlabeled cells. MMIL provides a flexible modeling framework for cell classification, especially in scenarios with unknown gold-standard cell labels.}, }
@article {pmid40864016, year = {2025}, author = {Ezzat, D and Uddin, MM and Xue, L and Pershad, Y and Zhang, S and Collins, JM and Kitzman, JO and Jaiswal, S and Desai, P and Kooperberg, C and Bick, AG and Natarajan, P and Manson, JE and Whitsel, EA and Reiner, AP and Honigberg, MC}, title = {Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women.}, journal = {Journal of the American College of Cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacc.2025.07.058}, pmid = {40864016}, issn = {1558-3597}, abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP's relevance to CVD may diminish with advancing age.
OBJECTIVES: This study aimed to test the association of CHIP and its key subtypes with incident CVD in an older population.
METHODS: Participants in the Women's Health Initiative Long Life Study completed study assessments in 2012-2013 and underwent high-coverage sequencing (median depth 4,580×). The co-primary exposures were composite CHIP and TET2 CHIP. DNMT3A, ASXL1, JAK2, and non-DNMT3A CHIP were examined as secondary exposures. The primary outcome was incident coronary heart disease. Secondary outcomes were incident heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, venous thromboembolism, and cardiovascular death. Multivariable-adjusted Cox models tested associations between CHIP and incident CVD.
RESULTS: Among 6,677 women (median age 80 years; median follow-up 10.1 years), 2,176 (32.6%) had any CHIP. TET2 CHIP was independently associated with incident coronary heart disease (aHR: 1.36 [95% CI: 1.05-1.77]; P = 0.02), whereas composite CHIP was not (aHR: 1.07 [95% CI: 0.89-1.28]; P = 0.49). Secondarily, TET2 CHIP was associated with HFpEF (aHR: 1.40 [95% CI: 1.03-1.90]; P = 0.03), ASXL1 CHIP with HFrEF (aHR: 3.16 [95% CI: 1.53-6.55]; P = 0.002), and JAK2 CHIP with ischemic stroke (aHR: 2.49 [95% CI: 1.17-5.30]; P = 0.02), venous thromboembolism (aHR: 2.71 [95% CI: 1.11-6.65]; P = 0.03), and cardiovascular death (aHR: 2.62 [95% CI: 1.68-4.11]; P < 0.001). No other significant associations were observed for composite or DNMT3A CHIP.
CONCLUSIONS: In an older female cohort, key CHIP subtypes (TET2, ASXL1, and JAK2) were associated with incident CVD, with associations that appeared to differ by CVD outcome. These findings suggest that CHIP remains associated with cardiovascular health into later life. (Women's Health Initiative [WHI]; NCT00000611).}, }
@article {pmid40863730, year = {2025}, author = {Lai, Y-T and Dingens, AS and DeMouth, M and Helmold Hait, S and O'Dell, S and Schon, A and Olia, AS and Wang, T and Shrader, HR and Lovelace, SE and Pegu, A and Doria-Rose, NA and Mascola, JR and Bloom, JD and Kwong, PD}, title = {Fostemsavir analog BMS-818251 has enhanced viral neutralization potency and similar escape mutation profile.}, journal = {Antimicrobial agents and chemotherapy}, volume = {}, number = {}, pages = {e0191024}, doi = {10.1128/aac.01910-24}, pmid = {40863730}, issn = {1098-6596}, abstract = {BMS-818251, a fostemsavir analog, is a next-generation HIV-1 attachment inhibitor with enhanced potency and a similar resistance profile. By using ex vivo viral outgrowth assays with HIV+ donor samples, we demonstrate here that BMS-818251 exhibits superior viral suppression compared to temsavir, the active form of fostemsavir. To map potential resistance pathways, we employed deep mutational scanning and pseudotyped virus neutralization assays to identify escape mutations within the HIV-1 envelope glycoprotein (Env). These mutations were largely clustered around the BMS-818251 binding site, with key resistance mutations reducing drug-binding affinity. Several of the enriched mutations, such as S375I/N, M426L, and M475I, have been previously observed in fostemsavir-treated patients, highlighting their clinical relevance. Isothermal titration calorimetry revealed reduced binding affinity as the primary mechanism of resistance, though with notable exceptions, such as R429G, suggesting additional factors to influence viral escape. Ex vivo Env sequencing confirmed selection of resistance mutations under BMS-818251 pressure, reinforcing the predictive value of deep mutational scanning for in vivo resistance monitoring. Compared to fostemsavir, BMS-818251 achieved more effective viral suppression at lower concentrations, even in donor samples harboring preexisting resistance mutations. These findings support the continued development of BMS-818251 as a promising alternative to fostemsavir, with potential benefits for patients with multidrug-resistant HIV-1.}, }
@article {pmid40860163, year = {2025}, author = {Westover, T and Walsh, MP and Abdelhamed, S and Xiong, E and Ma, J and Song, G and Thomas, ME and Umeda, M and Maciaszek, JL and Wong, JC and Wintering, A and Wang, L and Emanuel, PD and Loh, ML and Tasian, SK and Stieglitz, E and Schwartz, JR and Shannon, KM and Klco, JM}, title = {Genomic landscape and clonal architecture in pediatric myeloid neoplasms with chromosome 7 deletions.}, journal = {Blood neoplasia}, volume = {2}, number = {2}, pages = {100093}, pmid = {40860163}, issn = {2950-3280}, support = {R01 HL144653/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid40857443, year = {2025}, author = {O'Connor, TM and Garza, T and Alam, U and Vadathya, AK and Moreno, JP and Beltran, A and Haidar, S and Haidar, N and Hughes, SO and Thompson, D and Musaad, SMA and Baranowski, T and Mendoza, JA and Young, J and Sano, A and Veeraraghavan, A}, title = {The feasibility of passively tracking children's TV viewing and mobile device use in naturalistic settings.}, journal = {Behaviour & information technology}, volume = {}, number = {}, pages = {}, pmid = {40857443}, issn = {0144-929X}, support = {P01 HD109876/HD/NICHD NIH HHS/United States ; R01 DK113269/DK/NIDDK NIH HHS/United States ; }, abstract = {Research on children's technology and digital media (TDM) is hampered by a lack of robust approaches for assessing TDM use. This study assessed the feasibility of passively measuring children's TV screens and mobile devices (TDM) in a naturalistic setting. In the three-day feasibility study, FLASH-TV was set up on one to two TVs the child (5-12 year olds) typically used in the home (n=20). Children's mobile device use was assessed with either the Chronicle App or ScreenTime screenshots. Parents completed three TDM diaries. An exit interview with the parent explored their perceptions of the assessments and the child's TDM use report. Complete data were obtained on 86.7% of days for passive assessment of TV viewing and 84.3% of days for mobile device use. Fifteen parents reviewed complete TDM use reports for their child, with most stating the reports appeared correct for TV (80%) and mobile device (80%). Almost two-thirds had no concerns about having the FLASH-TV installed in their home, while some reported issues about feeling observed. Parents described high burden and frustration with the TDM diaries. Data provided preliminary evidence that passive measurement is feasible for assessing children's TV and mobile device use, with reduced burden for parents.}, }
@article {pmid40859413, year = {2025}, author = {Lu, G and Han, F and Wang, Y and Yuan, C and Zhu, Q and Xia, T and Chen, L and Dong, X and Ding, Y and Xiao, W and Zhang, Y and Pan, J and Xu, H and Chen, W and Tu, B and Li, W and Wang, F and Gong, W and Hu, L}, title = {Src Reduces Neutrophil Extracellular Traps Generation and Resolves Acute Organ Damage.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e06028}, doi = {10.1002/advs.202506028}, pmid = {40859413}, issn = {2198-3844}, support = {82070668//National Natural Science Foundation/ ; 82241043//National Natural Science Foundation/ ; 82270680//National Natural Science Foundation/ ; 82270679//National Natural Science Foundation/ ; 82400763//National Natural Science Foundation/ ; BK20240028//Natural Science Foundation of Jiangsu Province/ ; BK20240500//Natural Science Foundation of Jiangsu Province/ ; ZD2022011//The Medical research Project of Jiangsu Provincial Health Commission/ ; YZ2022080//Yangzhou key research and development plan/ ; YZ2022207//Yangzhou Policy guidance Program/ ; SZS2023001//Suzhou Innovation Platform Construction Projects- Municipal Key Laboratory Construction/ ; }, abstract = {Neutrophil extracellular traps (NETs) are key factors mediating acute inflammatory injury. However, the underlying mechanisms and potential therapeutic targets remain unclear. Previous results suggest Src may be involved in regulating the NETs formation. Here, Src is found activated in the NETs model in vitro, in the murine- and human-derived neutrophils (acute pancreatitis and sepsis). Moreover, p-Src expression correlates with the clinical prognosis of acute pancreatitis and sepsis patients. Meanwhile, the inhibition of Src activity (gene silencing or inhibitors) inhibits NETs formation in vitro. Mechanistically, Src directly activates RAF1 by regulating phosphorylation at the Ser 621 site and mediates the RAF/MEK/ERK pathway, thereby affecting the intracellular ROS production. Alternatively, Src activates the RAF/MEK/ERK pathway by mediating PKC phosphorylation. In vivo, neutrophil Src - specific defect significantly reduces acute inflammatory response, organ damage, and the NETs formation in damaged tissue. Eventually, Src inhibitors are used and validated their pharmacological effects. These results identify Src as a key mediator in intracellular ROS production, NETs formation, and acute organ injury. Hence, Src inhibition may represent a promising therapeutic strategy for treating acute organ injury.}, }
@article {pmid40858972, year = {2025}, author = {Kendra, KL and Bellasea, SL and Eroglu, Z and Hu-Lieskovan, S and Campbell, KM and Carson, WE and Wada, DA and Plaza, JA and Sosman, JA and In, GK and Ikeguchi, A and Hyngstrom, J and Brohl, AS and Khushalani, NI and Markowitz, J and Negrea, G and Kasbari, S and Doolittle, GC and Swami, U and Roberts, T and Mathew, BN and Medina, E and Baselga-Carretero, I and Gonzalez, CR and Garcilazo, IP and Vega-Crespo, A and Chen, JM and Naser Al-Deen, N and Patel, SP and Sharon, E and Moon, J and Wu, MC and Ribas, A}, title = {Publisher Correction: Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41591-025-03975-2}, pmid = {40858972}, issn = {1546-170X}, }
@article {pmid40858099, year = {2025}, author = {Oehler, VG and Walter, RB}, title = {Biology-Directed Therapy for Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangements.}, journal = {NEJM evidence}, volume = {4}, number = {9}, pages = {EVIDe2500196}, doi = {10.1056/EVIDe2500196}, pmid = {40858099}, issn = {2766-5526}, }
@article {pmid40857688, year = {2025}, author = {Orellana, MA and Pike, M and Katz, R and Robinson, W and Doll, KM}, title = {Risk Factors Impacting Endometrial Thickness Visibility and Information Availability in Black Patients.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1177/15409996251371097}, pmid = {40857688}, issn = {1931-843X}, abstract = {Background: Black patients experience worse endometrial cancer outcomes compared to white patients. Endometrial thickness (ET) measures from transvaginal ultrasound (TVUS) are used in diagnostic triage to determine if further endometrial tissue sampling is needed. However, recent work suggests that TVUS may disproportionately underdiagnose Black patients and those over 60 years old, contributing to Black patients' lower survival. Our study aimed to identify risk factors that impact ET measurement quality [visibility, missing data] from TVUS and result in nondiagnostic TVUS results. Methods: A retrospective analysis was conducted in a cohort of Black patients undergoing hysterectomy from 2014 to 2020. ET visibility documentation was categorized as visible or "compromised" (partially visible or nonvisible). The presence or absence of endometrial information was also assessed. Results: Of 2,705 patients with ultrasound information, 78% (N = 1,838) had documented ET visibility. Of those with visibility, 1,301 (71%) had complete ET visibility. Among those with compromised visibility (n = 537), 271 (50.5%) had partially visible ET, while 266 (49.5%) had nonvisible ET. Significant risk factors associated with compromised visibility included an enlarged uterus (OR: 2.89, 95% CI: 2.32-3.61) and fibroids (OR: 3.78, 95% CI: 1.94-7.39). Of 2,032 patients with ultrasound reports, 9.5% (N = 194) lacked endometrial information. Fibroids (OR: 1.81, 95% CI: 1.19-2.76) and enlarged uterus (OR: 2.61, 95% CI: 1.53-4.45) were also significantly associated with missing endometrial information. Conclusion: These findings suggest that a substantial proportion of TVUS examinations may not yield definitive data for diagnostic triage in Black women, potentially contributing to diagnostic delays and worse survival. Improved diagnostic approaches are needed in this population.}, }
@article {pmid40857092, year = {2025}, author = {Nagana Gowda, GA and Zhu, W and Pascua, V and McMillen, T and Tian, R and Raftery, D}, title = {Identification and Distribution of the Dietary Antioxidant Ergothioneine in Humans and Animal Models Combining NMR, RANSY, and MS Methods.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.5c03507}, pmid = {40857092}, issn = {1520-6882}, abstract = {Ergothioneine (ERG), a unique, naturally occurring antioxidant of dietary origin, is gaining increasing attention due to its crucial roles in human health and diseases. Despite its significance, ERG is rarely detected in biospecimens by mass spectrometry (MS) and, to date, has not been characterized by nuclear magnetic resonance (NMR) spectroscopy, two widely used analytical techniques in metabolomics. In this study, we investigated human plasma, whole blood (WB), and red blood cells (RBC), as well as mouse blood and tissues, combining NMR, LC-MS, and ratio analysis techniques. The results demonstrate the ability of simple 1D [1]H NMR to routinely identify and quantify ERG in various biological samples. The levels of ERG vary widely and depend on the type of biological sample, with human RBC exhibiting remarkably high concentrations, often exceeding 1.5 mM. The average levels of ERG in human plasma, WB, and RBC were in ratios of 1:70:140, respectively. Moreover, ERG levels showed a linear correlation between plasma and WB (R[2] = 0.59), plasma and RBC (R[2] = 0.75), and WB and RBC (R[2] = 0.98). In mice, ERG levels exhibit a distinct whole-body distribution, with average levels in the mouse skeletal muscle, brain, heart, kidney, and liver in ratios of 0:1:10:35:45, respectively. The demonstration of surprisingly high levels of ERG in biological samples using [1]H NMR opens new avenues for its analysis using both NMR and MS methods to explore its roles in human health and diseases, as part of routine global or targeted metabolomics studies.}, }
@article {pmid40857002, year = {2025}, author = {Bhatt, NS and Voutsinas, J and Winters, M and Leisenring, WM and Ballard, S and Jenssen, K and Baker, KS}, title = {Work Status, Absenteeism, Presenteeism, and Quality of Life in Young Adult Cancer Survivors.}, journal = {JAMA network open}, volume = {8}, number = {8}, pages = {e2528882}, pmid = {40857002}, issn = {2574-3805}, mesh = {Humans ; *Quality of Life/psychology ; Male ; Female ; Adult ; *Cancer Survivors/psychology/statistics & numerical data ; Cross-Sectional Studies ; *Absenteeism ; Young Adult ; *Presenteeism/statistics & numerical data ; Adolescent ; *Neoplasms/psychology ; Unemployment/statistics & numerical data/psychology ; *Employment/statistics & numerical data/psychology ; Washington ; }, abstract = {IMPORTANCE: Current literature lacks information on the association between the work status and performance of young adult cancer survivors and their quality of life (QOL).
OBJECTIVE: To assess self-reported work status, missed time at work (absenteeism), and performance (presenteeism) and their associations with QOL among young adult cancer survivors.
This cross-sectional survey study was performed from October 18, 2020, to September 17, 2022, at a single cancer center in Seattle, Washington. Participants included young adult cancer survivors (aged 18 to 39 years at diagnosis) who were 1 year or more from completion of cancer therapy. Data were analyzed from May 1, 2023, to February 1, 2025.
EXPOSURES: Cancer therapy.
MAIN OUTCOMES AND MEASURES: Unemployment rate compared with the age-, sex-, and calendar year-matched general population; standardized absolute and relative absenteeism and presenteeism scores; standardized scores for domains of anxiety, depression, physical function, fatigue, sleep disturbance, pain, social role, and cognition; and adjusted linear regressions to study factors associated with higher QOL scores.
RESULTS: A total of 198 survivors, with a median age at diagnosis of 31 (IQR, 26-35) years and a median age at survey of 39 (IQR, 35-44) years were included (142 [71.7%] female). The unemployment rate (14 [7.1%]) did not differ from that of the general population (4.7%) (P = .13). Compared with employed survivors, unemployed survivors reported significantly higher depression scores (coefficient, 5.11; 95% CI, 0.92-9.30) and lower scores for satisfaction with social roles and activities (coefficient, -6.59; 95% CI, -11.34 to -1.84) and physical function (coefficient, -6.63; 95% CI, -11.38 to -1.87). Higher absolute presenteeism score was associated with lower scores for anxiety (coefficient, -0.19; 95% CI, -0.26 to -0.11), depression (coefficient, -0.17; 95% CI, -0.24 to -0.10), fatigue (coefficient, -0.20; 95% CI, -0.30 to -0.10), pain interference (coefficient, -0.11; 95% CI, -0.21 to -0.02), and sleep disturbance (coefficient, -0.12; 95% CI, -0.21 to -0.03) and higher scores for physical function (coefficient, 0.08; 95% CI, 0.008-0.17), cognitive function (coefficient, 0.19; 95% CI, 0.11-0.27), and satisfaction in social roles and activities scores (coefficient, 0.16; 95% CI, 0.08-0.24). Additionally, a higher absolute absenteeism score was associated with a higher anxiety (coefficient, 0.03; 95% CI, 0.004-0.07) and lower cognitive function (coefficient, -0.04; 95% CI, -0.07 to -0.004).
CONCLUSIONS AND RELEVANCE: In this cross-sectional study of young adult cancer survivors, associations were found between survivors' self-reported work status and performance and their QOL affecting their mental, physical, and social health. These findings call for the development of effective communication strategies with employers to balance work expectations with survivors' treatment-related complications to achieve better performance and in turn higher QOL.}, }
@article {pmid40854792, year = {2025}, author = {Naik, A and Kanzaria, A and Chen, X and Kaur, N and Ho, CJ and Smith, SD and Gopal, AK and Shadman, M and Naresh, KN}, title = {Digital pathology and image analysis of p53 biomarker in lymphomas using two algorithms: correlation with genotype and visual inspection.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210280}, pmid = {40854792}, issn = {1472-4146}, abstract = {p53 immunohistochemistry (IHC) is widely used as a rapid surrogate for detecting TP53 mutations, with TP53 mutations being a key biomarker for poor outcomes in lymphomas. We developed two algorithms using digital quantification tools to assess p53 expression from whole slide images of 77 lymphoma samples. An experienced pathologist visually evaluated the p53 slides, classifying cases as likely wild-type or mutated TP53 genotype. We correlated the results of the algorithms and visual inspection with the actual TP53 genotype. For cases with p53 overexpression (likely missense mutations), the algorithms achieved 86.7% sensitivity and 98.2% specificity (visual inspection: 80% and 95.2%). For cases with reduced p53 expression (likely 'other' mutations), the algorithms showed 92.7% sensitivity and 100% specificity (visual inspection: 40% and 95.8%). This study demonstrates that combining digital pathology with digital quantification tools-based algorithms can reliably predict TP53 genotype from p53 IHC patterns, with comparable or slightly superior performance to an experienced pathologist.}, }
@article {pmid40832395, year = {2025}, author = {Tran-Kiem, C and Perofsky, AC and Lessler, J and Bedford, T}, title = {Characterizing the informativeness of pathogen genome sequence datasets about transmission between population groups.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40832395}, abstract = {Pathogen genome analysis helps characterize transmission between population groups. The information carried by pathogen sequences comes from the accumulation of mutations within their genomes; thus, that the pace at which mutations accumulate should determine the granularity of transmission processes that pathogen sequences can characterize. Here, we investigate how the complex interplay between mutation, transmission, population mixing and sampling impacts the power of phylogeographic studies. First, we develop a conceptual probabilistic framework to quantify the ability of pairs of sequences in capturing migration history. This allows us to comprehensively explore the space of possible phylogeographic analyses by explicitly considering the pace at which mutations accumulate and the pace at which migration events occur. Using this framework, we identify a pathogen-intrinsic limit in the mixing scale at which their sequence data remains informative, with faster mutating pathogens enabling finer spatial characterization. Secondly, we perform a simulation study exploring a range of assumptions regarding sequencing intensity. We find that sample size further imposes a limit on the characterization of mixing processes. This work highlights inherent horizons of observability for population mixing processes that depend on the interaction between evolution, transmission, mixing and sampling. Such considerations are important for the design of phylogeographic studies.}, }
@article {pmid40852372, year = {2025}, author = {Huang, TJ and Liu, Z and McKeague, IW}, title = {Post-selection inference for high-dimensional mediation analysis with survival outcomes.}, journal = {Scandinavian journal of statistics, theory and applications}, volume = {52}, number = {2}, pages = {756-776}, pmid = {40852372}, issn = {0303-6898}, support = {R01 AG062401/AG/NIA NIH HHS/United States ; R01 AG086379/AG/NIA NIH HHS/United States ; }, abstract = {It is of substantial scientific interest to detect mediators that lie in the causal pathway from an exposure to a survival outcome. However, with high-dimensional mediators, as often encountered in modern genomic data settings, there is a lack of powerful methods that can provide valid post-selection inference for the identified marginal mediation effect. To resolve this challenge, we develop a post-selection inference procedure for the maximally selected natural indirect effect using a semiparametric efficient influence function approach. To this end, we establish the asymptotic normality of a stabilized one-step estimator that takes the selection of the mediator into account. Simulation studies show that our proposed method has good empirical performance. We further apply our proposed approach to a lung cancer dataset and find multiple DNA methylation CpG sites that might mediate the effect of cigarette smoking on lung cancer survival.}, }
@article {pmid40854613, year = {2025}, author = {Ferris, RL and Leidner, RS and Chung, CH and Jimeno, A and Lee, SM and Sukari, A and Nieva, JJ and Grilley-Olson, JE and Redman, R and Wong, SJ and Villaflor, VM and Misleh, J and Finckenstein, FG and Chou, J and Gastman, B and Fiaz, R and Catlett, M and Yi, M and Cohen, EEW}, title = {Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, pmid = {40854613}, issn = {2051-1426}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Lymphocytes, Tumor-Infiltrating/immunology/transplantation ; *Squamous Cell Carcinoma of Head and Neck/therapy/immunology/pathology ; Aged ; *Head and Neck Neoplasms/therapy/immunology/pathology ; *Neoplasm Recurrence, Local/therapy/immunology ; Adult ; Neoplasm Metastasis ; Treatment Outcome ; }, abstract = {BACKGROUND: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.
METHODS: C-145-03 (NCT03083873) was a phase 2 study of TIL in patients with recurrent and/or metastatic HNSCC assigned to 1 of 4 treatment cohorts: cohort 1, non-cryopreserved TIL; cohort 2, cryopreserved lifileucel (22-day manufacturing); cohort 3, cryopreserved lifileucel (16-day manufacturing); cohort 4, cryopreserved LN-145-S1 programmed cell death protein-1 (PD-1) selected. Patients underwent tumor resection for TIL generation. After preparative non-myeloablative lymphodepletion, patients received a single infusion of TIL followed by interleukin-2 (IL-2) infusion(s). The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria for Solid Tumors (RECIST) V.1.1. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and incidence of treatment-emergent adverse events.
RESULTS: Overall, 53 patients received TIL: cohort 1 (n=8), cohort 2 (n=17), cohort 3 (n=16), cohort 4 (n=12). Median age was 57 years and most patients were males (87%; 46/53) with stage IV disease (98%; 52/53). Patients had a median of two prior lines of systemic therapy; 87% (46/53) of patients had prior anti-PD-1/programmed cell death ligand-1 therapy and 72% (38/53) had prior chemotherapy. The ORR was 11% (6/53) with six patients achieving partial response (cohort 1, n=3; cohort 2, n=1; cohort 4, n=2). At median follow-up of 17.9 months, the median DOR was 7.6 months. The DCR was 76% (40/53); 64% (34/53) of patients had stable disease. The safety profile was consistent with known toxicities associated with non-myeloablative lymphodepletion and IL-2 administration.
CONCLUSIONS: This study demonstrated the feasibility of consistently generating sufficient TIL from HNSCC tumors. Results from this study suggest TIL cell therapy may serve as a potential treatment option for patients with HNSCC and support further development, including TIL cell therapy combined with immune checkpoint inhibitors or other agents or with other TIL products.
TRIAL REGISTRATION NUMBER: NCT03083873.}, }
@article {pmid40853264, year = {2025}, author = {Bolier, M and Pluimakers, VG and Broer, L and Neggers, SJ and de Winter, DT and Wang, F and Baedke, JL and Uitterlinden, AG and Petrykey, K and Kremer, LC and Loonen, JJ and Louwerens, M and van der Pal, HJ and Feijen, ELA and Oeffinger, KC and Howell, RM and Chow, EJ and Leisenring, WM and Gramatges, MMM and Morton, LM and Robison, LL and Hudson, MM and Ness, KK and Sapkota, Y and Armstrong, GT and Bhatia, S and Yasui, Y and van den Heuvel-Eibrink, MM}, title = {Genetic Contribution to Treatment-Related Dyslipidemia in Adult Survivors of Childhood Cancer: Findings from the CCSS, SJLIFE, and DCCSS-LATER Cohorts.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0338}, pmid = {40853264}, issn = {1538-7755}, abstract = {BACKGROUND Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication. METHODS Discovery analysis was performed in the Original Childhood Cancer Survivor Study (CCSS) cohort (N=4,332). Replication analyses were carried out in the CCSS Expansion cohort (N=2,212), the St Jude Lifetime Cohort (SJLIFE, N=2,829), and the DCCSS-LATER Cohort (N=1,814). In the CCSS cohorts, dyslipidemia was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 self-reported high cholesterol or high triglycerides, whereas in SJLIFE and DCCSS-LATER, it was assessed by serum lipid measurements. Association analysis was performed in the entire cohort and stratified by cancer treatment. RESULTS The initial discovery analysis yielded one genome-wide significant (p<5x10-8) and 16 suggestive (p<5x10-6) loci associated with dyslipidemia risk. Of these, one genome-wide significant and eight suggestive loci with biological plausibility were selected for replication analysis, but none replicated. Additionally, treatment-stratified analysis revealed six significant (p<5x10-8) loci, none of which replicated in meta-analysis. CONCLUSIONS Further research with clinically assessed data and larger sample sizes is needed to explore the genetic contributions to dyslipidemia risk in childhood cancer survivors. IMPACT The establishment of larger, internationally collaborative consortia of childhood cancer survivors is critical for generating more robust findings, which will help the identification of those survivors at risk for dyslipidemia and subsequently cardiovascular disease.}, }
@article {pmid40850015, year = {2025}, author = {Kenny, A and van Duijn, J and Dintwe, O and Heptinstall, J and Burnham, R and Sawant, S and Zhang, L and Mielke, D and Khuzwayo, S and Omar, FL and Stanfield-Oakley, S and Keyes, T and Dunn, B and Goodman, D and Fong, Y and Benkeser, D and Zou, R and Hural, J and Hyrien, O and Juraska, M and Luedtke, A and van der Laan, L and Giorgi, EE and Magaret, C and Carpp, LN and Pattacini, L and van de Kerkhof, T and Korber, B and Willems, W and Fisher, LH and Schuitemaker, H and Swann, E and Kublin, JG and Pau, MG and Buchbinder, S and Tomaka, F and Nijs, S and Lavreys, L and Gelderblom, HC and Corey, L and Mngadi, K and Gray, GE and Borducchi, E and Hendriks, J and Seaton, KE and Zolla-Pazner, S and Barouch, DH and Ferrari, G and De Rosa, SC and McElrath, MJ and Andersen-Nissen, E and Stieh, DJ and Tomaras, GD and Gilbert, PB and , }, title = {Corrigendum to 'Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study'. EBioMedicine 2024;108: 105320.}, journal = {EBioMedicine}, volume = {119}, number = {}, pages = {105874}, doi = {10.1016/j.ebiom.2025.105874}, pmid = {40850015}, issn = {2352-3964}, }
@article {pmid40849910, year = {2025}, author = {Weis, AM and Bauer, KM and Tang, WW and Stephen-Victor, E and Bell, R and Brown, DG and Ekiz, HA and Tran, V and Klag, KA and Swanson, EA and Barrios, L and Harwood, M and Hill, JH and Ost, KS and Gigic, B and Schneider, M and Ose, J and Hardikar, S and Toriola, AT and Shibata, D and Li, CI and Figueiredo, JC and Byrd, DA and Siegel, EM and Arnolds, K and Lozupone, C and Ulrich, CM and O'Connell, RM and Stephens, WZ and Round, JL}, title = {A capsular polysaccharide from a healthy human microbiota member activates a Lag-3-NK cell axis to restrain colon cancer and augment immunotherapy.}, journal = {Cell reports}, volume = {44}, number = {9}, pages = {116172}, doi = {10.1016/j.celrep.2025.116172}, pmid = {40849910}, issn = {2211-1247}, abstract = {Colorectal cancer (CRC) is increasing globally, making identification of preventative measures necessary. Transplantation of the microbiota from CRC and non-CRC patients into mice demonstrates that non-diseased individuals possess organisms that reduce tumor formation and highlights Bacteriodes uniformis as protective. B. uniformis is reduced in humans with CRC, and proactive treatment with B. uniformis slows tumor growth in mice. Natural killer (NK) cells, but not T cells, are required for B. uniformis-mediated protection. CRC is recalcitrant to immunotherapies; however, addition of B. uniformis restores response to α-CTLA-4 treatment in an NK cell-dependent manner. We report that high Lag-3 expression is associated with greater survival in CRC patients and that B. uniformis-mediated protection is reliant on Lag-3 in innate cells. Induction of NK cell activity and reduced tumor growth is dependent on a specific B. uniformis capsular polysaccharide. Thus, healthy individuals possess tumor suppressor microbes that prevent cancer development and can be harnessed therapeutically.}, }
@article {pmid40849364, year = {2025}, author = {O'Connor, TE and Lin, C and Roloff, GW and Zhang, A and Miller, K and Aldoss, I and Kopmar, NE and Dekker, SE and Gupta, VK and Jeyakumar, N and Muhsen, IN and Valtis, Y and Ahmed, N and Sutherland, K and Dykes, KC and Ahmed, M and Chen, E and Zambrano, H and Bradshaw, D and Mercadal, S and Schwartz, M and Tracy, S and Connor, MP and Kubiak, M and Mukherjee, A and Majhail, N and Battiwalla, M and Mountjoy, L and Malik, SA and Mathews, J and Shaughnessy, P and Blunk, B and Logan, AC and Ladha, A and Advani, AS and Stefan, M and Guzowski, C and Hoeg, RT and Hilal, T and Moore, J and O'Dwyer, KM and Hill, LC and Sasine, J and Oliai, C and Solh, MM and Lee, CJ and Kota, VK and Koura, D and Kumaran, MV and Leonard, JT and Frey, NV and Park, JH and Luskin, MR and Bachanova, V and Galal, A and Pullarkat, V and Bishop, MR and Stock, W and Cassaday, RD and Shah, BD and Faramand, R and Muffly, LS and Tsai, SB and Dholaria, B}, title = {The impact of social determinants of health on outcomes of brexucabtagene autoleucel in adults with relapsed/refractory B-cell acute lymphoblastic leukemia.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40849364}, issn = {1476-5365}, abstract = {Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T (CAR T) cell therapy approved for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We studied the impact of social determinants of health (SDoH) on outcomes of adults with B-ALL receiving brexu-cel. This retrospective analysis included adults (≥18 years) with R/R B-ALL treated with brexu-cel between 2021 and 2023. Cox proportional hazards models evaluated the association of race, ethnicity, and SDoH with progression-free survival (PFS) and overall survival (OS). 189 patients received brexu-cel and 57% were male. 55% were non-Hispanic White, 30% Hispanic, 7% non-Hispanic Black, 6% Asian/Pacific Islander, and 2% other/unknown. 43% were referred from private/community-based practices and 35% lived 50 miles or greater from the CAR T center. Health insurance included public (47%) and private (41%). 31% had a high social deprivation index (SDI, 76-99th percentile). Black race was associated with worse OS (HR 3.48; 95% CI 1.01-12.03). There was no difference in PFS (HR 1.03, 95% CI 0.50-2.10) or OS (HR 1.43; 95% CI 0.56-3.65) in Hispanic patients. Outcomes appear independent of SDoH and SDoH did not impact OS. We observed comparable outcomes to non-Hispanic patients.}, }
@article {pmid40848054, year = {2025}, author = {Yang, J and Roy, I and Hunter, H}, title = {Prehabilitation for muscle wasting in cancer: do definitions matter?.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {9}, pages = {807}, pmid = {40848054}, issn = {1433-7339}, mesh = {Humans ; *Neoplasms/complications ; Quality of Life ; Body Composition ; Frailty/etiology ; *Preoperative Exercise ; *Muscular Atrophy/etiology/rehabilitation ; *Exercise Therapy/methods ; Aged ; }, abstract = {Frailty in older patients with cancer has been associated with functional impairments, decline in quality of life, and increased risk of mortality. There is growing interest in prehabilitation interventions designed to optimize function prior to cancer treatment to mitigate functional decline and to optimize post-treatment outcomes. This review aims to describe the heterogeneity in muscle wasting definitions, modalities used for body composition analysis, and functional outcomes investigated in exercise prehabilitation trials in cancer patients. Defining muscle loss among patients with cancer is needed to better diagnose, treat, and prevent functional decline. Utilization of a consensus on definitions for muscle wasting syndromes is critical to evaluate the efficacy of prehabilitation and exercise interventions in cancer care.}, }
@article {pmid40848024, year = {2025}, author = {Shetty, NS and Gaonkar, M and Pampana, A and Patel, N and Carson, AP and Haring, B and Psaty, BM and Kooperberg, C and Boerwinkle, E and Rotter, JI and Lima, JAC and Kizer, JR and Martin, LW and Taylor, KD and Hall, ME and Fornage, M and Shah, SJ and Rich, SS and Vasan, RS and Nassir, R and Li, P and Arora, G and Arora, P}, title = {Association of Pathogenic/Likely Pathogenic Inherited Cardiomyopathy Variants With Heart Failure: A TOPMed Multiancestry Analysis.}, journal = {Mayo Clinic proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mayocp.2025.01.021}, pmid = {40848024}, issn = {1942-5546}, abstract = {OBJECTIVE: To evaluate the prevalence of pathogenic/likely pathogenic inherited cardiomyopathy variants and their association with heart failure in the (TOPMed) TransOmic for Precision of Medicine cohorts.
METHODS: A retrospective cohort study using the TOPMed cohorts, including multi-ancestry US adults (≥18 years of age) with sequencing data, was conducted. Pathogenic/likely pathogenic inherited cardiomyopathy variant carrier status was determined based on ClinVar variants classified with two or more stars of evidence. Individuals without pathogenic/likely pathogenic variants were used as the reference group. The primary outcome was heart failure , adjudicated by an expert panel. Cox proportional hazards models assessed the association between carrier status and heart failure risk, adjusting for sex, study cohort, coronary artery disease, and genetic ancestry. Age was used as the timescale to account for the effect of variants since birth, and interval censoring was used to handle the uncertainty in the timing of heart failure events.
RESULTS: Among 30,977 individuals (median age, 61.0 years; 71.3% female; 37.0% non-European ancestry), 229 (0.7%) were identified as pathogenic/likely pathogenic inherited cardiomyopathy variant carriers. There were 3,298 events of heart failure (35 in carriers and 3,263 in non-carriers). The heart failure incidence rate was higher in variant carriers (2.06 per 1000 person-years) compared with noncarriers (1.40 per 1000 person-years), with an adjusted hazard ratio of 1.68 (95% CI, 1.29-2.22).
CONCLUSION: Approximately 1 in 140 US adults carry a cardiomyopathy variant, which increases heart failure risk. Targeted genetic screening may facilitate early identification and preventive interventions to reduce heart failure risk in carriers.}, }
@article {pmid40847340, year = {2025}, author = {Vu, K and Sánchez, H and Cabello, R and Hidalgo, J and Dasgupta, S and Duerr, A and Lankowski, A}, title = {Sexual behaviors and access to HIV services during the COVID-19 pandemic among cisgender men who have sex with men in Lima, Peru.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {2888}, pmid = {40847340}, issn = {1471-2458}, support = {NIH U54CA132381//Fred Hutchinson Cancer Center Summer Undergraduate Research Program/ ; D43TW009345/TW/FIC NIH HHS/United States ; NIH P30AI027757//University of Washington / Fred Hutch Center for AIDS Research/ ; K23MH126781/MH/NIMH NIH HHS/United States ; }, abstract = {BACKGROUND: The COVID-19 pandemic significantly impacted sexual behaviors, access to health services, and other factors related to HIV vulnerability among sexual and gender minority populations globally. This study investigates such changes among men who have sex with men (MSM) in Lima, Peru.
METHODS: We analyzed data from a cross-sectional survey that was conducted initially in 2018–2019 (‘pre-pandemic’ period, n = 382) and then repeated in 2020–2021 (‘mid-pandemic’ period, n = 387). The survey asked about participants’ sexual behaviors in the previous three months, including attendance of sex-on-premises venues (SOPVs) and the use of online platforms to meet partners, as well as their knowledge and behaviors related to HIV testing and prevention. We assessed for differences in sexual behaviors and HIV testing/prevention knowledge between the mid-pandemic period and the pre-pandemic period using robust Poisson regression, including in multivariable models adjusting for age and educational attainment. The mid-pandemic survey included additional questions asking about access to HIV services and changes in perceived health status during the pandemic, which we analyzed descriptively.
RESULTS: Participants in the mid-pandemic period were significantly less likely to report they had attended an SOPV, met a sex partner online, engaged in group sex, or had three or more partners in the past three months. However, the prevalence of other HIV-related sexual risk behaviors, including condomless anal sex and substance use in a sexual context, was unchanged compared to pre-pandemic. Among mid-pandemic survey participants, SOPV attendance and meeting a partner online were both associated with a range of sexual risk behaviors, similar to the relationship observed between these behaviors during the pre-pandemic period.
CONCLUSIONS: We observed relatively modest differences in the prevalence of sexual risk behaviors during, versus prior to, the COVID-19 pandemic. These findings underscore the importance of minimizing disruptions to HIV prevention and sexual health services for vulnerable populations such as MSM in Peru.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-23886-8.}, }
@article {pmid40845137, year = {2025}, author = {Nazha, A and Elemento, O and Ahuja, S and Lam, BD and Miles, M and Shouval, R and McWeeney, SK and Sirhan, S and Srisuwananukorn, A and Haferlach, T}, title = {Artificial Intelligence in Hematology.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025029876}, pmid = {40845137}, issn = {1528-0020}, abstract = {Artificial intelligence (AI) and its sub-discipline, machine learning (ML), have the potential to revolutionize healthcare, including hematology. The diagnosis and treatment of hematologic disorders depend on the integration of diverse data sources, such as imaging, pathology, omics, and laboratory parameters. The increasing volume and complexity of patient data have made clinical decision-making more challenging. AI/ML hold significant potential for enhancing diagnostic accuracy, risk stratification, and treatment response prediction through advanced modeling techniques. Generative AI, a recent advancement within the broader field of AI, is poised to have a profound impact on healthcare and hematology. Generative AI can enhance the development of novel therapeutic strategies, improve diagnostic workflows by generating high-fidelity images or pathology reports, and facilitate more personalized approaches to patient management. Its ability to augment clinical decision-making and streamline research represents a significant leap forward in the field. However, despite this potential, few AI/ML tools have been fully implemented in clinical practice due to challenges related to data quality, equity, advanced infrastructure, and the establishment of robust evaluation metrics. Despite its promise, AI implementation in hematology faces critical challenges, including bias, data quality issues, and a lack of regulatory frameworks and safety standards that keep pace with rapid technological advancements. In this review, we provide an overview of the current state of AI/ML in hematology as of 2025, identify existing gaps, and offer insights into future developments.}, }
@article {pmid40844776, year = {2025}, author = {Hill, JA and Pergam, SA and Halasa, NB and Kumar, D and Baden, LR and Boeckh, MJ}, title = {A Network for Advancing Prevention and Treatment of Infections Among Immunocompromised Individuals.}, journal = {JAMA network open}, volume = {8}, number = {8}, pages = {e2528383}, doi = {10.1001/jamanetworkopen.2025.28383}, pmid = {40844776}, issn = {2574-3805}, mesh = {Humans ; *Immunocompromised Host ; United States ; Clinical Trials as Topic ; Public-Private Sector Partnerships ; *Communicable Diseases/therapy ; }, abstract = {IMPORTANCE: Immunocompromised individuals are a large and growing population who are at increased risk for infectious diseases. There has and continues to be a lack of focus on clinical trials to establish the safety and efficacy of therapies for infectious diseases in immunocompromised patients. The establishment of a US-based clinical trial network to improve the study and subsequent implementation of therapies and strategies to treat and prevent infections in immunocompromised individuals would address this gap in research infrastructure and jumpstart public and private investment.
OBSERVATIONS: A national interdisciplinary meeting was convened on September 10, 2024, in Bethesda, Maryland, to discuss the outsized impact of infectious diseases in immunocompromised individuals and to identify the primary gaps and opportunities for clinical trials in this population. Approaches to achieve this goal include obtaining dedicated funding and support through public-private partnerships to establish alignment and feasibility for high-priority areas of research. This article outlines the relevance of this work; ongoing efforts to collaborate with the National Institutes of Health, US Congress, industry, and philanthropy to obtain funding for mutually beneficial outcomes; the network structure; and perspectives from clinicians, regulatory agencies, the pharmaceutical industry, and patients.
CONCLUSIONS AND RELEVANCE: There is a dearth of evidence to support the use of many therapies for infectious diseases in immunocompromised individuals, which has substantial impact at the individual and societal level. A multipronged approach to improve integration of, and funding for, rigorous research in this population into the core priorities of the public and private sectors could address important public health gaps by developing evidence-based guidance to protect a vulnerable community.}, }
@article {pmid40841141, year = {2025}, author = {Ng, N and Molina-Molina, M and Adegunsoye, A and Borie, R and Newton, CA and Raby, B and Zhang, D and Padilla, M and Crestani, B and Horwitz, MS and Keel, S and Murray, MF and Stergachis, AB and Knight, S and Garcia, CK and Wain, LV and Raghu, G}, title = {Genetics of Interstitial Lung Diseases: A State-of-the-Art Review.}, journal = {The European respiratory journal}, volume = {}, number = {}, pages = {}, doi = {10.1183/13993003.00788-2025}, pmid = {40841141}, issn = {1399-3003}, abstract = {Advancements in genetics and genomics continue to further our understanding of their contributions to the development of interstitial lung diseases. This state-of-the-art clinical review synthesizes current knowledge of the contribution of genetics when evaluating patients suspected to have ILD. We consider highly penetrant Mendelian disorders as well as common variants conferring smaller risk that act in concert with other genetic and acquired risk factors. Additionally, gene-by-environment and pharmacogenomic interactions are discussed to highlight their impact on disease course. Lastly, the approach to genetic ILDs is reviewed from available testing to future directions.}, }
@article {pmid40839373, year = {2025}, author = {Ligibel, JA and Ballman, KV and McCall, L and Goodwin, PJ and Alfano, CM and Bernstein, V and Crane, TE and Delahanty, LM and Frank, E and Hahn, O and Hershman, DL and Hopkins, JO and Irwin, M and Mayer, EL and Minasian, L and Nebeling, L and Neuhouser, ML and Paskett, ED and Spears, PA and Stearns, V and Thomson, CA and Weiss, A and White, J and Wadden, TA and Winer, EP and Hudis, C and Partridge, AH and Carey, LA}, title = {Impact of a Weight Loss Intervention on 1-Year Weight Change in Women With Stage II/III Breast Cancer: Secondary Analysis of the Breast Cancer Weight Loss (BWEL) Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {40839373}, issn = {2374-2445}, abstract = {IMPORTANCE: Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population.
OBJECTIVE: To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change.
The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease-free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2-negative breast cancer and a body mass index (BMI) of 27 or higher.
INTERVENTIONS: Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group.
MAIN OUTCOME AND MEASURES: The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status.
RESULTS: A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight (P < .001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities.
CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02750826.}, }
@article {pmid40839355, year = {2025}, author = {McTiernan, A}, title = {Achieving Healthy Weights for Improving Breast Cancer Prognosis.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.2711}, pmid = {40839355}, issn = {2374-2445}, }
@article {pmid40839241, year = {2025}, author = {Lin, CA and Lin, C and Rhodes, CT and Moseley, MC and Wang, Y and Berger, MS}, title = {Takeaways from meta-analysis: indications of combinational treatments for glioblastoma.}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {40839241}, issn = {1573-7373}, support = {P50CA097257//NIH/NCI/ ; }, abstract = {BACKGROUND: Patients with brain cancers are diagnosed based on MRI in the clinical setting while molecular signatures offer potential therapeutic targets. The necessity to re-form molecular and imaging information motivated our meta-analysis to decipher the correlation between the MRI-classified tumor locations, gene expression, and protein signatures in GBM.
METHODS: We analyzed spatial and omics data alongside the assessment of post-translational modifications. We first utilized MRI data to classify GBM into 4 groups. We then integrated imaging groups with RNA-Seq and proteomic data to determine the association between tumor locations, gene signatures, and protein abundance. Furthermore, we scrutinized independent measurements of post-translational modifications in each group of MRI-classified GBM.
RESULTS: The coherent layer of imaging and molecular data collectively showed the dysregulation of cell cycle, ECM organization, immune infiltration or surveillance in all GBM cases regardless of tumor locations. Several neuronal and synaptic-specific genes were differentially altered, indicative of aberrant neuroactivity in GBM. These dysregulated genes and networks provided druggable targets that led to small compounds identification, possessing cytotoxicity against primary GBM and spanning histological boundaries. Our analysis also revealed lesion-specific molecular signatures in each group of GBM, suggesting pathological features uniquely in subgroups of GBM with prognostic or therapeutic potential. Moreover, alterations in post-translational modifications would be noteworthy to explore clinical applications.
CONCLUSIONS: Deliverables from our meta-analysis hold the potential to inform therapeutic intervention. Despite heterogeneity in GBM, our findings implicate new directions of emerging treatments that may be used as concomitants to chemo-, radio- or immunological therapies.}, }
@article {pmid40832333, year = {2025}, author = {Elhaw, AT and Tang, PW and Cheng, YY and Kamlapurkar, S and Javed, Z and Al-Saad, S and White, SR and Abdelnaby, AE and Khan, H and Choi, AS and Cole, AR and Kim, YS and Atiya, HI and Trebak, M and Zervantonakis, I and Buckanovich, RJ and Aird, KM and Coffman, LG and Mythreye, K and Hempel, N}, title = {RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832333}, issn = {2692-8205}, support = {R01 CA230628/CA/NCI NIH HHS/United States ; P50 CA272218/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA242021/CA/NCI NIH HHS/United States ; T32 HL110849/HL/NHLBI NIH HHS/United States ; }, abstract = {All ovarian cancer subtypes spread via transcoelomic metastasis, where cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This represents the main driver of morbidity and mortality for peritoneal cancer patients. Mechanisms necessary for cancer cells to survive matrix detachment and initiate transcoelomic metastasis remain poorly defined. To address this, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived cancer cell lines. RHOV, an atypical, constitutively active and understudied member of the Rho GTPase family, emerged as a top upregulated transcript, which was confirmed in patient ascites-derived tumor cells. Functionally, loss of RHOV impairs anoikis resistance, multicellular aggregate integrity, migration and invasion, and completely abolishes transcoelomic tumor progression in vivo. RHOV enhances c-Jun signaling and cytoskeletal remodeling, which is dependent on both RHOV GTP-binding and membrane localization. These findings define RHOV as a novel detachment-sensitive Rho GTPase and establish RHOV as a critical regulator of peritoneal metastasis for the first time.}, }
@article {pmid40832245, year = {2025}, author = {Furlong, J and Goya, S and Nawrocki, EP and Calhoun, V and Hatcher, E and Yankie, L and Greninger, AL}, title = {Automated Annotation and Validation of Human Respiratory Virus Sequences using VADR.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832245}, issn = {2692-8205}, abstract = {Accurate annotation of viral genomes is essential for reliable downstream analysis and public data sharing. While NCBI's Viral Annotation DefineR (VADR) pipeline provides standardized annotation and quality control, it only supports six viral groups to date. Here, we developed and validated 12 new reference sequence-based VADR models targeting key human respiratory viruses: measles virus, mumps virus, rubella virus, human metapneumovirus, human parainfluenza virus types 1-4, and seasonal coronaviruses (229E, NL63, OC43, HKU1). Model construction was guided by a comprehensive analysis of intra-species genomic and phylogenetic diversity, enabling the development of genotype-specific models associated with reference genomes that defined expected genome structure and annotation. Models were trained on 5,327 publicly available complete viral genomes and tested on 372 viral genomes not yet submitted to GenBank. VADR passed 96.3% of publicly available viral genomes and 98.1% of viral genomes not in the training set, correctly identifying overlapping ORFs, mature peptides, and transcriptional slippage as well as genome misassemblies. VADR detected novel viral biology including the first reported HCoV-OC43 NS2 knockout in a human infection and novel G and SH coding sequence lengths in human metapneumovirus. These VADR models are publicly available and are used by NCBI curators as part of the GenBank submission pipeline, supporting high-quality, scalable viral genome annotation for research and public health.}, }
@article {pmid40838867, year = {2025}, author = {Major, A and Chou, J and Lam, H and Kim, KE and Turcotte, LM and Leisenring, W and Yasui, Y and Neglia, JP and Curry, M and Howell, RM and Oeffinger, KC and Hodgson, D and Nathan, PC and Armstrong, GT and Moskowitz, CS and Henderson, TO}, title = {Mortality after colorectal cancer among survivors of childhood cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf127}, pmid = {40838867}, issn = {1460-2105}, abstract = {Mortality after diagnosis of colorectal subsequent malignant neoplasms (CRC-SMN) among childhood cancer survivors is understudied. Using data from the Childhood Cancer Survivor Study (CCSS) and the Surveillance, Epidemiology, and End Results (SEER) program, we compared all-cause mortality of survivors with CRC-SMN to survivors without CRC-SMN and CRC patients in the general population without a childhood cancer history. Among 25,656 childhood cancer survivors, 96 developed CRC-SMN, with 50% diagnosed before age 40 and 19% before age 30. Of those diagnosed before age 40, 35% had no prior abdominal/pelvic-directed radiation therapy. The cumulative incidence of CRC-SMN in CCSS survivors was 0.7% (95%CI: 0.5%-0.9%) by age 45 and 1.1% (95%CI: 0.8%-1.4%) by age 50. There were 31 deaths after CRC-SMN. Adjusted all-cause mortality was threefold higher (HR 3.34, 95%CI: 2.25-4.59) than for survivors without CRC and significantly higher for survivors diagnosed under age 30 compared to SEER CRC patients (HR 2.51, 95%CI: 1.29-4.89).}, }
@article {pmid40838594, year = {2025}, author = {Ashby, E and Janes, H and Follmann, D and Gilbert, PB and Zhou, H and Wang, X and Girard, B and Priddy, F and Kublin, JG and Corey, L and Neuzil, KM and Baden, LR and El Sahly, HM and Zhang, B and Cove Study Group, OBO}, title = {Validating and leveraging non-SARS-CoV-2 respiratory infection as a negative control outcome in a phase 3 COVID-19 vaccine trial with extended observational follow-up.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaf176}, pmid = {40838594}, issn = {1476-6256}, abstract = {Negative control outcomes (NCOs) are useful tools for hidden bias detection, but empirical evidence validating NCOs for COVID-19 is lacking. To address this gap, we examined the blinded phase of the randomized, placebo-controlled Coronavirus Vaccine Efficacy (COVE; NCT04470427) trial of the mRNA-1273 COVID-19 vaccine. We confirmed that acute respiratory illness with a positive test for a non-SARS-CoV-2 respiratory pathogen on a multiplex PCR panel was a valid NCO for COVID-19, considering that it was unaffected by vaccination (vaccine efficacy, VE=3.3% (95% CI, -22.3-23.6)) yet strongly associated with COVID-19 (odds ratio=2.95 (95% CI, 2.00-4.24)). Subsequently, we leveraged non-SARS-CoV-2 infections to detect bias in time-varying VE estimates from COVE's blinded and booster phases. Balanced incidence of non-SARS-CoV-2 infection between vaccinated and unvaccinated COVID-19-free risk sets suggested low selection bias in VE estimates of two-dose mRNA-1273 against COVID-19 during the blinded phase (VE=92.5% (95% CI, 88.8-94.9) 14 days post-dose-two, stable for 5 months). In COVE's booster phase, higher non-SARS-CoV-2 incidence was observed after the single booster (intensity ratio, IR=2.38 (95% CI, 1.75-3.25) 14 days post-boost), suggesting that booster VE estimates may underestimate the true VE against COVID-19. Our findings demonstrate the potential of off-target infections for unraveling complex biases in COVID-19 vaccine studies.}, }
@article {pmid40838528, year = {2025}, author = {Melchio, M and Hill, JA and Shah, M and Neofytos, D and Gambella, M and Raiola, AM and Delfino, E and Balletto, E and Angelucci, E and Bassetti, M and Mikulska, M}, title = {Old Pathogens-New Patient Types: Infections in a CAR T-Cell Recipient. Could It Get Any More Complicated?.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70093}, doi = {10.1111/tid.70093}, pmid = {40838528}, issn = {1399-3062}, abstract = {The case discussed involves a 41-year-old Italian man who was a candidate for chimeric antigen receptor T-cell therapy (CAR-T) for mediastinal diffuse large B-cell lymphoma. His CAR-T treatment was postponed several times due to prolonged relapsing COVID-19 and new onset of pulmonary Mycobacterium tuberculosis diseases. After 11 weeks of antimycobacterial treatment, CAR T-cell therapy was performed, but complicated by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Two months after CAR-T, the patient developed invasive pulmonary aspergillosis due to A. fumigatus. He was successfully treated with a 6-month course of antitubercular therapy and an 8-month course of antifungal therapy with isavuconazole. Lobectomy was performed due to episodes of severe hemoptysis. The challenging issues of diagnosis, choice, and management of treatments, including drug-drug interactions and length of therapy, are discussed.}, }
@article {pmid40838500, year = {2025}, author = {Ogimi, C and Waghmare, A}, title = {Risk Stratification for Seasonal Coronavirus Infections in HCT Recipients: Advances and Challenges.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70096}, doi = {10.1111/tid.70096}, pmid = {40838500}, issn = {1399-3062}, }
@article {pmid40835749, year = {2025}, author = {Zhao, LP and Papadopoulos, GK and McFarland, BJ and Skyler, JS and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, Å}, title = {Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.}, journal = {Diabetologia}, volume = {}, number = {}, pages = {}, pmid = {40835749}, issn = {1432-0428}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; }, abstract = {AIMS/HYPOTHESIS: The aim of this work was to explore associations between type 1 diabetes progression from stages 1 or 2 to stage 3 and interacting ligand-receptor complexes of HLA class I (HLA-I) and KIR gene products.
METHODS: Applying next-generation sequencing technology to genotype HLA-I genes (HLA-A, -B, -C) and KIR genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1) from 1215 participants in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07), we systematically explored associations of HLA-I-KIR ligand-receptor interactions (LRIs) with disease progression via a Cox regression model. We investigated the structural properties of identified LRI complexes.
RESULTS: KIR and HLA-I genes had no or sporadic associations with disease progression. Out of all possible LRIs, nine HLA-A ligands and 14 HLA-B ligands with corresponding receptors had modest associations with progression (p<0.05). As an example, carriers of A*03:01-KIR2DS4 had slower progression (HR 0.36, p=3.06 × 10[-2]), as did B*07:02-KIR2DL3 carriers (HR 0.26, p=7.76 × 10[-3]). Structural investigations of KIR-HLA-I complexes via homology modelling based on already-solved respective complex structures suggested that the respective electrostatic and van der Waals interactions encoded in the protein sequences result in strong biophysical LRIs, which could alter the progression of type 1 diabetes.
CONCLUSIONS/INTERPRETATION: These results reveal that LRIs of KIR-HLA-I gene products, rather than individual genes, contribute to type 1 diabetes progression, and such interactions are likely to be stabilised by electrostatic and van der Waals forces. As the KIR-HLA-I interactions involve part of the C-terminus of the antigen-binding groove of HLA-I, but may be affected by the respective bound peptide, this suggests a new mechanism for type 1 diabetes pathogenesis.
DATA AVAILABILITY: Clinical data on participants in DPT-1 and TN07 can be obtained from the NIDDK-Central Repository (https://repository.niddk.nih.gov/home) following the formal approval process.}, }
@article {pmid40835222, year = {2025}, author = {Christopher, CN and Evenson, KR and Howard, AG and Cuthbertson, CC and Di, C and Dieli-Conwright, CM and Eaton, CB and LaCroix, AZ and Lee, IM}, title = {Association of Self-Reported Walking Pace With Cancer Incidence and Mortality: The Women's Health Accelerometry Collaboration.}, journal = {Journal of physical activity & health}, volume = {}, number = {}, pages = {1-8}, doi = {10.1123/jpah.2024-0839}, pmid = {40835222}, issn = {1543-5474}, abstract = {BACKGROUND: While the health benefits of walking are well-established, it is not clear if walking pace is associated with cancer-related outcomes.
PURPOSE: To investigate associations of self-reported walking pace with cancer incidence and mortality among women 62-99 years of age in the Women's Health Accelerometry Collaboration.
METHODS: Women self-reported walking pace, classified as brisk (≥3 mph), average (2-2.9 mph), casual (<2 mph), or does not walk regularly, and were followed for cancer outcomes. Multivariable stratified Cox proportional hazards models estimated hazard ratios and 95% confidence intervals.
RESULTS: There were 22,358 women in the analytic sample. During a mean 8.0 years of follow-up, 1891 women developed cancer (n = 615 cancer deaths). Self-reported walking paces were not associated with all site cancer incidence (compared with a brisk walking pace: average walking pace hazard ratio, 1.08 (95% confidence interval, 0.95-1.23); casual walking pace, 1.15 (0.97-1.33), and does not walk regularly 1.14 (0.97-1.34) nor cancer mortality (average walking pace, 0.97 [0.76-1.25], casual walking pace, 0.98 [0.74-1.30], and does not walk regularly 1.20 [0.90-1.60]). Findings were similar when colon, endometrial, and lung cancer were examined, separately. However, casual walking pace was associated with a higher risk of a composite of inactivity-related cancers (1.21 [1.00-1.47]), and breast cancer (1.40 [1.09-1.80]) compared with a brisk walking pace.
CONCLUSIONS: Slower, compared with faster, self-reported walking paces may be related to a higher risk of some cancers in postmenopausal women. Future research is needed to confirm these findings and investigate mechanisms underlying the associations of walking pace with these cancers.}, }
@article {pmid40833999, year = {2025}, author = {Singal, AG and Quirk, L and Boike, J and Chernyak, V and Feng, Z and Giamarqo, G and Kanwal, F and Ioannou, GN and Manes, S and Marrero, JA and Mehta, N and Pillai, A and Shaheen, NJ and Shaukat, A and Sirlin, CB and Verna, E and Wani, S and Wilson Woods, A and Yang, JD and Parikh, ND}, title = {Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified Delphi panel.}, journal = {Hepatology (Baltimore, Md.)}, volume = {82}, number = {3}, pages = {794-809}, pmid = {40833999}, issn = {1527-3350}, mesh = {Humans ; *Liver Neoplasms/diagnosis/prevention & control ; Delphi Technique ; *Carcinoma, Hepatocellular/diagnosis/prevention & control ; *Early Detection of Cancer/methods ; Population Surveillance/methods ; }, abstract = {HCC surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The experts had high agreement on 21 statements about primary prevention, HCC surveillance benefits, HCC surveillance harms, and the evaluation of emerging surveillance modalities. The experts agreed that current data have methodologic limitations as well as unclear generalizability to Western populations. Although a randomized clinical trial of surveillance versus no surveillance is unlikely feasible, they concurred that alternative designs, such as a comparison of 2 surveillance modalities, could provide indirect evidence of surveillance efficacy. The panel acknowledged the presence of surveillance harms, but concurred the overall value of surveillance appears high, particularly given a greater emphasis on benefits over harms by both patients and clinicians. The experts underscored the importance of a framework for measuring both benefits and harms when evaluating emerging surveillance strategies. The panel acknowledged performance metrics of emerging methods may differ from other cancer screening programs given differences in populations, including higher risk of cancer development and competing risk of morality, and differences in diagnostic workflow in patients at risk of HCC. These data provide insights into the perceived value of HCC surveillance in an era of emerging blood- and imaging-based surveillance strategies.}, }
@article {pmid40833820, year = {2025}, author = {Beydoun, HA and Manson, JE and Beydoun, MA and Tsai, J and Shadyab, AH and Jung, SY and Liu, S and Allison, M and Ikramuddin, F and Mouton, CP and Nuño, T and Zonderman, AB and Tinker, LF}, title = {SARS-CoV-2 Positivity, Indicators of COVID-19 Severity, COVID-19 Hospitalization, and Diabetes Risk in the Women's Health Initiative.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1177/15409996251369820}, pmid = {40833820}, issn = {1931-843X}, abstract = {Objective: To examine prospective associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity, coronavirus disease 2019 (COVID-2019) symptom severity, and COVID-2019 hospitalization with incident clinical diabetes among aging women. Methods: A cohort study was conducted using data from 34,405 eligible Women's Health Initiative participants who completed ≥1 COVID-2019 surveys (Survey 1: June-December 2020; Survey 2: June 2021-February 2022) and were followed up for an average of 1.86 (±0.49) years, yielding 399 incident diabetes cases. Results: SARS-CoV-2 test positivity was associated with diabetes risk in the age-adjusted Cox regression model (hazard ratio [HR] = 1.76, 95% confidence interval [CI]: 1.10, 2.82), but not when fully adjusted (HR = 1.43, 95% CI: 0.88, 2.31). Diabetes risk was higher among those with 1-2 COVID-19 symptoms (HR = 1.39, 95% CI: 1.09, 1.77) and those with 3± COVID-2019 symptoms (HR = 1.53, 95% CI: 1.06, 2.22) compared with those without COVID-2019 symptoms in fully-adjusted models, irrespective of self-reported SARS-CoV-2 testing. COVID-2019 hospitalization was associated with 2-3 times the risk of clinical diabetes in age-adjusted (HR = 2.95, 95% CI: 1.52, 5.72) and fully-adjusted (HR = 1.90, 95% CI: 0.97, 3.72) models. Conclusions: Age-adjusted self-reported SARS-CoV-2 test positivity was associated with a higher incidence of diabetes. Reporting of COVID-2019 symptoms and being hospitalized for COVID-2019 were each associated with higher incidence of diabetes in aging women, after controlling for demographic, socioeconomic, lifestyle, and health characteristics.}, }
@article {pmid40791471, year = {2025}, author = {Skeate, JG and Slipek, NJ and Lahr, WS and Roy, S and Wick, BJ and Stelljes, EM and Gilkey, AK and Thenge, PP and Diers, MD and Kar, B and Krueger, JB and Niemeyer, EM and Lonetree, CL and Kluesner, MG and Bell, JB and Clement, K and Provenzano, P and Moriarity, BS and Webber, BR}, title = {A Singular Base Editing Platform for Polyfunctional Multiplex Engineering of Immune Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40791471}, issn = {2692-8205}, abstract = {Current methods to engineer antigen-specific receptors rely on randomly integrating vectors or double-strand break induced targeted integration, both of which pose safety risks. To implement an all-in-one tool for multiplex knockout (KO) and knock in (KI), we expand the use of cytosine and adenine base editor (ABE) nickase activity to stimulate homology-directed repair (HDR) and insert clinically relevant chimeric antigen receptors (CARs) into specific loci. Through a novel sgRNA design strategy and a recombinant adeno-associated virus (rAAV) delivered DNA template, we enhanced the efficiency of ABE8e-stimulated HDR in human T cells. By combining KI of CD19-, CD33-, or mesothelin-targeting CARs with >95% quadplex gene KO (B2M/CD3ε/PDCD1/CISH), we achieve single-step generation of highly functional off-the-shelf CAR T cell products with enhanced function. Importantly, we found no detectable translocations or significant off-target edits and demonstrated efficacy against multiple cancer lines, and a suppressive 3D spheroid culture model. This efficient engineering process of Iterative Nicking for Synchronous Engineered Reprogramming of T cells (INSERT) establishes a safe, simplified platform for advanced therapeutic CAR T engineering.}, }
@article {pmid40833763, year = {2025}, author = {Childers, CP and Selzer, DJ and Green, ML and Sutherland, MJ and Senkowski, CK and Mabry, CD}, title = {Generating a New CPT Code Set for Adult and Pediatric Appendectomy.}, journal = {JAMA surgery}, volume = {}, number = {}, pages = {}, pmid = {40833763}, issn = {2168-6262}, abstract = {IMPORTANCE: There are 3 Current Procedural Terminology (CPT) codes for appendectomy-2 codes describing open appendectomy with or without peritonitis or abscess and 1 code for laparoscopic appendectomy regardless of presentation-which have remained the same for more than 30 years. It is possible that physician work (assessed in work relative value units) for these codes will eventually need to be reassessed, and this study may provide an opportunity for modernizing the CPT codes and their descriptions.
OBJECTIVE: To provide empirical data to determine what a new code structure for appendectomy could look like.
This cross-sectional study performed a retrospective review of 2021-2023 US National Surgical Quality Improvement Program (NSQIP) adult and pediatric appendectomy-specific files among adults and children undergoing appendectomy. Data analysis was completed in May 2025.
MAIN OUTCOME AND MEASURES: We sought to identify distinct populations of patients that require different levels of surgeon work, which we measured using operative time, postoperative length of stay, and rates of complications.
RESULTS: The final sample included 110 379 encounters for appendectomy. Approximately one-quarter (28 583 [25.9%]) had complicated disease; only 3057 cases (2.8%) were performed open. Compared to uncomplicated appendicitis in children and adults (aged 6-64 years), we found the following factors were significantly associated with changes (generally increases) in surgeon work using our measures: complicated disease, age 5 years or younger and 65 years or older, and whether the procedure was for interval appendectomy or performed for tumor. Based on these stratifying variables, we propose 16 new codes-8 laparoscopic and 8 open-that identify unique populations of patients undergoing appendectomy with different work profiles.
CONCLUSIONS AND RELEVANCE: In this cross-sectional study, we provide the first empirical strategy for identifying new codes for appendectomy using objective measures of surgeon work. If appendectomy ever undergoes review of its relative work, this study provides a potential framework for improving the CPT codes and describing the nuances of appendectomy in the modern era.}, }
@article {pmid40831667, year = {2025}, author = {Gross, ME and Pike, M and Alson, J and Williams, P and Wood, ME and Marsh, E and Carey, E and Stürmer, T and Katz, R and Robinson, WR and Doll, KM}, title = {Risk factors for delayed diagnosis of endometrial cancer among black individuals: Results from the GUIDE-EC study.}, journal = {Gynecologic oncology reports}, volume = {60}, number = {}, pages = {101922}, pmid = {40831667}, issn = {2352-5789}, abstract = {OBJECTIVE: Black patients with endometrial cancer (EC) experience disproportionately advanced stage at diagnosis. We aimed to identify variables, beyond race and histologic subtype, which increase risk for delayed diagnosis of EC.
METHODS: This is a retrospective study of Black individuals with EC in a large academic-affiliated healthcare system from 2014 to 2020. Primary outcome was delayed diagnosis of EC, defined as prolonged time to diagnosis (>28 days to reach diagnosis). We used descriptive statistics, univariate regression, and factor analysis to identify variables associated with delayed diagnosis, achieve data reduction, and calculate odds ratios for delayed diagnosis.
RESULTS: Of 388 patients with EC included for analysis, one fifth (n = 79, 20 %) experienced delayed diagnosis. Ultrasound had the strongest association with delayed diagnosis in univariate regression (OR 4.4, 95 % CI 2.4, 7.8) and factor analysis (OR 2.2, 95 % CI 1.6, 3.0). BMI ≥ 40 (OR 1.9, 95 % CI 1.1, 3.3) was also associated with delayed diagnosis. Age ≥ 50 was associated with decreased odds of delayed diagnosis (OR 0.3, 95 % CI 0.2, 0.7). Presence of an endometrial biopsy was associated with decreased odds of delayed diagnosis on univariate regression (OR 0.4, 95 % CI 0.2, 1.4).
CONCLUSIONS: A fifth of Black patients with EC experienced delayed diagnosis, and preoperative ultrasound was most strongly associated with delayed diagnosis. Providers should consider a tissue-sampling-first approach in Black patients at risk for EC.}, }
@article {pmid40829965, year = {2025}, author = {Gustav, M and van Treeck, M and Reitsam, NG and Carrero, ZI and Loeffler, CML and Rabasco Meneghetti, A and Märkl, B and Boardman, LA and French, AJ and Goode, EL and Gsur, A and Brezina, S and Gunter, MJ and Murphy, N and Hönscheid, P and Sperling, C and Foersch, S and Steinfelder, R and Harrison, T and Peters, U and Phipps, A and Kather, JN}, title = {Assessing genotype-phenotype correlations in colorectal cancer with deep learning: a multicentre cohort study.}, journal = {The Lancet. Digital health}, volume = {}, number = {}, pages = {100891}, doi = {10.1016/j.landig.2025.100891}, pmid = {40829965}, issn = {2589-7500}, abstract = {BACKGROUND: Deep learning-based models enable the prediction of molecular biomarkers from histopathology slides of colorectal cancer stained with haematoxylin and eosin; however, few studies have assessed prediction targets beyond microsatellite instability (MSI), BRAF, and KRAS systematically. We aimed to develop and validate a multi-target model based on deep learning for the simultaneous prediction of numerous genetic alterations and their associated phenotypes in colorectal cancer.
METHODS: In this multicentre cohort study, tissue samples from patients with colorectal cancer were obtained by surgical resection and stained with haematoxylin and eosin. These samples were then digitised into whole-slide images and used to train and test a transformer-based deep learning algorithm for biomarker detection to simultaneously predict multiple genetic alterations and provide heatmap explanations. The primary dataset comprised 1376 patients from five cohorts who underwent comprehensive panel sequencing, with an additional 536 patients from two public datasets for validation. We compared the model's performance against conventional single-target models and examined the co-occurrence of alterations and shared morphology.
FINDINGS: The multi-target model was able to predict numerous biomarkers from pathology slides, matching and partly exceeding single-target transformers. In the primary external validation cohorts, mean area under the receiver operating characteristic curve (AUROC) for the multi-target transformer was 0·78 (SD 0·01) for BRAF, 0·88 (0·01) for hypermutation, 0·93 (0·01) for MSI, and 0·86 (0·01) for RNF43; predictive performance was consistent across metrics and supported by co-occurrence analyses. However, biomarkers with high AUROCs largely correlated with MSI, with model predictions depending considerably on morphology associated with MSI at pathological examination.
INTERPRETATION: By use of morphology associated with MSI and more subtle biomarker-specific patterns within a shared phenotype, the multi-target transformers efficiently predicted biomarker status for diverse genetic alterations in colorectal cancer from slides stained with haematoxylin and eosin. These results highlight the importance of considering mutational co-occurrence and common morphology in biomarker research based on deep learning. Our validated and scalable model could support extension to other cancers and large, diverse cohorts, potentially facilitating cost-effective pre-screening and streamlined diagnostics in precision oncology.
FUNDING: German Federal Ministry of Health, Max-Eder-Programme of German Cancer Aid, German Federal Ministry of Education and Research, German Academic Exchange Service, and the EU.}, }
@article {pmid40829964, year = {2025}, author = {Maughan, BL and Dyrskjøt, L and Grivas, P and Alcaraz, A and Antonarakis, ES and Bilen, MA and Bivalacqua, T and Cooperberg, MR and Cheng, L and Gupta, S}, title = {The Role of Liquid Biopsy in the Management of Patients with Genitourinary Malignancies.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.07.016}, pmid = {40829964}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Liquid biopsy testing refers to the use of specific analytical methods to detect disease-related biomarkers in blood or its components. These tests can be either qualitative or quantitative. Liquid biopsy testing is increasingly used in patient care. Here, we explore all the current Food and Drug Administration (FDA)-approved indications for liquid biopsies related to genitourinary oncology. The secondary objective is to describe a few other potential uses of this technology that may become approved soon.
METHODS: We conducted a systematic review of all FDA approvals from 2015 through 2025. We interrogated multiple FDA databases to capture both tumor-specific and tissue-agnostic approvals. We limited the search to indications related to or requiring biomarker testing to assess the value of liquid biopsy testing. A total of 1119 approvals were identified. Of these, nine unique drug approvals related to genitourinary cancers require molecular testing. We then identified the registrational trials used for those approvals through PubMed and present the results here. For the secondary endpoints, we identified examples published within the past 10 yr.
KEY FINDINGS AND LIMITATIONS: The current use for liquid biopsy testing based on regulatory approval is for predicting treatment response. There are nine FDA-approved drugs or drug combinations applicable to clinical practice for patients with genitourinary malignancies. Liquid biopsy testing is currently available to identify patients for most of these indications. We highlight the limitations associated with current liquid biopsy testing.
Currently, there are multiple clinical indications for liquid biopsy in routine clinical practice. These FDA-approved indications can significantly improve the outcomes for biomarker-selected patients. All providers treating patients with a genitourinary malignancy are encouraged to use these tools regularly when indicated to improve patient care. Additional applications are expected to become available for routine clinical use in the future.}, }
@article {pmid40829691, year = {2025}, author = {Schaefer, DA and Longley, RM and Wolfe, ED and Keane, EP and Larizza, IS and Boardman, AC and Rosenberg, J and Mate-Kole, M and Waldman, LP and Majhail, N and Lee, SJ and Khera, N and Amonoo, HL}, title = {Financial toxicity, psychological well-being, and quality of life in hematopoietic stem cell transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.08.012}, pmid = {40829691}, issn = {2666-6367}, abstract = {BACKGROUND: Financial toxicity is a well-documented consequence of cancer care and may disproportionately impact patients with hematologic malignancies due to high cost and intensity of hematopoietic stem cell transplant (HSCT). This population is particularly vulnerable to the psychological consequences of financial toxicity; however, the longitudinal relationship between financial toxicity and psychological well-being-particularly positive psychological well-being-remains understudied.
OBJECTIVE: To assess longitudinal associations between financial toxicity and patient-reported psychological distress (anxiety, depression, and post-traumatic stress disorder [PTSD] symptoms), positive psychological well-being (PPWB), coping, and quality of life (QOL) in patients with hematologic malignancies who received allogeneic HSCT.
STUDY DESIGN: We conducted a secondary analysis of prospective longitudinal data from 150 adult allogeneic HSCT recipients to examine the associations between financial toxicity and patient-reported psychological distress, PPWB, coping, and QOL in allogeneic HSCT survivors. Financial toxicity was measured using the Comprehensive Score for Financial Toxicity. Patient-reported psychological distress was assessed with the Hospital Anxiety and Depression Scale and the PTSD Checklist. PPWB was measured using the Revised Life Orientation Test, Positive and Negative Affect Scale, Flourishing Scale, and Satisfaction with Life Scale. Coping was assessed using the Brief-COPE, and QOL with the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. We fitted a mixed-effects model for each outcome, adjusting for age, employment status, income, type of transplant, and transplant setting.
RESULTS: Among 150 participants (58.7% men; 94.6% non-Hispanic/Latino; 92.0% White; mean age 57.5 years [SD 13.5]), adjusted mixed-effects models indicated that lower financial toxicity was associated with lower anxiety (β=-0.104; p<0.001), lower depression (β=-0.117; p<0.001), and fewer PTSD symptoms (β=-0.280; p<0.001). Lower financial toxicity was also associated with higher optimism (β=0.112; p<0.001), positive affect (β=0.197; p<0.001), flourishing (β=0.201; p<0.001), and life satisfaction (β=0.181; p<0.001), as well as lower avoidant coping (β=-0.043; p<0.001) and improved quality of life (β=0.596; p<0.001).
CONCLUSION: Lower financial toxicity was significantly associated with improved psychological distress (anxiety, depression, and PTSD symptoms), positive psychological well-being (optimism, positive affect, flourishing, and satisfaction with life), avoidant coping, and QOL in allogeneic HSCT survivors. These findings suggest that supportive interventions targeting financial toxicity in the HSCT population have the potential to impact psychological well-being, coping, and QOL, warranting further study.}, }
@article {pmid40829344, year = {2025}, author = {Gaspar-Maia, A and Sasamoto, N}, title = {Prevention, early detection & interception: 15th biennial ovarian cancer research symposium.}, journal = {Gynecologic oncology}, volume = {201}, number = {}, pages = {83-85}, doi = {10.1016/j.ygyno.2025.08.012}, pmid = {40829344}, issn = {1095-6859}, abstract = {This article summarizes the key findings presented in the Prevention, Early Detection, & Interception Session at 15th Biennial Ovarian Cancer Research Symposium organized by the Rivkin Center for Ovarian Cancer and American Association for Cancer Research on September 20-21st in Seattle, Washington. The wide range of topics covered in this session included prevention, early detection, and its interception in basic science, clinical science, and population science. More specifically, risk-reducing salpingo-oophorectomy in women at high-risk of ovarian cancer, biology of early progression, mechanisms involved in the transition from precursor lesion to high grade serous ovarian cancer, population-based studies on prevention, and early detection biomarkers of ovarian cancer were discussed.}, }
@article {pmid40829117, year = {2025}, author = {Naik, S and Aplenc, R and Baumeister, SHC and Becilli, M and Bhagwat, AS and Bonifant, CL and Budde, LE and Chien, CD and Curran, KJ and Daniyan, AF and Dreyzin, A and Gardner, RA and Ghorashian, S and Gottschalk, S and Hill, LC and Kohler, ME and Lamble, AJ and Locatelli, F and Mamonkin, M and Omer, B and Park, JH and Quintarelli, C and Rambaldi, B and Richards, RM and Sallman, DA and Sauer, T and Shah, NN and Subklewe, M and Summers, C and Tasian, SK and Taylor, N and Tettamanti, S and Verneris, MR and Velasquez, MP and Gill, SI}, title = {International Consensus Guidelines for the Conduct and Reporting of CAR T-Cell Clinical Trials in AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017011}, pmid = {40829117}, issn = {2473-9537}, abstract = {Early clinical experience with the use of chimeric antigen receptor (CAR)-T cell therapies for patients with acute myeloid leukemia (AML) has been beset by high rates of toxicities and low rates of response. We convened an international workshop with the goal of bringing investigators in the field of AML-directed CAR-T cell therapy together to facilitate discussion of roadblocks and to brainstorm potential solutions. Based on discussions at the workshop, it was evident (i) that treating and targeting AML with CAR-T cells is associated with unique clinical challenges, and (ii) that variability in clinical trial design, definitions of toxicities, correlative data collection, and reporting methods hinders the field's ability to compare study outcomes and to develop best practices. Further, details of fundamental CAR-T cell attributes and key correlates of efficacy and toxicity were not uniformly reported in published studies, limiting understanding of barriers to success. These observations led to a concerted team effort in which experts in basic/translational science and clinical investigation from pediatric and adult centers worked together to streamline key attributes of clinical trial design and reporting. Consensus criteria were discussed and agreed upon leading to the creation of a white paper. These guidelines aim to bolster the overall quality of AML-directed CAR-T cell research, allow for comparisons across trials and to inform the next phase of development of AML-directed CAR-T cell therapies that we hope will improve patient outcomes.}, }
@article {pmid40829104, year = {2025}, author = {Tam, CS and Anderson, MA and Simkovic, M and Ghia, P and Flinn, IW and Laribi, K and Opat, SS and Cull, G and Munir, T and Österborg, A and Tedeschi, A and Wang, MY and Szeto, AH and Allewelt, H and Salmi, T and Li, J and Xu, L and Wu, K and Vezan, R and Shadman, M and Brown, JR}, title = {Zanubrutinib in the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025015986}, pmid = {40829104}, issn = {2473-9537}, abstract = {Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N=301; n=132, treatment-naive; n=169, relapsed/refractory), data from SEQUOIA (phase 3; treatment-naive; zanubrutinib; NCT03336333), ALPINE (phase 3; relapsed/refractory; zanubrutinib versus ibrutinib; NCT03734016) and AU-003 (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n=127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n=75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among zanubrutinib-treated patients and 38.5% among ibrutinib-treated patients, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n=24; median follow-up, 69.6 months), 10/24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% CI: 95.2-98.8), in ALPINE was 89.3% (95% CI: 80.1-95.3) with zanubrutinib versus 76.0% (95% CI, 64.7-85.1%) with ibrutinib. Responses deepened over time in both treatment-naive and relapsed/refractory populations. The most frequent non-hematologic treatment-emergent adverse events occurring in >20% zanubrutinib-treated patients with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and relapsed/refractory settings.}, }
@article {pmid40828791, year = {2025}, author = {Maenetje, N and Oladimeji, M and Mlotshwa, M and Hoft, D and Lindan, C and Wallis, R and Charalambous, S and Churchyard, G and Edward, V and Fiore-Gartland, A and Shai, J and Maenetje, P}, title = {Epidemiological factors associated with immunological resistance in household contacts exposed to active tuberculosis in South Africa: A logistic regression analysis.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0329562}, pmid = {40828791}, issn = {1932-6203}, abstract = {INTRODUCTION: Studying individuals who do not get infected with tuberculosis (TB) despite being persistently exposed to infectious TB may enable us to identify TB protective mechanisms.
METHODS: Between Apr 2015 and Apr 2017, we recruited adult household contacts (HHCs) of index TB cases (GeneXpert and sputum smear-positive) in Rustenburg, South Africa. HIV-uninfected HHCs who tested positive on both Tuberculin Skin Test (TST) and QuantiFERON-TB Gold In-tube (QFT) were defined as having latent TB infection (QFT + TST+), and those who tested double negative (QFT-TST-) were defined as uninfected with TB. The level of risk for TB infection was evaluated using an epidemiologic risk score. We compared epidemiological and clinical characteristics between the groups and used logic regression to identify factors associated with being QFT-TST-.
RESULTS: Of the 235 household contacts screened, 109 (46.3%) were QFT + TST + , 46 (19.5%) were TST-QFT-, 73 (30.1%) had discordant results, and 7 (2.9%) were excluded based on being HIV positive, already having active TB disease or had missing QFT/TST results. After 3 months, 27 (58.6%) of HHCs remained persistently negative. Younger age, higher number of household windows and habitable rooms, and relations with the index case were independently associated with being QFT-TST-. In the multivariable analysis, younger age (OR: 2.81, 95% CI, 1.23-6.47) and living in homes with more rooms (OR: 4.62, 95% CI, 1.81-11.79) remained associated with being QFT-TST-. We found no association between QFT-TST- and factors such as time spent with the index case, type of house, number of household occupants, or the risk score.
CONCLUSION: Our findings that both younger age and larger living quarters were associated with QFT-TST- status may suggest reduced exposure to TB. We found no association between the epidemiological TB risk score consisting of multiple TB infection risk factors and QFT-TST- status, suggesting other factors may play a role in remaining TB uninfected despite exposure.}, }
@article {pmid40827718, year = {2025}, author = {Lindsay, J and Zamora, D}, title = {Mortality Associated With Cytomegalovirus Reactivation After Umbilical Cord Blood HCT.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70091}, doi = {10.1111/tid.70091}, pmid = {40827718}, issn = {1399-3062}, support = {//National Institute of Allergy and Infectious Diseases/ ; T32AI118690/GF/NIH HHS/United States ; K23AI163343/GF/NIH HHS/United States ; }, }
@article {pmid40826184, year = {2025}, author = {Tran, DT and Jin, R and Zhu, H and Schmidt, G and Spellman, SR and Ballen, KK}, title = {Real-world graft utilization after CTN-1101: a registry-based analysis of haploidentical graft versus umbilical cord blood trends.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40826184}, issn = {1476-5365}, support = {U24CA076518//U.S. Department of Health & Human Services | U.S. Public Health Service (United States Public Health Service)/ ; U24CA076518//U.S. Department of Health & Human Services | U.S. Public Health Service (United States Public Health Service)/ ; }, abstract = {Randomized clinical trials are expensive and not always practice changing. The Blood and Marrow Transplant Clinical Trials Network (CTN) 1101 trial (2012-2018) showed a lower two-year overall survival after umbilical cord blood (UCB) compared to haploidentical graft (haplo) transplants. To quantify the change in graft utilization after the trial's publication, a cohort of 11,190 U.S. adult HCT recipients selected with inclusion/exclusion criteria similar to CTN-1101's were analyzed across three time periods: 2010-2012 (pre-study), 2013-2018 (during-study), and 2019-2022 (post-study). We found a significant increase in haplo utilization compared to UCB, with the trend beginning around 2013. Compared to non-Hispanic White, Black recipients were more likely to receive haplo, Asian recipients were less likely, and Hispanic recipients had similar rates. We also expanded our analyses to 61,465 patients to assess haplo and UCB utilization compared to other allogeneic donors. In this cohort, utilization of alternative donor grafts increased when compared to HLA-matched related or unrelated donor grafts for Black, Hispanic, and Asian recipients. Our findings demonstrate practice change toward haplo transplants had begun before the CTN-1101 trial's publication and continued to significantly increase afterward. HLA-mismatched donors are vital alternative graft sources, allowing patients of all backgrounds to receive HCT.}, }
@article {pmid40824476, year = {2025}, author = {Jones, SMW and Kent, EE and Caru, M and Arem, H and Kim, Y and Song, L and Langer, SL}, title = {Educational Targets for Patient-Reported Outcomes and Caregiver-Reported Outcomes in Psycho-oncology Research.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40824476}, issn = {1543-0154}, abstract = {Patient-reported outcomes (PROs) and caregiver-reported outcomes (CROs) are tools for evaluating behavioral medicine interventions and for bringing the patient voice into observational research. This study aimed to identify barriers to using PROs/CROs in behavioral cancer research and to equitably address those barriers. Forty-nine members of a cancer special interest group from a research society completed surveys in early 2023 about needs related to the use of PROs and CROs. Descriptive statistics were used to summarize results. Most participants used PROs (n = 34, 69%) but few frequently used CROs (n = 12, 24%). More than 80% of the sample were familiar with common PRO/CRO properties such as reliability and validity. Participants reported considering a wide variety of population characteristics when using PROs and CROs, including language (n = 31, 70%) and education level (n = 31, 70%). The most common barriers to using PROs/CROs in research were time, funding, and technology with many reflecting potential reasons for inequitable representation of certain groups in research. Webinars were the most preferred educational format (n = 38, 78%) for resources related to PROs/CROs. Many participants encountered barriers to using PROs in research. Creation and dissemination of educational resources to promote equitable use of PROs/CROs across underrepresented groups and overcome common barriers to use of these measurement tools are warranted.}, }
@article {pmid40778152, year = {2025}, author = {Huerta-Chagoya, A and Kim, J and Mandla, R and Lu, Y and Suzuki, K and Petty, LE and Ng, HK and Choi, J and Lee, S and Rout, M and Lin, K and Adair, LS and Adeyemo, A and Ahsan, H and Akiyama, M and An, P and Anand, SS and Becker, DM and Bertoni, AG and Bian, Z and Bielak, LF and Blangero, J and Boehnke, M and Bottinger, EP and Bowden, DW and Bragg, F and Brody, JA and Buchanan, TA and Cade, BE and Chai, JF and Chambers, JC and Chandak, GR and Chang, LC and Chang, KM and Chee, ML and Chen, CH and Chen, YT and Chen, Z and Chen, YI and Chen, J and Chen, G and Chen, SH and Chen, WM and Cheng, CY and Cho, YS and Choi, HS and Chuang, LM and Cruz, M and Cushman, M and Das, SK and DeFronzo, RA and deSilva, HJ and Dimitrov, L and Doumatey, AP and Du, S and Duan, Q and Duggirala, R and Emery, LS and Engert, JC and Evans, DS and Evans, MK and Finer, S and Florez, JC and Floyd, JS and Fornage, M and Frankel, EG and Freedman, BI and García-García, L and Genter, P and Gerstein, HC and Goodarzi, MO and Gordon-Larsen, P and Graff, M and Gross, M and Guo, Y and Guo, X and Hai, Y and Hanis, CL and Hayes, M and Horikoshi, M and Howard, AG and Hsu, S and Hsueh, W and Huang, W and Huang, M and Hung, YJ and Hwang, MY and Hwu, CM and Ichihara, S and Igase, M and Ipp, E and Islam, MT and Isono, M and Jang, HM and Jasmine, F and Jonas, JB and Joo, YY and Kabagambe, E and Kadowaki, T and Kamatani, Y and Kandeel, FR and Kardia, SLR and Karlson, EW and Kasturiratne, A and Kato, N and Katsuya, T and Kaur, V and Kawaguchi, T and Keaton, JM and Kho, AN and Khor, CC and Kibriya, M and Kim, BJ and Koh, WP and Kohara, K and Kooner, JS and Kooperberg, C and Kreienkamp, RJ and Lamri, A and Lange, LA and Lee, NR and Lee, MS and Lee, JJ and Lehman, DM and Li, L and Li, Y and Lim, VJ and Liu, J and Liu, Y and Liu, S and Long, J and Louie, T and Luo, X and Lv, J and Lynch, JA and Maeda, S and Mahajan, A and Maruthur, NM and Matsuda, F and McCarthy, MI and McKean-Cowdin, R and Meigs, JB and Millwood, IY and Mohlke, KL and Motala, AA and Nadkarni, GN and Nadler, JL and Nakatochi, M and Nalls, MA and Nayak, U and Nicolas, A and North, KE and Nousome, D and Okada, Y and Pan, I and Pankow, JS and Paré, G and Park, J and Park, KS and Parra, EJ and Patel, SR and Pereira, MA and Peyser, PA and Pirie, FJ and Preuss, M and Province, MA and Psaty, BM and Raffel, LJ and Raffield, LM and Rasmussen-Torvik, LJ and Redline, S and Reiner, AP and Rich, SS and Rohde, R and Roll, K and Roshani, R and Rotimi, CN and Sabanayagam, C and Saleheen, D and Sandow, K and Schurmann, C and Shahriar, M and Shaw, DM and Sheu, WH and Shi, J and Shu, XO and Shuey, MM and Siddiqui, MK and Smith, JA and Sofer, T and Spracklen, CN and Stilp, AM and Sun, M and Tabara, Y and Tai, ES and Tajuddin, SM and Takahashi, A and Takeuchi, F and Tan, J and Taylor, KD and Taylor, K and Thameem, F and Tong, L and Tsai, FJ and Tsao, PS and Udler, MS and Valladares-Salgado, A and van Heel, DA and vanDam, RM and Varma, R and Vora, M and Wacher-Rodarte, N and Wang, YX and Wheeler, E and Whitsel, EA and Wickremasinghe, AR and Wojcik, GL and Wong, TY and Wu, JY and Xiang, YB and Xiang, AH and Yajnik, CS and Yamamoto, K and Yamauchi, T and Yanek, LR and Yao, J and Yokota, M and Yu, C and Yuan, JM and Yusuf, S and Zeggini, E and Zhang, L and Zhang, W and Zheng, W and Zonderman, AB and , and , and , and Aguilar-Salinas, CA and González-Villalpando, C and Haiman, CA and Kim, YJ and Kwak, SH and Leong, A and Loos, RJF and Moreno-Estrada, A and Morris, AP and Orozco, L and Rotter, JI and Sanghera, D and Tusie-Luna, T and Voight, BF and Vujkovic, M and Walters, RG and Ge, T and Manning, AK and Loh, M and Below, JE and Sim, X and Mercader, JM and Ng, MCY and , }, title = {Multi-ancestry polygenic risk scores for the prediction of type 2 diabetes and complications in diverse ancestries.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778152}, abstract = {BACKGROUND: Polygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility.
METHODS: We conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta-analyses across five ancestries-European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)-including 360,000 T2D cases and 1·8 million controls (41% non-EUR). We constructed ancestry-specific and multi-ancestry PRSs in training datasets including 11,000 T2D cases and 32,000 controls, and validated their performance in independent datasets including 39,000 T2D cases and 126,000 controls of diverse ancestries. In the All of Us Research Program, we compared these PRSs to those from the Polygenic Score Catalog and assessed their ability to predict diabetes micro- and macrovascular complications.
FINDINGS: Ancestry-specific PRSs showed limited prediction power for T2D in AFR, AMR, and SAS compared to EUR and EAS. In contrast, multi-ancestry PRSs, built using GWAS data from five ancestries, substantially improved T2D prediction across all ancestries. Compared to those in the interquartile range, individuals at the 97·5[th] percentile of their PRSs had a 6-fold increased T2D risk in AMR, EAS, and EUR, and ≥3-fold in AFR and SAS. These PRSs were also associated with the development of microvascular complications and outperformed all previously reported PRSs for all ancestries.
INTERPRETATION: We developed and extensively validated the most up-to-date T2D PRSs across diverse ancestry groups. These PRSs are publicly available to support further evaluation of their clinical utility in diverse ancestries.}, }
@article {pmid40777412, year = {2025}, author = {Gao, G and Yan, R and Song, AH and Hsieh, HC and Barner, LAE and Wang, F and Brenes, D and Chow, SSL and Wang, R and Bishop, KW and Liu, Y and Farre, X and Divatia, M and Downes, MR and Vakar-Lopez, F and Lal, P and Burke, W and Madabhushi, A and True, LD and Reddi, DM and Grady, WM and Mahmood, F and Liu, JTC}, title = {Deep-learning triage of 3D pathology datasets for comprehensive and efficient pathologist assessments.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777412}, issn = {2692-8205}, abstract = {Standard-of-care slide-based 2D histopathology severely undersamples spatially heterogeneous tissue specimens, with each thin 2D section representing <1% of the entire tissue volume (in the case of a biopsy). Recent advances in non-destructive 3D pathology, such as open-top light-sheet microscopy (OTLS), enable comprehensive high-resolution imaging of large clinical specimens. While fully automated computational analyses of such 3D pathology datasets are being explored, a potential low-risk route for accelerated clinical adoption would be to continue to rely upon pathologists to provide final diagnoses. Since manual review of these massive and complex 3D datasets is infeasible for routine clinical practice, we present CARP3D, a deep learning triage framework that identifies high-risk 2D cross sections within large 3D pathology datasets to enable time-efficient pathologist evaluation. CARP3D assigns risk scores to all 2D levels within a tissue volume by leveraging context from a subset of neighboring depth levels, outperforming models in which predictions are based on isolated 2D levels. In two use cases - risk stratification based on prostate cancer biopsies and screening for dysplasia/cancer in endoscopic biopsies of Barrett's esophagus - AI-triaged 3D pathology, enabled by CARP3D, demonstrates the potential to improve the detection of high-risk diseases in comparison to slide-based 2D histopathology while optimizing pathologist workloads.}, }
@article {pmid40823432, year = {2024}, author = {Evenson, KR and Howard, AG and Wen, F and Di, C and Lee, IM}, title = {Identifying Multicomponent Patterns and Correlates of Accelerometry-Assessed Physical Behaviors Among Postmenopausal Women: The Women's Health Accelerometry Collaboration.}, journal = {Journal for the measurement of physical behaviour}, volume = {7}, number = {1}, pages = {}, pmid = {40823432}, issn = {2575-6613}, support = {R01 CA227122/CA/NCI NIH HHS/United States ; }, abstract = {Understanding the simultaneous patterning of accelerometer-measured physical activity and sedentary behavior (physical behaviors) can inform targeted interventions. This cross-sectional study described multi-component patterns and correlates of physical behaviors using accelerometry among diverse postmenopausal women. The Women's Health Accelerometry Collaboration combined two United States-based cohorts of postmenopausal women with similar accelerometry protocols and measures. Women (n=22,612) 62 to 97 years enrolled in the Women's Health Study (n=16,742) and the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study (n=5870) wore an ActiGraph GT3X+ accelerometer on their hip for one week. Awake-time accelerometry data were summarized using the accelerometer activity index into sedentary behavior, light (low, high), and moderate-to-vigorous physical activity. Latent class analysis was used to classify physical behavior hour-by-hour. Five unique patterns were identified with higher total volume of physical activity and lower sedentary behavior with each successively higher-class number based on percentage of the day in physical activity/sedentary behavior per hour over seven days. The percentage assignment was 16.3% class 1, 33.9% class 2, 20.2% class 3, 18.0% class 4, and 11.7% class 5. Median posterior probabilities ranged from 0.99-1.00. Younger age, higher education and general health, normal weight, never smokers, weekly drinking, and faster self-reported walking speed generally had higher class assignment compared to their counterparts. History of diabetes and cardiovascular disease generally had lower class assignment compared to those without these conditions. These results can inform targeted interventions based on common patterns of physical behaviors by time of day among postmenopausal women.}, }
@article {pmid40821852, year = {2025}, author = {Choo, S and Tong, AH and Fields, E and Mack, HM and Humbert, O and Radtke, S and Kiem, HP}, title = {A rescue fanconi anemia humanized mouse model with endogenous FA mutation and high human hematopoietic stem cell chimerism.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101528}, pmid = {40821852}, issn = {2329-0501}, abstract = {Autologous transplantation of ex vivo gene-modified/corrected hematopoietic stem cells (HSCs) offers a definitive therapeutic approach to restore hematopoiesis in Fanconi anemia (FA) patients. However, this approach not only requires ex vivo treatment of patient HSCs in specialized facilities but also inevitably results in a loss of fragile and limited patient HSCs. In vivo correction of HSCs directly in the patient can overcome these limitations. To develop such in vivo gene therapy (GT) strategies, an appropriate in vivo model with sufficient target human HSCs carrying the disease-associated mutation is crucial. However, due to the proliferative defect imposed on FA-mutant cells, it is difficult to establish a humanized mouse model with a high engraftment of mutant HSCs. Here, we report a humanized mouse model of FA that results in high chimerism with FA-mutant human HSCs. We demonstrate successful engraftment, uncompromised proliferation, and long-term persistence of the FA-mutant HSCs facilitated by the full-length FANCA expression introduced via a lentiviral vector. This model resolves the lack of an in vivo FA disease model with human HSCs and is a promising platform for testing in vivo gene editing strategies targeting human cells.}, }
@article {pmid40820767, year = {2025}, author = {Mizuno, S and Gras, L and Baaij, LGA and Koster, L and D'Souza, A and Hari, PN and Estrada-Merly, N and Saber, W and Cowan, AJ and Iida, M and Okamoto, S and Takamatsu, H and Kawamura, K and Kodera, Y and Hamad, N and Ko, BS and Liam, C and Ho, KW and Goh, AS and Keat, TS and Elhaddad, AM and Bazarbachi, A and Chaudhry, BQUN and Alfar, R and Bekadja, MA and Benakli, M and Ortiz, CAF and Riva, E and Verburgh, E and Galeano, S and Bass, F and Mian, H and McCurdy, A and Wang, FR and Neumann, D and Koh, MBC and Snowden, JA and Schönland, S and McLornan, DP and Hayden, PJ and Balari, AMS and Greinix, HT and Aljurf, M and Atsuta, Y and Rondelli, D and Niederwieser, DW and Garderet, L}, title = {The impact of age on survival and excess mortality after autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288041}, pmid = {40820767}, issn = {1592-8721}, abstract = {Despite the availability of novel agents, autologous hematopoietic cell transplantation (auto-HCT) remains the standard of care in newly diagnosed multiple myeloma (MM) patients. The impact of age on overall survival (OS), progression-free survival (PFS), relapse incidence, non-relapse mortality (NRM), and excess mortality (taking account of general population mortality) was investigated using information on 61,797 MM patients transplanted between 2013 and 2017. The median age at auto-HCT was 60.8 (range: 18.1-83.2) years of whom 2.0% were 18-39 years, 68.9% 40-64 years, 21.8% 65-69 years, 6.5% 70-74 years, and 0.8% ≥75 years of age, respectively. The corresponding OS probabilities at three years were 85.9%, 82.8%, 81.1%, 78.4%, and 74.8%, respectively (p<0.001). Excess mortality cumulative incidences were 13.1%, 15.0%, 14.6%, 15.0%, and 14.1% at three years, respectively (p=0.67). In multivariable analyses, older age was a significant risk factor for OS, PFS, and NRM but not for excess mortality or relapse risk. Our results indicate that advanced age alone should not preclude the use of auto-HCT in patients with MM.}, }
@article {pmid40820557, year = {2025}, author = {Cooper, N and Kruse, C and Deneen Morgan, S and Laurent, J and Arvelo-Saillant, M and Roussy, JP and Cordoba, M and Gouia, I and Schmitt, LA and Reineke, E and Gernsheimer, T}, title = {Patient survey in immune thrombocytopenia (ITP): Identifying unmet needs related to treatment and disease control in patients living in the United States.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.20257}, pmid = {40820557}, issn = {1365-2141}, support = {//Sanofi/ ; }, abstract = {Immune thrombocytopenia (ITP) is a chronic disease with primary therapeutic goals of platelet count recovery to safe levels to minimize active/future bleeding, alongside easing additional symptoms negatively impacting overall patient well-being with consequent improvement in physical fatigue/energy levels, daily/work-related activities and social/emotional health. Documentation of this rare disease is important for evaluating real-world experiences in treatment satisfaction, expectations and unmet needs in disease management. This cross-sectional, real-world evidence survey was conducted from 9 February 2023 to 4 April 2023, by the Platelet Disorder Support Association and Sanofi in US adults diagnosed with ITP for ≥1 year. Results showed that although most patients receive and adhere to treatment, lack of sustained efficacy fuels a need for more effective therapy. Patients desired long-term ITP control and were most concerned with increasing/stabilizing platelet counts and decreasing fatigue and bleeding severity. Better treatment was needed to ease burdensome health-related quality of life symptoms, especially physical fatigue and anxiety, and decrease effects on daily life and activities. Additionally, involvement in shared decision-making and engagement in educational, digital healthcare and psychological support were preferred. Overall, ITP patients desired long-term disease management options that improved platelet counts, minimized bleeding and reduced physical fatigue and anxiety, while also engaging in patient support options.}, }
@article {pmid40819165, year = {2025}, author = {Wu, E and Bieniosek, M and Wu, Z and Thakkar, N and Charville, GW and Makky, A and Schürch, CM and Huyghe, JR and Peters, U and Li, CI and Li, L and Giba, H and Behera, V and Raman, A and Trevino, AE and Mayer, AT and Zou, J}, title = {ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7633}, pmid = {40819165}, issn = {2041-1723}, abstract = {Hematoxylin and eosin (H&E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&E images. Our model is trained on a dataset of over 1300 paired and aligned H&E and multiplex immunofluorescence (mIF) samples from over a dozen tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.}, }
@article {pmid40818320, year = {2025}, author = {McElvania, E and Rao, D and Greninger, AL and Harnett, G and Larcena, A and Patel, A and Webster, B and Ulen, C and Green, DF and King, D and Patel, DR and Jandali, I and Gibson, J and Killion, J and Atwi, J and Bergmann, KR and Slade, L and Staat, MA and Faron, M and Washington, M and Patel, R and Annamalai, R and Ackerman, R and Stewart, WP and Mora Amador, Y and Raman, A and Liu, X}, title = {Evaluation of Cepheid Xpert Xpress CoV-2/Flu/RSV plus for nasal and nasopharyngeal specimens tested in CLIA-accredited and CLIA-waived settings.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {180}, number = {}, pages = {105851}, doi = {10.1016/j.jcv.2025.105851}, pmid = {40818320}, issn = {1873-5967}, abstract = {BACKGROUND: Respiratory viruses are responsible for millions of healthcare visits annually. The unpredictable periodicity of Coronavirus disease 2019 and seasonal patterns of influenza and respiratory syncytial virus result in concurrent circulation of these viruses with non-specific and overlapping clinical symptoms.
STUDY DESIGN: This study evaluated the Cepheid Xpert Xpress CoV-2/Flu/RSV plus test using 3011 nasopharyngeal swab (NPS) and 2943 anterior nasal (NS) specimens. The assay was evaluated in CLIA-accredited (CA) laboratories with laboratory trained operators and CLIA-waived (CW) settings with non-laboratory personnel. Results were compared to the BioFire Respiratory Panel 2.1 for SARS-CoV-2 and Hologic Panther Fusion Flu A/B/RSV for influenza A, influenza B, and RSV. Cepheid Xpert Xpress CoV-2/Flu/RSV plus testing of NPS and NS specimens had high positive and negative agreement with reference testing.
RESULTS: Overall agreement for NPS was 98.8 %, 99.1 %, 99.9 %, and 100 % for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. For NS, overall agreement was 98.7 %, 99.3 %, 99.9 %, and 99.9 % for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. Specimen testing performed at CA and CW locations also had high positive and negative agreement with reference testing. Overall agreement for CA testing was 97.7 %, 99.6 %, 100 %, and 100 % for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. For CW testing, overall agreement was 98.8 %, 99.0 %, 99.9 %, and 99.9 % for SARS-CoV-2, influenza A, influenza B, and RSV, respectively.
CONCLUSIONS: This study demonstrates that Xpert Xpress CoV-2/Flu/RSV plus provides rapid and accurate results from NPS and NS specimens in CA and CW testing facilities regardless of staff experience with molecular testing.}, }
@article {pmid40817396, year = {2025}, author = {Raggi, D and Crupi, E and Pederzoli, F and Martini, A and Briganti, A and Alhalabi, O and O'Donnell, PH and Ross, J and Gupta, S and Kamat, AM and Faltas, BM and Black, PC and Spiess, PE and Grivas, P and Gao, J and Apolo, AB and Huddart, RA and Necchi, A and Galsky, MD}, title = {HER2 and urothelial carcinoma: current understanding and future directions.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {40817396}, issn = {1759-4820}, abstract = {Human epidermal growth factor receptor 2 (HER2) has emerged as a crucial biomarker across various cancers, shaping therapeutic strategies and prognostic evaluations. In urothelial carcinoma, HER2 positivity rates can reach up to 68% when HER2-low tumours (immunohistochemistry 1+) are included in the analysis. HER2 overexpression and ERBB2 genomic alterations have been linked to advanced disease stages and poor outcomes in urothelial carcinoma. Emerging evidence suggests that HER2-low tumours might be a distinct and actionable subgroup. Accurate and consistent assessment of HER2 status is increasingly vital to identify patients likely to benefit from HER2-targeted therapies, raising interest in refining thresholds for HER2 expression, aiming to predict treatment response. HER2 heterogeneity across stages and histological subtypes complicates its evaluation, with definitions of HER2 positivity differing between clinical trials and treatments. In urothelial carcinoma, HER2-targeted therapies, such as tyrosine kinase inhibitors, monoclonal antibodies and antibody-drug conjugate (ADCs) have been explored. Unlike tyrosine kinase inhibitors and monoclonal antibodies, which act through HER2-related pathways, ADCs use HER2 as a target but achieve efficacy through additional mechanisms, enabling their activity even at low HER2 expression levels. Trastuzumab deruxtecan, a novel anti-HER2 ADC, has received FDA tumour-agnostic approval for unresectable or metastatic HER2+ solid tumours, including urothelial carcinoma, after prior therapies. Interactions between HER2 protein and putative biomarkers such as EGFR, NECTIN4, PDL1 and FGFR3 genomic alterations might influence therapeutic outcomes, offering opportunities for improved patient selection and innovative combination strategies.}, }
@article {pmid40815506, year = {2025}, author = {Reddi, S and Banerjee, R}, title = {Avoid burning bridges before CAR-T therapy in myeloma.}, journal = {Blood advances}, volume = {9}, number = {16}, pages = {4232-4234}, doi = {10.1182/bloodadvances.2025016774}, pmid = {40815506}, issn = {2473-9537}, }
@article {pmid40815487, year = {2025}, author = {Schwartz, J and Wangen, M and Odebunmi, OO and Waters, A and Ferrari, R and Marciniak, M and Brenner, AT and Wheeler, SB and Shah, PD}, title = {Patient preferences and perceived barriers to follow-up care in a pharmacy-based colorectal cancer screening program: a national survey.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40815487}, issn = {1573-7225}, abstract = {BACKGROUND: Fecal immunochemical tests (FIT) are recommended for routine colorectal cancer (CRC) screening because they are cost-effective, non-invasive, and convenient. Pharmacy-based CRC screening using FIT kits could be effective to improve screening rates, particularly in medically underserved communities. However, data on follow-up procedures and barriers after positive FIT results in this context remain sparse.
METHODS: We conducted a national survey of 1,045 US adults aged 45-75 to assess preferences for follow-up care in a pharmacy-based CRC screening program we call PharmFIT™ and identify perceived barriers to follow-up colonoscopy after positive FIT results. We evaluated patient preferences and barriers using descriptive statistics. We used multinomial logistic regressions to identify correlates of patient preferences for follow-up and multiple logistic regressions to identify correlates of perceived psychosocial and structural barriers to follow-up colonoscopy.
RESULTS: Participants showed a strong preference for digital communication for negative FIT results and reminders, but favored direct, interpersonal communication from healthcare providers for positive results and follow-up. Psychosocial barriers, such as fear of colonoscopy or cancer diagnosis, were more prevalent than structural barriers like cost and transportation. Older adults, those with a regular healthcare provider, and higher-income individuals were less likely to report barriers, while non-white and Medicaid patients showed lower preferences for automated notifications.
CONCLUSION: PharmFIT should use tailored, multimodal communication strategies to address patient preferences and include strategies, like patient navigation, to address potential barriers to follow-up colonoscopy. This study reinforces the potential of pharmacy-based CRC screening programs to increase screening access and opportunities, particularly in medically underserved communities.}, }
@article {pmid40813711, year = {2025}, author = {Kendra, KL and Bellasea, SL and Eroglu, Z and Hu-Lieskovan, S and Campbell, KM and Carson, WE and Wada, DA and Plaza, JA and Sosman, JA and In, GK and Ikeguchi, A and Hyngstrom, J and Brohl, AS and Nikhil, IK and Markowitz, J and Negrea, G and Kasbari, S and Doolittle, GC and Swami, U and Roberts, T and Mathew, BN and Medina, E and Baselga-Carretero, I and Gonzalez, CR and Garcilazo, IP and Vega-Crespo, A and Chen, JM and Naser Al-Deen, N and Patel, SP and Sharon, E and Moon, J and Wu, MC and Ribas, A}, title = {Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40813711}, issn = {1546-170X}, abstract = {Desmoplastic melanoma is a distinct subtype of melanoma known to have preexisting immune infiltrates and high ultraviolet light damage, resulting in a high tumor mutational burden. We hypothesized that this may result in high response rates with single-agent anti-programmed death protein 1 (PD-1) therapy. SWOG S1512 was a two-cohort clinical trial testing the activity of pembrolizumab in patients with surgically resectable (cohort A) and unresectable (cohort B) desmoplastic melanoma. Here we report on the cohort B single-arm clinical trial, which enrolled 27 patients with unresectable desmoplastic melanoma receiving pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years, with the primary endpoint of complete response rate. The complete response rate was 37% (95% confidence interval: 19-58%), and the post hoc endpoint of objective response rate was 89% (95% confidence interval: 71-98%). The estimated secondary endpoints of 3-year melanoma-specific progression-free survival and overall survival were 84% and 96%, respectively, with only one patient having died from melanoma progression. Ten patients (37%) experienced grade 3 or 4 adverse events, and nine patients (33%) discontinued treatment because of adverse events. Patients with advanced desmoplastic melanoma have a high response rate to single-agent PD-1 blockade therapy, supporting single-agent anti-PD-1 as the treatment of choice, but are limited by a frequency of toxicities that is numerically higher than in other patient populations. ClinicalTrials.gov identifier: NCT02775851.}, }
@article {pmid40812489, year = {2025}, author = {Ellyson, AM and Mendoza, JA and Liese, AD and Tabah, A and Bekelman, TA and Rudisill, AC and Dabelea, D and Frongillo, EA and Pihoker, C and Malik, FS and Wright, DR}, title = {Healthcare and non-healthcare costs: youth with diabetes and food insecurity.}, journal = {American journal of preventive medicine}, volume = {}, number = {}, pages = {108028}, doi = {10.1016/j.amepre.2025.108028}, pmid = {40812489}, issn = {1873-2607}, abstract = {INTRODUCTION: This study prospectively evaluated the association of household food insecurity and acute care costs and productivity loss in youth and young adults (YYA) with type 1 and type 2 diabetes.
METHODS: This observational cohort study included 1,256 YYA with type 1 and type 2 diabetes from the SEARCH for Diabetes in Youth Food Security Study with data collected at three time points between 2015-2022. Both household food insecurity (HFI, measured using the US Household Food Security Survey Module) and costs (measured using survey responses on utilization and productivity losses) were self-reported by young adult participants or caregivers of adolescents. The relationship between HFI and costs was analyzed using generalized adjusted linear regression. We also analyzed the moderating role of continuous health insurance coverage.
RESULTS: Each additional 1-point increase in the HFI score was associated with a $1,077 (95%CI= [663, 1,491]) increase in measured 12-month costs. Costs were $4,384 (95%CI=[2,635, 6,133]) higher in households that were experiencing HFI versus those who were not. Youth and young adults with continuous health insurance coverage saw smaller increases in costs ($864, 95%CI=[461, 1,267]) compared to those without continuous coverage ($1,820, 95%CI=[379, 3,261]).
CONCLUSIONS: This study found a positive association between HFI and costs for YYA with diabetes, and this relationship was modified by continuous health insurance coverage. Future work should use linked claims and electronic health record data to better inform efforts aiming to reduce HFI burden and improve the continuity of insurance coverage for this population.}, }
@article {pmid40812340, year = {2025}, author = {Hill, JA and Boonyaratanakornkit, J and Mikulska, M and Teh, BW and Hahn, WO and Haidar, G and Liu, C and Kumar, D and Ison, MG and Halasa, N}, title = {Innovation in active and passive immunisation of people who are immunocompromised: a call to action.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00345-7}, pmid = {40812340}, issn = {1474-4457}, abstract = {The proportion of the population with immunocompromising conditions, who are at increased risk for complications from infectious diseases, continues to grow. Concurrently, outbreaks due to known and emerging pathogens are increasing. Vaccines are the foundation of infection prevention; however, attenuated immune responses in people who are immunocompromised necessitates innovation in design and delivery strategies. Passive immunisation, whereby the desired immunity is directly transferred to an individual, albeit transiently, could be valuable for patients who are unable to generate robust immune responses with vaccination or infection. However, existing therapies are insufficient. Considerable technical and conceptual advancements in the field of immunology have created unprecedented opportunities for the development of novel strategies and therapies to prevent and treat infectious diseases, and studies in people who are immunocompromised are an important setting in which to apply these developments. In this Series paper, we consider key unmet needs in the areas of vaccinology, monoclonal antibody design, study endpoints, health systems approaches, and policy considerations for people who are immunocompromised.}, }
@article {pmid40812338, year = {2025}, author = {Pergam, SA}, title = {The smallest faith.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00355-X}, pmid = {40812338}, issn = {1474-4457}, }
@article {pmid40812337, year = {2025}, author = {Liu, C and Rosen, EA and Stohs, EJ and Imlay, H and Nigo, M and Gottesdiener, LS and So, M and Tverdek, F and Dadwal, S and Gudiol, C and Satlin, MJ and Seo, SK and Trubiano, JA and Banerjee, R and Hanson, KE and Abbo, LM}, title = {Tackling antimicrobial resistance in people who are immunocompromised: leveraging diagnostic and antimicrobial stewardship.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00311-1}, pmid = {40812337}, issn = {1474-4457}, abstract = {Antimicrobial resistance (AMR) disproportionately affects people who are immunocompromised due to their frequent encounters with the health-care system and repeated, prolonged exposure to antibiotics. AMR threatens to undermine continued advances in cancer care, haematopoietic cell transplantation, and solid organ transplantation by severely restricting therapeutic options. The convergence of several factors in the diagnostic evaluation of infection among individuals with immunocompromising conditions contributes to excess and inappropriate antibiotic use. Diagnostic and antimicrobial stewardship are key complementary strategies to address these challenges with shared goals of improving patient outcomes, reducing harm, and mitigating the risk of AMR. In this Series paper, we discuss opportunities to enhance use of existing diagnostic tools (eg, culture-based diagnostics, molecular diagnostics, and other tools such as antibiotic allergy delabelling), emerging diagnostic tools (eg, metagenomic sequencing and host response profiling), and digital innovation, to optimise antibiotic use, and the potential for precision medicine approaches to combat AMR in people who are immunocompromised.}, }
@article {pmid40777454, year = {2025}, author = {Mayer-Blackwell, K and Minervina, A and Pogorelyy, M and Rawat, P and Shapiro, MR and Peters, LD and Ford, ES and Posgai, AL and Vengesana, K and Minot, S and Koelle, DM and Greiff, V and Bradley, P and Brusko, TM and Thomas, PG and Fiore-Gartland, A}, title = {TCR2HLA: calibrated inference of HLA genotypes from TCR repertoires enables identification of immunologically relevant metaclonotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777454}, issn = {2692-8205}, support = {P01 AI042288/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 AI144616/AI/NIAID NIH HHS/United States ; P01 AI165077/AI/NIAID NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; 75N93019C00063/AI/NIAID NIH HHS/United States ; K99 DK140511/DK/NIDDK NIH HHS/United States ; }, abstract = {T cell receptors (TCRs) recognize peptides presented by polymorphic human leukocyte antigen (HLA) molecules, but HLA genotype data are often missing from TCR repertoire sequencing studies. To address this, we developed TCR2HLA, an open-source tool that infers HLA genotypes from TCRβ repertoires. Expanding on work linking public TRBV-CDR3 sequences to HLA genotypes, we incorporated "quasi-public" metaclonotypes - composed of rarer TCRβ sequences with shared amino acid features - enriched by HLA genotypes. Using four TCRβseq datasets from 3,150 individuals, we applied TRBV gene partitioning and locality-sensitive hashing to identify ~96,000 TCRβ features strongly associated with specific HLA alleles from 71M input TCRs. Binary HLA classifiers built with these features achieved high balanced accuracy (>0.9) across common HLA-A (9/12), B (9/12), C (6/13), DRB1 (11/11) alleles and prevalent DPA1/DPB1 (6/10), DQA1/DQB1 (8/17) heterodimers. We also introduced a high-sensitivity calibration to support predictions in samples with as few as 5,000 unique clonotypes. Calibrated predictions with confidence filtering improved reliability. Beyond genotype imputation, TCR2HLA enables the discovery of novel HLA- and exposure-associated TCRs, as shown by the identification of SARS-CoV-2 related TCRs in a large COVID-19 dataset lacking HLA data. TCR2HLA provides a scalable framework for bridging the gap between TCRseq data and HLA genotype for biomarker discovery.}, }
@article {pmid40812311, year = {2025}, author = {Jagota, M and Hsu, C and Mazumder, T and Sung, K and DeWitt, WS and Listgarten, J and Matsen Iv, FA and Ye, CJ and Song, YS}, title = {Learning antibody sequence constraints from allelic inclusion.}, journal = {Cell systems}, volume = {}, number = {}, pages = {101368}, doi = {10.1016/j.cels.2025.101368}, pmid = {40812311}, issn = {2405-4720}, abstract = {Although antibody sequences are highly diverse, they are constrained by requirements for expression and limited off-target reactivity. Describing which sequences violate such constraints has proven to be difficult. Here, we introduce a machine-learning framework to leverage a previously underutilized source of data for this problem. We use human single-cell sequencing data to find instances of allelic inclusion, a rare event where B cells express two different antibody light chains as mRNA. Previous studies suggest that one of these chains is either autoreactive or non-expressing as protein. We train machine-learning models to identify abnormal sequences associated with allelic inclusion. The resulting models generalize to predict antibody properties including polyreactivity, surface expression, and mutation usage, outperforming methods that do not use allelic inclusion data. We also investigate similar selection forces on the heavy chain in mice and observe that surrogate light-chain pairing has a large impact on heavy-chain diversity.}, }
@article {pmid40811854, year = {2025}, author = {Maynard, LH and Cavanaugh, EJ and Zhu, H and Starke, CE and Doherty, SM and Einhaus, TK and Pérez-Osorio, AC and Stensland, L and Blair, C and Roche, AM and Everett, JK and Murnane, RD and Hoffman, ME and Nelson, V and Herrin, SA and Littlewood, C and Camou, K and Wilson, E and Wessel, C and Bushman, F and Jerome, KR and Kiem, HP and Peterson, CW}, title = {Pooled CAR-T screening in nonhuman primates identifies designs with enhanced proliferation, trafficking, and persistence.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025028683}, pmid = {40811854}, issn = {1528-0020}, abstract = {Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized treatment for B-cell malignancies, yet over 60% of patients relapse within one year, often due to insufficient CAR-T persistence. While mouse and primary cell models have been instrumental in advancing CAR-T therapy, they frequently fail to predict clinical outcomes, underscoring the need for more translationally relevant models. To address this limitation, we conducted the first systematic evaluation of CAR structure-function relationships in an immunocompetent nonhuman primate (NHP) model. We engineered an array of 20 CD20-targeted CARs with distinct combinations of hinge, transmembrane, and costimulatory domains. Following ex vivo characterization, we administered pooled autologous CAR-T arrays to three NHPs and tracked CAR abundance longitudinally using a novel digital droplet PCR assay. Ex vivo, CAR-T cells incorporating the MyD88-CD40 costimulatory domain exhibited markedly distinct functional profiles, including increased activation, unique cytokine secretion, tonic signaling, and resistance to exhaustion. In vivo, MyD88-CD40 CARs expanded dramatically, comprising up to 100% of peripheral CAR-T cells and significantly outperforming canonical CD28- and 4-1BB-based CARs. This expansion was associated with robust B-cell depletion across all animals. MyD88-CD40 CARs, particularly those with a CD28 hinge and transmembrane domain, demonstrated superior trafficking to secondary lymphoid tissues and persistence through study endpoint, unlike other CARs which waned by day 28. Our findings highlight the value of NHP models for screening CAR designs and identify MyD88-CD40 CARs as candidates with unmatched potency. The unique functional attributes conferred by this domain may provide key insights into features that drive enhanced CAR-T cell activity.}, }
@article {pmid40811818, year = {2025}, author = {Greenbaum, U and Hashmi, H and Elsawy, M and Kim, S and Moskop, A and Oloyede, T and Awan, FT and Bachanova, V and Badar, T and Bar, M and Barba, P and Beitinjaneh, AM and Cashen, AF and Dholaria, B and Farooq, U and Foglesong, J and Ganguly, S and Hematti, P and Hill, LC and Jain, MD and Jain, T and Kebriaei, P and Kittai, AS and Locke, FL and Lulla, PD and McGuirk, JP and Mead, E and Mussetti, A and Nishihori, T and Olson, AL and Pennisi, M and Perales, MA and Ramakrishnan Geethakumari, P and Riedell, PA and Saber, W and Shouval, R and Shpall, EJ and Magalhaes-Silverman, M and Strouse, CS and Turtle, CJ and Valluripalli, A and Wudhikarn, K and Pasquini, MC and Ahmed, S and Sorror, ML}, title = {New Comorbidity Index Associated with Survival After Chimeric Antigen Receptor T Cell Therapy for Large B-Cell Lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015599}, pmid = {40811818}, issn = {2473-9537}, abstract = {The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T cell (CAR-T) therapy is not well-established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017-2020 were selected from the CIBMTR registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37; 95% CI, 1.16-1.62; P < .001. CT-CI 2: HR, 1.49; 95% CI, 1.17-1.89; P = .001. CT-CI ≥ 3: HR, 2.55; 95% CI, 1.90-3.42; P < .001). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T-related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.}, }
@article {pmid40811667, year = {2025}, author = {Jatt, LP and Gillespie, KM and Van, P and Hoffman, SL and Jackson, LA and Murphy, SC and Heath, JR and Kublin, JG}, title = {Manuscript title: Cytokines Associated With Moderate and Severe Adverse Events During a Sporozoite Malaria Vaccine Trial with Controlled Human Malaria Infection.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf435}, pmid = {40811667}, issn = {1537-6613}, abstract = {Ensuring the safety and efficacy of candidate vaccines is critical. Although mechanisms underpinning protective immune responses to malaria vaccines are frequently investigated, immune responses correlating with moderate and severe adverse events are rarely examined. Here, we leverage a malaria vaccine trial with a higher-than-expected adverse event rate and frequent sampling to investigate cytokine profiles associated with adverse events. We found that Interleukin-6 was elevated on days in which individuals experienced moderate and severe adverse events. More research on immune responses associated with adverse events is warranted in order to identify biomarkers associated with systemic reactogenicity and accelerate vaccine development.}, }
@article {pmid40811558, year = {2025}, author = {Shenoy, MK and Rico, DM and Lorant, AK and Touré, H and Gordon, S and Milburn, LJ and Schwensen, JS and Cabán, ME and Koch, MA}, title = {Breast milk IgG engages the mouse neonatal immune system to instruct responses to gut antigens.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6761}, pages = {eado5294}, doi = {10.1126/science.ado5294}, pmid = {40811558}, issn = {1095-9203}, abstract = {Maternal antibodies fundamentally regulate gut immunity in the developing infant, yet the mechanisms underlying this process remain elusive. We found that maternal immunoglobulin G (IgG), ingested in the first week of life, restrained microbiota-dependent adaptive immune responses weeks later, after weaning. This activity was linked to maternal antibodies that could bind bacteria in the neonatal gut and the ability of microbe-IgG complexes to engage Fc and complement-dependent effector functions in offspring. Ingestion of microbiota-specific maternal IgG also limited aberrant neonatal responses to dietary antigens encountered at weaning. These discoveries suggest that maternal IgG engages the immune system of offspring in early postnatal life to tune mucosal responses and reinforce intestinal homeostasis in the face of dynamic shifts in food and bacterial antigens during development.}, }
@article {pmid40811246, year = {2025}, author = {Fang, A and Kumar, L and Creevy, KE and Promislow, DEL and Ma, J and , }, title = {Constructing the first comorbidity networks in companion dogs in the Dog Aging Project.}, journal = {PLoS computational biology}, volume = {21}, number = {8}, pages = {e1012728}, pmid = {40811246}, issn = {1553-7358}, abstract = {Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n = 160) and included only dogs that had at least one of those health conditions (n = 26,614). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with cataracts and blindness, and hypertension with chronic kidney disease (CKD). In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes precedes cataracts, elbow/hip dysplasia before osteoarthritis, and keratoconjunctivitis sicca before corneal ulcer, which are consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Only the Senior group identified the association between hypertension and CKD. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.}, }
@article {pmid40766360, year = {2025}, author = {Dosey, A and Dadonaite, B and Gillespie, RA and Leaf, EM and Vukovich, MJ and McGowan, J and Grey, E and Muramatsu, H and Jun, RHJ and Pardi, N and Kanekiyo, M and Bloom, JD and King, NP}, title = {Stabilization of H5 highly pathogenic avian influenza hemagglutinin improves vaccine-elicited neutralizing antibody responses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766360}, issn = {2692-8205}, support = {P01 AI167966/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI181881/AI/NIAID NIH HHS/United States ; }, abstract = {Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses adapted to transmission in birds and some other animals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively high pH levels. Here, we combine five mutations within H5 HA that dramatically increase its melting temperature and promote stable closure of the HA trimer. Structural analysis by cryo-electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions, while maintaining local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than non-stabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site (RBS), eliciting a higher proportion of neutralizing antibodies. These findings highlight that H5 HA-stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.}, }
@article {pmid40810606, year = {2025}, author = {Ryser, MD and Holloway, ST and Morsomme, R and Ryan, A and Apostolidou, S and Gentry-Maharaj, A and Gogebakan, KC and Lange, J and Xu, J and Menon, U and Etzioni, R}, title = {Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0498}, pmid = {40810606}, issn = {1538-7755}, abstract = {BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) did not detect a reduction in ovarian cancer (OC) mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared to no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in OC.
METHODS: We used Bayesian inference to estimate OC natural history based on individual screening and cancer diagnosis records from UKCTOCS, a randomized controlled OC screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women aged 50 to 74 years with no family history of OC, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the Risk of Ovarian Cancer Algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses.
RESULTS: Among high-grade serous cancers (HGSCs), the estimated preclinical detectable phase (PCDP) was 1.7 years (95% credible interval [CI], 1.3-2.2), compared with 7.8 years (95% CI, 5.7-10.6) for non-HGSCs. The PCDP depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years).
CONCLUSIONS: The interception opportunity for OC strongly depends on histological subtype and screening modality.
IMPACT: Achieving a clinically significant benefit of OC early detection will require prolonging the interception window through judicious combination of first- and second-line tests.}, }
@article {pmid40809738, year = {2025}, author = {Ye, T and He, Q and Chen, S and Zhang, B}, title = {Role of placebo samples in observational studies.}, journal = {Journal of causal inference}, volume = {13}, number = {1}, pages = {}, pmid = {40809738}, issn = {2193-3677}, abstract = {In an observational study, it is common to leverage known null effects to detect bias. One such strategy is to set aside a placebo sample - a subset of data immune from the hypothesized cause-and-effect relationship. Existence of an effect in the placebo sample raises concerns about unmeasured confounding bias while absence of it helps corroborate the causal conclusion. This paper describes a framework for using a placebo sample to detect and remove bias. We state the identification assumptions and develop estimation and inference methods based on outcome regression, inverse probability weighting, and doubly-robust approaches. Simulation studies investigate the finite-sample performance of the proposed methods. We illustrate the methods using an empirical study of the effect of the earned income tax credit on infant health.}, }
@article {pmid40809030, year = {2025}, author = {Garfall, AL and Banerjee, R and Frenzel, L and Khandanpour, C and Lin, Y and Ottoni, E and Rifkin, R and Rockwell, S and Rodriguez, C and Villefort, H and Zamagni, E}, title = {A roadmap to implementing outpatient administration of bispecific antibodies in multiple myeloma.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1630146}, pmid = {40809030}, issn = {2234-943X}, abstract = {INTRODUCTION: Bispecific antibodies (BsAbs) are novel immunotherapy agents for the treatment of relapsed/refractory multiple myeloma (RRMM). Currently, 3 BsAbs (teclistamab, talquetamab, and elranatamab) are approved for the treatment of RRMM. Administering BsAbs in different practice settings is crucial to improving treatment access and patient outcomes. This report provides actionable guidance to implement safe and effective administration of BsAbs for patients with RRMM in outpatient and community settings.
METHODS: Three clinician advisory workshops were held in the United States, Europe, and Latin America to discuss key factors to operationalize BsAb use in outpatient and community settings, focusing on the critical phases of practice setup, treatment initiation, and ongoing management.
RESULTS: BsAb administration in outpatient and community settings requires careful planning, a well-prepared multidisciplinary team (MDT) of healthcare professionals, and clear protocols, including MDT composition, roles/responsibilities, capacity planning, patient selection criteria, step-up dosing procedure, admission processes, patient/caregiver education requirements, and adverse event (AE) monitoring/management. Comprehensive MDT training on protocols and preparedness to manage AEs is essential. Patients initiating outpatient BsAb therapy should have a reliable caregiver, access to a hospital, controlled comorbidities, and no active infections. Ensuring patients and caregivers understand the benefits, risks, and expectations of BsAb therapy is vital for successful treatment and a positive patient experience.
CONCLUSION: Administering BsAbs in outpatient and community settings can be done safely and effectively with appropriate planning and protocols. Enabling safe and effective BsAb administration in these settings is essential to ensure more patients with RRMM have access to treatment and improved outcomes.}, }
@article {pmid40805242, year = {2025}, author = {Amonoo, HL and Wolfe, ED and Keane, EP and Larizza, IS and Boardman, AC and Healy, BC and Traeger, LN and Cutler, C and Lee, SJ and Greer, JA and El-Jawahri, A}, title = {Medication Adherence in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.}, journal = {Cancers}, volume = {17}, number = {15}, pages = {}, doi = {10.3390/cancers17152546}, pmid = {40805242}, issn = {2072-6694}, support = {K08CA251654/CA/NCI NIH HHS/United States ; n/a//Robert Wood Johnson and American Society of Hematology Harold Amos Medical Faculty Development Award/ ; n/a//Doris Duke Foundation Clinician-Scientist Development Award/ ; }, abstract = {Introduction: Medication adherence is essential for treatment and recovery following hematopoietic stem cell transplantation (HSCT). However, limited data exist on the most effective methods to measure adherence and the factors influencing it in HSCT patients. Materials and Methods: A prospective longitudinal study assessed immunosuppressant medication adherence in 150 patients with hematologic malignancies undergoing allogeneic HSCT. Adherence was assessed using pill counts, immunosuppressant medication levels, patient-reported medication logs, and the Medication Adherence Response Scale-5 (MARS-5) at 30, 100, and 180 days post-HSCT. We evaluated adherence rates, agreement between methods, and sociodemographic and clinical predictors. From patient-reported logs, we calculated dose adherence (comparing reported doses to expected doses) and timing adherence (comparing medication intake within ±3 h of the prescribed time). Kappa analysis assessed agreement among methods. Results: Of 190 eligible patients, 150 (78.9%) enrolled. The mean age was 57.5 years (SD = 13.5); 41.3% (n = 62) were female, 85.3% (n = 128) were non-Hispanic White, and 73.3% (n = 110) were married or living with a partner. Medication adherence varied across the three timepoints and by measurement type: 52-64% (pill counts), 18-24% (medication levels), 96-98% (medication log dose adherence), 83-84% (medication log timing adherence), and 97-98% (MARS-5). There was minimal agreement between measures (Kappa range: 0.008-0.12). Conclusions: Despite the feasibility of leveraging objective and patient-reported measures to assess medication adherence in HSCT patients, there was little agreement between these measures. Patient-reported measures showed high adherence, while objective measures like pill counts and medication levels revealed more modest adherence. The complexity of medication regimens likely contributes to this discrepancy. A rigorous approach to understanding medication adherence in the HSCT population may entail both objective and subjective measures of medication adherence.}, }
@article {pmid40805227, year = {2025}, author = {Sarfraz, Z and Jayram, D and Ozair, A and Hodgson, L and Bellur, S and Maharaj, A and Venur, VA and Mukherjee, S and Ahluwalia, MS}, title = {Survival in Patients with Colorectal Cancer and Isolated Brain Metastases: Temporal Trends and Prognostic Factors from the National Cancer Database (2010-2020).}, journal = {Cancers}, volume = {17}, number = {15}, pages = {}, doi = {10.3390/cancers17152531}, pmid = {40805227}, issn = {2072-6694}, abstract = {Background: The development of brain metastases (BM) is a relatively uncommon but significantly adverse event in the spread of colorectal cancer (CRC). Although management of CRC BM has improved with advances in imaging and systemic therapies, clinical outcomes remain poor. Methods: This retrospective cohort study used the U.S. National Cancer Database to evaluate survival outcomes, treatment patterns, and prognostic factors in CRC patients diagnosed with BM between 2010 and 2020. Patients with isolated brain-only metastases formed the primary analytic cohort, while those with additional extracranial metastases were included for descriptive comparison. Multivariable Cox proportional hazards and logistic regression models were used to assess factors associated with of survival. Proportional hazards assumptions were tested using Schoenfeld residuals. Accelerated failure time models were also employed. Results: From a cohort of 1,040,877 individuals with CRC, 795 had metastatic disease present along with relevant data, of which 296 had isolated BM. Median overall survival (mOS) in BM-only metastatic disease group was 7.82 months (95% CI: 5.82-9.66). The longest survival was observed among patients treated with stereotactic radiosurgery combined with systemic therapy (SRS+Sys), with a median OS of 23.26 months (95% CI: 17.51-41.95) and a 3-year survival rate of 35.8%. In adjusted Cox models, SRS, systemic therapy, and definitive surgery of the primary site were each independently associated with reduced hazard of death. Rectal cancer patients had longer survival than those with colon primaries (mOS: 10.35 vs. 6.08 months). Age, comorbidity burden, and insurance status were not associated with survival in adjusted analyses. Conclusions: SRS+Sys was associated with longer survival compared to other treatment strategies. However, treatment selection is highly dependent on individual clinical factors such as performance status, comorbidities, and disease extent; therefore, these findings must be interpreted with caution Future prospective studies incorporating molecular and biomarker data are warranted to better guide care in this rare and high-risk group.}, }
@article {pmid40803815, year = {2025}, author = {Naresh, KN and Karube, K and Borges, A and Cheuk, W and Gujral, S and Sayed, S and Sohani, A and Lazzi, S and Ott, G and Du, MQ and Leoncini, L and Chan, JKC}, title = {Fifth edition WHO classification: mature B-cell neoplasms.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210260}, pmid = {40803815}, issn = {1472-4146}, abstract = {We present a review of mature B-cell neoplasms as described in the fifth edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5). Entities have expanded, and definitions are increasingly reliant on genomic and other technologies. However, the WHO-HAEM5 employs a hierarchical structure with family (class)-level definitions that group several specific entities. This approach enables the assignment of a family-level diagnosis when criteria for specific entities cannot be met due to resource constraints. To facilitate application in resource-limited settings, WHO-HAEM5 divides diagnostic criteria into 'essential' and desirable criteria for most entities. This review focuses on changes and updates in B-cell lymphoma classification, providing guidance on how to apply the WHO classification in resource-limited settings.}, }
@article {pmid40803814, year = {2025}, author = {Love, JE and Naresh, KN}, title = {Splenic EBV-positive inflammatory follicular dendritic cell sarcoma with fibroblastic/myoid immunophenotype in a patient with EBV-negative diffuse large B cell lymphoma.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210303}, pmid = {40803814}, issn = {1472-4146}, }
@article {pmid40802906, year = {2025}, author = {Roschewski, M and Kurtz, DM and Westin, JR and Lynch, RC and Gopal, AK and Alig, SK and Sworder, BJ and Cherng, HJ and Kuffer, C and Blair, D and Brown, K and Goldstein, JS and Schultz, A and Close, S and Chabon, JJ and Diehn, M and Wilson, WH and Alizadeh, AA}, title = {Remission Assessment by Circulating Tumor DNA in Large B-cell Lymphoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {101200JCO2501534}, doi = {10.1200/JCO-25-01534}, pmid = {40802906}, issn = {1527-7755}, abstract = {PURPOSE: Large B-cell lymphomas (LBCL) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal measurable residual disease (MRD) may improve the determination of remission.
METHODS: We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL. Tumor-specific phased variants were identified from pretreatment samples and monitored at landmark timepoints. Serial plasma specimens were blindly analyzed for detectable ctDNA as MRD. MRD status was compared to conventional response criteria for prognosis of progression-free survival (PFS).
RESULTS: We studied ctDNA-MRD in 137 patients by monitoring 409 plasma specimens over time. Detectable ctDNA rates decreased during therapy with 55% and 78% of patients achieving undetectable ctDNA after 2 cycles and at end of therapy, respectively. After a median follow-up of 37 months, the 2-year PFS for patients with detectable vs undetectable ctDNA after 2 cycles was 67% vs 96% (p=0.0025, hazard ratio 6.9) and after therapy was 29% vs 97% (p<0.0001, hazard ratio 28.7), respectively. Ninety-two (94%) patients with undetectable ctDNA at end of therapy remained alive without progression, while 19 (68%) patients with detectable ctDNA progressed or died. MRD status at end of therapy had greater prognostic utility than conventional lymphoma response criteria using PET scans (hazard ratio 3.6 for positive PET, and 28.3 for detectable ctDNA).
CONCLUSION: Ultrasensitive circulating tumor DNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined definition of remission with ctDNA-MRD may improve clinical and psychological outcomes for patients with LBCL (Funded by the National Cancer Institute and others; ClinicalTrials.gov numbers, NCT04002947; NCT00398177; NCT02529852; NCT04231877; NCT04134936).}, }
@article {pmid40802741, year = {2025}, author = {Radtke, S and Fields, E and Swing, K and Kanestrom, G and Yen, JS and Pande, D and Enstrom, MR and Humbert, O and Weiss, MJ and Liu, DR and Newby, GA and Kiem, HP}, title = {Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.}, journal = {Science translational medicine}, volume = {17}, number = {811}, pages = {eadn2601}, doi = {10.1126/scitranslmed.adn2601}, pmid = {40802741}, issn = {1946-6242}, abstract = {Sickle cell disease (SCD) is caused by a single nucleotide change in the β-globin gene that adenine base editors can convert to the nonpathogenic Makassar β-globin variant. Here, we evaluated the long-term efficiency and off-target editing potential of autologous Makassar base editing in three rhesus macaques as a step toward human translation. Base editing of CD34[+]CD90[+] hematopoietic stem cells (HSCs) at the Makassar locus reached greater than 60% efficiency using a bystander nucleotide as a proxy for the sickle cell target in cells from healthy macaques. No impact on myeloid and erythroid colony formation was seen, and clonal analysis revealed that >90% of HSCs were edited, >20% with biallelic editing. After transplantation of autologous gene-edited HSCs, all three macaques rapidly recovered neutrophils, red blood cells, and platelets with stable editing of 25.6%, on average, observed across nucleated blood cells. Similarly, the bone marrow stem cell compartment maintained over 20% of cells harboring mono- or biallelic edits. Off-target editing was assessed at over 900 candidate sites, with editing observed at eight sites, but no selection for or impact of these edits was observed throughout engraftment. These data support further translation of base editing of autologous HSCs for the treatment of patients with SCD.}, }
@article {pmid40802264, year = {2025}, author = {Turner, NA and Hamasaki, T and Doernberg, SB and Lodise, TP and King, HA and Ghazaryan, V and Cosgrove, SE and Jenkins, TC and Liu, C and Sharma, S and Zaharoff, S and Wahid, L and Renard, VJ and Cook, P and Raad, I and Hachem, R and Chaftari, AM and Sims, M and DeMarco, C and Miller, LG and McCarthy, MW and Morse, CG and Lucasti, C and Forrest, GN and Cherabuddi, K and Polk, C and Fazili, T and Rupp, ME and Thompson, GR and Kim, K and Strnad, L and Schnee, AE and McKinnell, JA and Ramesh, M and Silveira, FP and McCarty, TP and Lee, TC and McDonald, EG and Paolino, K and Wiegand, K and Wall, A and Riccobene, T and Patel, R and Rappo, U and Evans, S and Chambers, HF and Fowler, VG and Holland, TL and , }, title = {Dalbavancin for Treatment of Staphylococcus aureus Bacteremia: The DOTS Randomized Clinical Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.12543}, pmid = {40802264}, issn = {1538-3598}, abstract = {IMPORTANCE: Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.
OBJECTIVE: To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.
Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus bacteremia who achieved blood culture clearance following at least 72 hours but no more than 10 days of initial antibacterial therapy were included. Participants were excluded if they had central nervous system infection, retained infected prosthetic material, left-sided endocarditis, or severe immune compromise.
INTERVENTIONS: Participants were randomly assigned to receive either 2 doses of intravenous dalbavancin (n = 100; 1500 mg on days 1 and 8) or 4 to 8 total weeks of standard intravenous therapy (n = 100; cefazolin or antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant).
MAIN OUTCOMES AND MEASURES: The primary outcome was the desirability of outcome ranking (DOOR) at day 70, which involved 5 components (clinical success, infectious complications, safety complications, mortality, and health-related quality of life) and was assessed for superiority (achieved if the 95% CI for the probability of dalbavancin having a superior DOOR was >50%). Secondary outcomes included clinical efficacy at day 70 (prespecified noninferiority margin of 20%) and safety.
RESULTS: Of 200 participants randomized (mean [SD] age, 56 [16.2] years; 62 females [31%]), 167 (84%) survived to day 70 and had an efficacy assessment. Participants without a day 70 efficacy assessment were treated as clinical failures in the analyses. The probability of a more desirable day 70 outcome with dalbavancin vs standard therapy was 47.7% (95% CI, 39.8% to 55.7%). Regarding secondary outcomes, clinical efficacy was documented in 73 of 100 for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, -11.5% to 13.5%]), meeting the noninferiority criterion. Serious adverse events were reported in 40 of 100 participants who received dalbavancin and 34 of 100 participants who received standard therapy; treatment-related adverse events were uncommon in both groups.
CONCLUSIONS AND RELEVANCE: Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes these findings may help inform use of dalbavancin in clinical practice.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04775953.}, }
@article {pmid40801398, year = {2025}, author = {Childers, CP and Foe, LM and Mujumdar, V and Mabry, CD and Selzer, DJ and Senkowski, CK and Ko, CY and Tsai, TC}, title = {Longitudinal Trends in Efficiency and Complexity of Surgical Procedures: Analysis of 1.7 Million Operations Between 2019 and 2023.}, journal = {Journal of the American College of Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1097/XCS.0000000000001588}, pmid = {40801398}, issn = {1879-1190}, abstract = {BACKGROUND: CMS has proposed reducing the work RVU valuations for most surgical procedures by 2.5% through an efficiency adjustment based on the assumption that surgical work and operative length have decreased over time. Whether the length and complexity of surgical procedures has decreased or increased is unknown. Empirical data on trends in surgical length and complexity are needed to guide evidence-based regulations by federal policymakers.
STUDY DESIGN: The National Surgical Quality Improvement Program registry was analyzed in 2019 and 2023. Analysis was performed at the CPT level and limited to codes with at least 1,000 underlying cases. The primary outcome was surgical efficiency defined as skin-to-skin operative time. Secondary outcomes were measures of patient complexity including preoperative risk factors (e.g., age, comorbidities) and 30-day morbidity and mortality.
RESULTS: The sample included 1,704,311 operations across 249 CPT codes and 11 surgical specialties. Collectively, these codes accounted for $3.2B in fee-for-service Medicare spending in 2023. Overall, operative times increased by 3.1% (CI 3.0-3.3%, p<0.001) in 2023 compared to 2019, or 0.8%/year (CI 0.7-0.8%/year, p<0.001). At the procedure level, 90% of CPT codes had longer or similar operative times in 2023 compared to 2019. Statistically, all measures of complexity also increased over the study time period, without a change in operative mortality.
CONCLUSIONS: For the majority of surgical procedures, operative times have stayed the same or increased from 2019 to 2023. Patient complexity also correspondingly increased. The rationale for an efficiency adjustment to the Medicare physician fee schedule for surgical procedures is not supported by objective data from a national surgical registry.}, }
@article {pmid40798950, year = {2025}, author = {Fouda, GG and Singh, A and Nelson, A and Janes, H and Martin, T and Levy, O and Wu, D and Zou, F and Jean-Philippe, P and De Paris, K and Van Rompay, KKA and Permar, SR}, title = {Integration of Preclinical and Clinical Vaccine Safety and Immunogenicity Testing for Development of a Pediatric HIV Vaccine to Achieve Protective HIV Immunity Prior to Adolescence.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570162X366522250721113420}, pmid = {40798950}, issn = {1873-4251}, abstract = {An optimal HIV vaccine should provide protective immunity before sexual debut to prevent infection in adolescents and young adults, including acute infections in women of childbearing age. Such a vaccine will likely require multiple sequential immunization doses and would therefore be ideally initiated in childhood. Many of the world's most successful vaccines are initiated in childhood for the induction of lifelong immunity and/or immunity that can be boosted later in life as part of the WHO Expanded Program on Immunization (EPI). Thus, the EPI vaccine framework provides an infrastructure that could be leveraged for the implementation of a multidose HIV immunization regimen. Early childhood also provides a window of time in which there is minimal HIV exposure risk, and the plasticity of the early life immune landscape may present advantages for the elicitation of broadly neutralizing Antibodies (bnAbs), a primary target for HIV vaccination. Sequential vaccination with adjuvanted immunogens targeting spe-cific bnAb lineages is a promising HIV vaccine strategy, and several vaccine candidates are cur-rently being tested in adult clinical trials. It will be critical also to evaluate the most promising immunogens and adjuvants in pediatric settings. Preclinical studies, including in vitro and in sil-ico modelling as well as studies in animal models, will be essential to guide the design of future pediatric vaccine trials. This review summarizes current advances in bnAb germline targeting immunization. It provides the rationale for a better integration of preclinical and clinical vaccine studies to facilitate the development of a vaccine that achieves protective immunity in preadoles-cence.}, }
@article {pmid40796223, year = {2025}, author = {Grignani, G and Rutkowski, P and Lebbé, C and Guida, M and Gaudy-Marqueste, C and Spagnolo, F and Burgess, M and Morano, F and Montaudié, H and Depenni, R and Spada, F and Yeung, CCS and Pulini, J and Cornfeld, M and Tian, C and Bhatia, S}, title = {Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201).}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, doi = {10.1136/jitc-2025-012478}, pmid = {40796223}, issn = {2051-1426}, abstract = {BACKGROUND: POD1UM-201, an open-label, single-arm, phase II multiregional study, evaluated efficacy and tolerability of retifanlimab, a humanized monoclonal antibody targeting programmed cell death protein-1 (PD-1) in chemotherapy-naive patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).
METHODS: Patients were enrolled across 34 sites in the USA, Canada, and Europe. Eligible patients were ≥18 years with confirmed recurrent advanced locoregional or metastatic MCC not amenable to surgery or radiation therapy, had not received previous systemic treatment, had measurable disease, and Eastern Cooperative Oncology Group performance status 0-1. Retifanlimab 500 mg was administered intravenously every 4 weeks (Q4W) for up to 2 years. The primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: A total of 101 patients were enrolled between February 12, 2019, and June 16, 2021, with a median duration of follow-up for response of 22.2 (range: 1.1-55.3) months. ORR was 54.5% (95% CI: 44.2% to 64.4%; n=55), including 18 patients (17.8%) with complete responses (CRs) and 37 (36.6%) with partial responses (PRs). DCR was 60.4% (95% CI: 50.2% to 70.0%; n=61). Median DOR was not reached (95% CI: 14.0 months to not estimable (NE)) in patients who achieved CR and was 25.3 months (95% CI: 14.2 months to NE) in those with PR. With a median follow-up of 9.3 (range: 0.0-57.1) months, the estimated median PFS was 16.0 months (95% CI: 9.0 months to 32.2). Median OS was not reached with 63% of patients alive at 3 years. The safety profile was representative of the PD-(ligand)1 inhibitor class, with grade 3 immune-related adverse events occurring in 11 patients (10.9%).
CONCLUSIONS: Retifanlimab 500 mg Q4W led to frequent and durable responses in chemotherapy-naive patients with advanced MCC with an acceptable safety profile. Retifanlimab represents a new immunotherapy option for patients with locally advanced or metastatic MCC.
TRIAL REGISTRATION NUMBER: NCT03599713; EudraCT 2018-001627-39.}, }
@article {pmid40796174, year = {2025}, author = {Sevilla-González, M and Hanson, PA and Islam, J and Hsu, S and Tsoukas, MA and Marliss, EB and Reiner, AP and Gravel, M and Kooperberg, C and Clish, CB and Manning, AK and Sladek, R and Meigs, JB and Burgos, SA}, title = {Compartment-Specific Metabolic Alterations to Insulin Reflect Adiposity-Driven Variation and Predict Type 2 Diabetes.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgaf454}, pmid = {40796174}, issn = {1945-7197}, abstract = {CONTEXT: The metabolic mechanisms underlying insulin resistance (IR) are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D).
OBJECTIVE: To characterize insulin-induced metabolomic changes during a hyperinsulinemic-euglycemic clamp and evaluate a derived risk score's predictive value for T2D.
Clamp studies were conducted in 80 adults (38 with T2D, 42 without) to measure plasma and muscle metabolites in fasting and hyperinsulinemic states. An IR metabolomic score was developed and tested in a prospective case-control study (367 cases, 910 controls) from the Women's Health Initiative (28.5-year follow-up).
MAIN OUTCOME MEASURES: Metabolite changes during hyperinsulinemia and incident T2D.
RESULTS: Hyperinsulinemia altered 79.5% of plasma metabolites (notably fatty acids, lactate, pyruvate) and 15.8% of muscle metabolites (e.g., branched-chain and aromatic amino acids). T2D was associated with higher triglycerides and lower tricarboxylic acid intermediates during clamp. Adiposity amplified insulin-induced increases in plasma lipids. The risk score predicted incident T2D (HR 1.20 per SD; 95% CI: 1.09-1.32; P = 7.4 × 10⁻⁴).
CONCLUSIONS: Compartment-specific metabolic responses to insulin are shaped by adiposity and predict future T2D risk, supporting use of metabolomic signatures for early identification and prevention.}, }
@article {pmid40795788, year = {2025}, author = {van der Heijden, MS and Powles, T and Gupta, S and Loriot, Y and Galsky, MD and Valderrama, BP and Sridhar, SS and Yu, EY and Iyer, G and Kikuchi, E and Castellano, D and Hoffman-Censits, J and Drakaki, A and Mar, N and Maroto Rey, JP and Vulsteke, C and Arafat, W and Duran, I and Dawson, NA and Swami, U and Gorla, S and Moreno, BH and Yu, X and Lu, YT and Bedke, J}, title = {Exploratory subgroup analyses of EV-302: a phase III global study to evaluate enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma.}, journal = {ESMO open}, volume = {10}, number = {8}, pages = {105544}, doi = {10.1016/j.esmoop.2025.105544}, pmid = {40795788}, issn = {2059-7029}, abstract = {BACKGROUND: In the phase III EV-302 study (NCT04223856), enfortumab vedotin (EV) plus pembrolizumab (P) demonstrated superior efficacy and safety versus platinum-based chemotherapy in patients with previously untreated locally advanced/metastatic urothelial cancer (la/mUC). We report the efficacy of EV+P in prespecified subgroups, including those defined by cisplatin eligibility status, the presence or absence of liver metastases, and metastatic disease sites.
METHODS: Patients with previously untreated la/mUC were randomly assigned 1 : 1 to receive either EV 1.25 mg/kg and pembrolizumab 200 mg, or gemcitabine plus cisplatin or carboplatin, all intravenously. The two primary endpoints were progression-free survival (PFS) and overall survival (OS). Confirmed objective response rate was one of the secondary endpoints.
RESULTS: Overall, 886 patients were randomized: 442 to EV+P and 444 to chemotherapy. Baseline characteristics were balanced across treatment groups. Efficacy and safety data for the intention-to-treat (ITT) population, along with PFS and OS data for cisplatin-eligible and -ineligible patients, were previously published (Powles et al. N Eng J Med, 2024). In this analysis, EV+P showed benefit across prespecified subgroups that was consistent with the ITT population. OS benefit in the EV+P arm versus chemotherapy was seen across all subgroups, including patients with liver metastases (OS 19.1 versus 10.1 months), patients without liver metastases [OS not estimable (NE) versus 17.9 months], patients with visceral metastases (OS 25.6 versus 13.6 months), and in patients with lymph node-only disease (OS NE versus 27.5 months). In addition, confirmed objective response rate and PFS benefit with EV+P versus chemotherapy was seen across all examined subgroups.
CONCLUSION: Along with previously published safety data, EV+P demonstrated benefit compared with chemotherapy across all prespecified subgroups, consistent with the ITT population and supporting EV+P as the standard of care for first-line treatment of la/mUC.}, }
@article {pmid40795197, year = {2025}, author = {Paturi, S and Banerjee, R}, title = {Step Count, Step Aside: Newer Physical Activity Metrics to Predict Survival in Oncology.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500197}, doi = {10.1200/CCI-25-00197}, pmid = {40795197}, issn = {2473-4276}, }
@article {pmid40794593, year = {2025}, author = {Matsen, FA and Sung, K and Johnson, MM and Dumm, W and Rich, D and Starr, T and Song, YS and Bradley, P and Fukuyama, J and Haddox, HK}, title = {A sitewise model of natural selection on individual antibodies via a transformer-encoder.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msaf186}, pmid = {40794593}, issn = {1537-1719}, abstract = {During affinity maturation, antibodies are selected for their ability to fold and to bind a target antigen between rounds of somatic hypermutation. Previous work has identified patterns of selection in antibodies using B cell repertoire sequencing data. However, this work is constrained by needing to group many sequences or sites to make aggregate predictions. In this paper, we develop a transformer-encoder selection model of maximum resolution: given a single antibody sequence, it predicts the strength of selection on each amino acid site. Specifically, the model predicts for each site whether evolution will be slower than expected relative to a model of the neutral mutation process (purifying selection) or faster than expected (diversifying selection). We show that the model does an excellent job of modeling the process of natural selection on held out data, and does not need to be enormous or trained on vast amounts of data to perform well. The patterns of purifying vs diversifying natural selection do not neatly partition into the complementarity-determining vs framework regions: for example, there are many sites in framework that experience strong diversifying selection. There is a weak correlation between selection factors and solvent accessibility. When considering evolutionary shifts down a tree of antibody evolution, affinity maturation generally shifts sites towards purifying natural selection, however this effect depends on the region, with the biggest shifts toward purifying selection happening in the third complementarity-determining region. We observe distinct evolution between gene families but a limited relationship between germline diversity and selection strength.}, }
@article {pmid40792429, year = {2025}, author = {Zhou, P and Mills, CB and Dong, ZM and Barber, BR and Beronja, S}, title = {Barcoded Orthotopic Patient-Derived Head & Neck Squamous Cell Carcinoma Model Demonstrating Clonal Stability and Maintenance of Cancer Driver Mutational Landscape.}, journal = {Cancer medicine}, volume = {14}, number = {15}, pages = {e71137}, pmid = {40792429}, issn = {2045-7634}, support = {//Fred Hutchinson Cancer Research Center/ ; //Dick and Loraine Burger Pilot Funding/ ; //AAO-HNSF Resident Research Grant/ ; }, mesh = {Humans ; Animals ; Mice ; *Squamous Cell Carcinoma of Head and Neck/genetics/pathology ; *Head and Neck Neoplasms/genetics/pathology ; *Mutation ; Disease Models, Animal ; Female ; Xenograft Model Antitumor Assays ; Mice, SCID ; Exome Sequencing ; Male ; *DNA Barcoding, Taxonomic ; }, abstract = {OBJECTIVE: To illustrate a new barcoded orthotopic patient-derived xenograft (PDX) mouse model where one can investigate phenotypic effects of single-cell level gene manipulation in a pooled format. To address some concerns of current PDX mouse models of head and neck squamous cell carcinoma (HNSCC): (1) genomic evolution with passage by generating high-purity cancer cells, which can also be utilized for other downstream applications, including cell culture-based studies, and (2) cost-effectiveness of current PDX models.
METHODS: Two-millimeter tumor cubes from nine patients were implanted into immunodeficient mouse flanks subcutaneously. Purified tumor cells were obtained from subcutaneous xenografts. Various numbers of purified tumor cells were then injected into the lingual tissue of immunodeficient mice, and the lowest amount of cells needed to achieve a 100% orthotopic engraftment rate were identified. Clonal stability was tested using a lentiviral barcoding system. The orthotopic PDXs' genetic landscapes were characterized using whole exome sequencing.
RESULTS: This approach yielded an overall engraftment rate of 88.9%. The purification process increased cancer cell purity from 34% to 92%. Lingual injection of 100,000 purified tumor cells achieved a 100% orthotopic engraftment rate from purified subcutaneous PDX tumor cells while maintaining clonal and genetic stability.
CONCLUSION: Our study presents a barcoded orthotopic patient-derived xenograft model for head and neck squamous cell carcinoma with clonal stability. This model provides a way to study phenotypic effects of single cell level gene manipulation in a pooled format. The method can be adapted for in vitro work as well.}, }
@article {pmid40792015, year = {2025}, author = {Raychaudhuri, S and Othus, M and Percival, MM and Garcia-Manero, G and Appelbaum, FR and Erba, HP and Appelbaum, JS}, title = {Treatment discontinuation due to toxicity for patients with acute myeloid leukemia receiving intensive chemotherapy.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100129}, pmid = {40792015}, issn = {2950-3280}, }
@article {pmid40792014, year = {2025}, author = {DaSilva, B and Darwin, A and Zhang, A and Vyas, RD and Russell, K and Gilbert, JS and Tan, V and Feldt, S and Johnston, H and Liang, EC and DuVall, AS and Liedtke, M and Stock, W and Cassaday, RD and Schwartz, M and Leonard, JT and Muffly, LS and Luskin, MR}, title = {Real-world performance of the CALGB 10403 regimen in young adults in the United States.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100111}, pmid = {40792014}, issn = {2950-3280}, abstract = {The Cancer and Leukemia Group B 10403 (C10403) trial prospectively demonstrated the safety and efficacy of administering an asparaginase-containing pediatric regimen for the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia. Since its implementation as standard of care, it is unknown how the C10403 regimen performs beyond the clinical trial setting. To bridge this knowledge gap, we designed a multicenter retrospective cohort study to examine the safety, efficacy, and challenges of completing C10403 in the "real world." From October 2012 through June 2020, a total of 139 patients began induction as per the C10403 regimen across 6 US academic cancer centers. The median age was 26 years (range, 17-39), 69% were male, 55% were non-Hispanic White, and 27% were Hispanic. Among them, 122 patients (88%) achieved complete remission or complete remission with incomplete count recovery (CR/CRi) with C10403, 48 (35%) completed maintenance therapy, and 47 (34%) changed postremission regimens while in CR/CRi. The 3-year event-free survival (EFS) was 66% (95% confidence interval [CI], 55-74), and the 3-year overall survival (OS) was 81% (95% CI, 74-87). Four deaths occurred while on C10403 treatment: 1 during induction; and 3 later in the treatment course. The most common grade 3 or 4 adverse events during induction included alanine aminotransferase elevation (22%) and sepsis (14%). B-cell immunophenotype (hazard ratio [HR], 2.45; 95% CI, 1.09-5.48), Philadelphia chromosome-like genetics (HR, 3.05; 95% CI, 1.25-7.44), and Hispanic ethnicity (HR, 2.00; 95% CI, 1.06-3.78) were associated with worse EFS in univariate analyses. Overall, these real-world results are comparable to those of the C10403 trial. Further improvements are needed to enhance outcomes and regimen tolerability in the AYA population.}, }
@article {pmid40789739, year = {2025}, author = {Tachiki, L and Moshiri, Y and Hippe, DS and Gong, E and Zawacki, L and Pulliam, T and Lachance, K and Church, C and Fu, A and Huynh, E and Remington, AJ and Harikrishnan, N and Bierma, M and Doolittle-Amieva, C and Akaike, T and Park, SY and Alexander, NA and Zaba, L and Bhatia, S and Nghiem, PT}, title = {Risk of disease progression after discontinuing immunotherapy in 105 patients with Merkel cell carcinoma who responded to PD-1 pathway blockade.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, doi = {10.1136/jitc-2025-012123}, pmid = {40789739}, issn = {2051-1426}, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/pathology/mortality ; Male ; Female ; Disease Progression ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/pathology ; *Immunotherapy/methods ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors ; }, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) are the preferred systemic therapy for most patients with advanced Merkel cell carcinoma (MCC). However, the optimal duration of treatment for patients responding to ICI is unclear. Emerging data from retrospective analyses indicate a higher risk of MCC progression after ICI discontinuation, as compared with continuing ICI.
METHODS: We performed a retrospective cohort study to evaluate the rate of progressive disease (PD) after treatment discontinuation in patients with advanced MCC who experienced objective responses to first-line ICI. We evaluated whether the risk of PD was associated with the reason for treatment discontinuation (elective vs due to toxicity) and depth of response (complete vs partial response (CR vs PR)).
RESULTS: Among 105 responders, 58 discontinued ICI (median treatment duration: 12 months), and 47 continued ICI (median treatment duration: 20 months) at data cut-off. With a median follow-up of 34 months from ICI initiation, 33% of the entire cohort experienced disease progression at 2 years. 2 years after ICI initiation, 39% of patients who discontinued ICI had disease progression, compared with 14% of patients who continued ICI (HR=2.34 (95% CI: 1.07 to 5.12), p=0.034). Among patients who discontinued ICI, those with PR had a numerically higher rate of progression compared with patients with CR at 2 years after ICI discontinuation (56% vs 29%, respectively; HR=1.74 (95% CI: 0.72 to 4.20), p=0.22). Patients who discontinued due to toxicity had numerically higher rates of progression at 2 years (N=28) compared with patients who discontinued electively (N=30) (45% vs 31%, respectively; HR=2.08 (95% CI: 0.79 to 5.46), p=0.14). Among responders who stayed on ICI and had not progressed by 1 year, those who electively discontinued ICI had a high chance of remaining progression-free at 2 years (89%), similar to those who continued ICI (96%, p=0.59).
CONCLUSIONS: This study highlights the high progression risk following ICI discontinuation in advanced MCC, especially among patients with non-CRs or those discontinuing early. While elective discontinuation may be appropriate after durable CRs (response≥1 year), greater caution is warranted in other settings.}, }
@article {pmid40789102, year = {2025}, author = {Bhandari, R and Chen, Y and Chow, EJ and Howell, RM and Kenney, LB and Krull, KR and Leisenring, W and Nathan, PC and Neglia, JP and Ness, KK and Oeffinger, KC and Snyder, C and Turcotte, LM and Wong, FL and Yasui, Y and Armstrong, GT and Armenian, SH}, title = {Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500385}, pmid = {40789102}, issn = {1527-7755}, support = {K12 CA001727/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: There are limited data on the risk for mortality and health outcomes among the increasing population of older (age >50 years) survivors of childhood cancer during this later stage in life when there is an expected increase in aging-related morbidities.
METHODS: We assessed cause-specific mortality, incident new cancers, chronic health conditions (CHCs), frailty, and health status among survivors from the Childhood Cancer Survivor Study, conditional on surviving to 50 years. We calculated conditional survival rates, standardized mortality ratios (SMRs), and, for incident new cancers, cumulative burden, standardized incidence ratios (SIRs), and relative rates (RRs), compared with the general US population. RRs for CHCs and prevalence ratios for frailty and health status outcomes were calculated for survivors compared with siblings. Piecewise exponential regression identified risk factors.
RESULTS: Among 7,490 childhood cancer survivors alive at age 50 years, subsequent 5-, 10-, and 15-year mortality risks were 8%, 18%, and 32%, respectively; overall SMR was 3.2 (95% CI, 3.0 to 3.4). SMRs were highest for death due to new cancer (SMR = 4.7; 95% CI, 4.2 to 5.2). In subset analysis, survivors without radiation therapy (RT) exposure had similar new cancer rates as the general population. The population attributable fraction of new cancers to RT was 40%. Survivors had >2-fold risk of severe, life-threatening, or fatal CHCs (any: RR, 2.6 [95% CI, 2.2 to 3.1]; multiple: RR, 3.3 [95% CI, 2.5 to 4.4]), specifically among survivors with history of RT exposure, compared with siblings. We identified no associations between chemotherapy and late health outcomes.
CONCLUSION: Older survivors of childhood cancer continue to have an elevated burden of premature mortality, new cancers, and adverse health outcomes as they age. The increased risk for cancer and CHCs among these older survivors is associated with RT, but not chemotherapy, exposure.}, }
@article {pmid40766425, year = {2025}, author = {Chambwe, N and Kennedy, SR and Kohrn, BF and Lazarchuk, P and Leutert, M and Qin, G and Tercan, B and Sanchez-Contreras, M and Tang, W and Graber, JJ and Paddison, PJ and Villén, J and Shmulevich, I and Monnat, RJ}, title = {Cellular heterogeneity and therapeutic response profiling of human IDH+ glioma stem cell cultures.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766425}, issn = {2692-8205}, abstract = {Glioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. They can capture and propagate key GBM primary tumor molecular and cellular features. We have deeply characterized four isocitrate dehydrogenase (IDH)-expressing (or IDH+) GSC cultures from unrelated adults to serve as cellular models for the majority of adult primary GBM. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without requiring specialized growth substrates; have well-defined genomic and mtDNA variants and gene/protein expression profiles; and highly reproducible dose-survival curves when treated with the GBM standard-of-care therapies of ionizing radiation (IR) and temozolomide (TMZ). We also illustrate how expressed lentiviral barcodes, mtDNA variants and single cell gene expression profiling can be used to define and track cellular heterogeneity over 40 days after IR treatment. These well-characterized IDH+ GSC cultures can support many high throughput in vitro assay formats, including xenograft, organoid and other GBM disease modeling protocols. They should prove a useful resource to better understand GBM biology, and to identify new and more effective GBM therapies and treatment regimens.}, }
@article {pmid40789098, year = {2025}, author = {Johns, TS and Estrella, MM and Hébert, J and Franceschini, N and Larson, JC and Boulware, LE and Snetselaar, L and Golestaneh, L and Shadyab, AH and Shivappa, N and Mossavar-Rahmani, Y and Melamed, ML}, title = {Dietary Inflammatory Potential and the Risk of Incident Kidney Failure in the Women's Health Initiative.}, journal = {Kidney360}, volume = {}, number = {}, pages = {}, doi = {10.34067/KID.0000000801}, pmid = {40789098}, issn = {2641-7650}, abstract = {BACKGROUND: Diet affects inflammation and kidney health, but few studies have investigated dietary inflammatory potential in CKD progression, particularly in women. We aim to examine this association in the Women's Health Initiative (WHI).
METHODS: We conducted a non-concurrent prospective cohort study among WHI participants enrolled in the clinical trials and observational study (1993-1998) without baseline CKD and with available dietary intake assessments, Medicare data, and creatinine measurements at enrollment. The inflammatory potential of diets was assessed using the dietary inflammatory index (DII®), an acultural tool that quantifies diets from anti-inflammatory to pro-inflammatory. Scores were categorized into quartiles, with Q1 (reference group) and Q4 indicating the least and most inflammatory diets, respectively. Incident kidney failure (CKD stage G5, ESKD, or transplantation) was identified using diagnosis codes in Medicare claims from enrollment through 12/31/2019. We performed multivariable Cox proportional hazards regression and modeled death as a competing risk to determine the risk of incident kidney failure.
RESULTS: Among the 17,334 women included in our study, the baseline mean age was 64.9 years (standard deviation 7.1); 33.5% self-identified as Black, 8.8% as Hispanic, 38% had hypertension, and 6.8% had diabetes mellitus. Baseline mean estimated glomerular filtration rate (eGFR) was 87.2 ml/min/1.73m2. Over a mean follow-up of 11.2 years, 1852 women (10.7%) developed kidney failure. Compared to Q1, women with dietary patterns in Q4 had a 18% higher risk (95% confidence interval 1.03-1.37; p-trend=0.01) of developing kidney failure after adjusting for age, race/ethnicity, education, region, comorbidities, medications, smoking, energy intake, physical activity, eGFR, and body mass index. Competing risk models yielded similar results.
CONCLUSIONS: A pro-inflammatory diet (e.g., enriched in processed foods, refined sugars, and red meat) was associated with incident kidney failure in postmenopausal women without baseline CKD. Clinical trials are needed to assess the impact of an anti-inflammatory dietary pattern on CKD risk and progression.}, }
@article {pmid40788762, year = {2025}, author = {Khyzha, N and Ahmad, K and Henikoff, S}, title = {Protocol for the spatiotemporal profiling of RNA within nuclear compartments in human cell lines using SLAM-RT&Tag.}, journal = {STAR protocols}, volume = {6}, number = {3}, pages = {104017}, doi = {10.1016/j.xpro.2025.104017}, pmid = {40788762}, issn = {2666-1667}, abstract = {Measuring RNA residence time within nuclear compartments provides insight into their roles as either storage sites or transient processing hubs. This protocol describes SLAM-RT&Tag, a genomic technique that integrates RNA metabolic labeling with RT&Tag, an RNA proximity labeling method. We detail steps for RNA labeling, library preparation, and computational quantification of T-to-C conversion events to infer RNA dynamics within nuclear compartments in human cell lines. For complete details on the use and execution of this protocol, please refer to Khyzha et al.[1].}, }
@article {pmid40785644, year = {2025}, author = {Gauthier, J and Ahn, KW and Patel, J and Lian, Q and Badawy, S and Cairo, MS and Delgado, J and Grover, N and Haverkos, B and de Lima, M and Malone, A and Mussetti, A and Nieto, Y and Pawarode, A and Pearson, L and Solh, M and Sureda, A and Tun, AM and Wudhikarn, K and Yamshon, S and Shadman, M and Turtle, CJ and Hamadani, M and Herrera, AF}, title = {CD19 CAR T-Cell Therapy for Primary Mediastinal Large B-Cell Lymphoma: A CIBMTR Analysis.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70033}, pmid = {40785644}, issn = {1096-8652}, support = {U24CA076518/CA/NCI NIH HHS/United States ; HHSH250201700006C/HRSA/HRSA HHS/United States ; N00014-20-1-2705//Office of Naval Research/ ; N00014-20-1-2832//Office of Naval Research/ ; }, abstract = {T cells engineered with CD19-directed chimeric antigen receptors (CD19 CAR) T cells have become standard treatment for patients with high risk, relapsed or refractory (R/R) large B-cell lymphomas (LBCL). However, outcomes in patients with rare subsets of LBCL, such as primary mediastinal large B-cell lymphoma (PBMCL), have not been well characterized. The impact of prior immune checkpoint inhibitor (ICI) treatment, commonly used to treat R/R PMBCL, is also unknown. To address these gaps, we retrospectively analyzed CIBMTR registry data including PMBCL patients undergoing CD19 CAR T-cell therapy per standard-of-care. A total of 135 PMBCL adults from 66 centers were included. Median age at the time of CAR T-cell therapy was 32. Thirty-nine patients (28.9%) had received an ICI prior to CAR T-cell therapy. The best overall and complete response (CR) rates after CD19 CAR T-cell therapy were 79% and 67.7%, respectively. The 2-year progression-free (PFS) and overall survival (OS) were 58.6% (95% CI, 49.7-67.3) and 80.8% (95% CI, 72.6-87.8), respectively. The 2-year cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were 36% (95% CI, 27.8-44.7) and 5.4% (95% CI, 1.9-10.5), respectively. We observed grade ≥ 3 CRS and ICANS in 6.1% and 14.7%, respectively. Prior ICI exposure was associated with lower 2-year CI of relapse (ICI-exposed, 21.7%; ICI-naïve, 41.6%; p = 0.03) and higher 2-year NRM (ICI-exposed, 11.7%; ICI-naïve, 2.8%; p = 0.03). We could not confirm statistically different PFS (p = 0.19) or OS (p = 0.26) between ICI-exposed and ICI-naïve patients. CD19 CAR T-cell therapy led to high rates of durable responses in PMBCL patients with low rates of severe toxicities.}, }
@article {pmid40784763, year = {2025}, author = {Puschel, K and Arancibia, V and Rioseco, A and Paz, S and Soto, MG and Martinez, J and Faundez, M and Acevedo, F and Di Biase, F and Emery, J and León, A and Are, C and Thompson, B}, title = {Challenges of cancer survivorship care in Chile: a longitudinal study comparing the quality of care and quality of life for cancer survivors in a primary care network and a cancer centre in Chile.}, journal = {BMJ open}, volume = {15}, number = {8}, pages = {e097015}, pmid = {40784763}, issn = {2044-6055}, mesh = {Humans ; *Quality of Life ; Chile/epidemiology ; Female ; *Cancer Survivors/psychology/statistics & numerical data ; Male ; *Primary Health Care/standards ; Middle Aged ; *Quality of Health Care ; Retrospective Studies ; Longitudinal Studies ; Aged ; Adult ; *Survivorship ; *Cancer Care Facilities ; *Colorectal Neoplasms/therapy/psychology ; *Breast Neoplasms/therapy/psychology ; }, abstract = {OBJECTIVE: The rapid growth in the cancer survivor population in Chile and Latin America raises new challenges in addressing their care needs. This study assesses the health status and compares the quality of care and quality of life in cancer survivors at a primary care network and a private cancer centre in Santiago, Chile.
DESIGN: Retrospective cohort study.
SETTING: Three primary care clinics and one cancer centre in Chile.
PARTICIPANTS: All breast and colorectal cancer patients identified from a primary care retrospective cohort of 61 174 were followed from 2018 to 2023 and compared with an equivalent sample of patients from a university cancer centre identified during the same period.
OUTCOME MEASURES: Quality of care was assessed based on American Cancer Society standards, while quality of life was measured using the EuroQol 5 Dimensions-5 Levels survey instrument.
RESULTS: A total of 420 cancer survivors participated in the study; 208 from primary care and 212 from the cancer centre. All participants received substandard care. Patients in primary care had lower educational levels and higher rates of comorbidity. They reported a lower quality of life score (72.22 vs 78.43, p<0.001), a higher prevalence of chronic pain (37.02% vs 25.6%, p=0.016) and more severe mental health symptoms (19.89% vs 10.05%, p=0.03). Differences in educational level and cancer stage at diagnosis explained the observed disparities in chronic pain and mental health disorders between the two populations. Primary care patients received more psychosocial care (OR=2.29; 95% CI: 1.55 to 3.39), cardiovascular assessment (OR=2.66; 95% CI:2.17 to 3.26) and psychosocial evaluations (OR: 9.07; 95% CI:4.75 to 17.32).
CONCLUSION: Cancer survivors face a significant disease burden and receive substandard care in Chile. As the primary source of care for this population, primary care is challenged to better integrate with speciality care to develop an effective shared care model for cancer survivors.}, }
@article {pmid40781843, year = {2025}, author = {Zhang, QS and Kang, J and Lybarger, K and Glenn, MC and Sponseller, P and Blau, KH and Ford, E}, title = {Semi-automated topic identification for radiation oncology safety event reports using natural language processing and statistical modeling.}, journal = {Medical physics}, volume = {52}, number = {8}, pages = {e17936}, doi = {10.1002/mp.17936}, pmid = {40781843}, issn = {2473-4209}, mesh = {*Natural Language Processing ; *Radiation Oncology ; *Models, Statistical ; Automation ; Humans ; *Safety ; Bayes Theorem ; }, abstract = {BACKGROUND: Incident learning provides valuable narrative text about safety and quality, but the large-volume unstructured data is difficult to analyze.
PURPOSE: We present a semi-automated method to categorize safety-related event reports and validate it using Radiation Oncology reports.
METHODS: We analyzed English text from 7174 safety-related event reports in a Radiation Oncology department, dated between 2012 and 2021. Units of text called "tokens" were preprocessed for meaningful content, resulting in 4216 tokens. 6760 reports had at least one filtered token. We fit a correlated topic model (CTM) with K = 50 topics, estimating Bayesian posterior probability distributions over tokens and proportions of each report that were about each topic. To validate the model by assessing for expert agreement on meaningful topic labels for topics, five experts independently assigned topic labels to topics by reading the top-10 most probable tokens per topic and tokens' posterior probabilities ("top-10 tokens" approach), and by separately reading any reports that were estimated to be at least 90% about a topic ("case-reports" approach). Consensus topic labels (CTLs) such as "Brachytherapy" or "Orders" were assigned to topics.
RESULTS: Of 50 modeled topics, 37 (74%) had a majority agreement of experts on the CTL assignment, supporting the model's validity. 36 topics had a CTL assigned to them via the top-10 tokens approach. Of 50 topics, 20 had at least one report that was ≥ 90% about the topic such that the case-reports approach applied. 18 of the 20 had a CTL assigned via that approach. Of 55 CTLs assigned, seven were not found by prior labeling of reports' topics during review of reports over the years.
CONCLUSIONS: We demonstrated a semi-automated method to categorize Radiation Oncology safety-related event reports by topic, offering an expedited alternative to a person reading many reports and enabling the identification of topics not discovered by reading individual reports.}, }
@article {pmid40781345, year = {2025}, author = {Alson, JG and Doll, KM and Hempstead, BH and Barr, L and Lavallee, DC and Sage, L and Moore, A and Ramsey, SD and Wolff, EM and Comstock, BA and Monsell, SE and Katz, R and Gamble, CR and Beavis, AL and Watat, M and , }, title = {Advancing equity in cancer research through principled partnership: stakeholder engagement practices in The Social Interventions for Support during Treatment for Endometrial cancer and Recurrence (SISTER) Study.}, journal = {Research involvement and engagement}, volume = {11}, number = {1}, pages = {95}, pmid = {40781345}, issn = {2056-7529}, support = {AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; }, abstract = {BACKGROUND: In cancer, lack of social support is associated with reduced survival. Peer support interventions have reduced social isolation among Black women with cancer but have yet to be adapted for Black people diagnosed with endometrial cancer - a growing, high-need demographic that has been historically excluded from community-engaged research. Our research team at the University of Washington addressed this gap by working within an established community partnership to develop a pragmatic randomized controlled trial to adapt and test social support interventions among Black women with EC - the Social Interventions for Support during Treatment of Endometrial Cancer and Recurrence (SISTER) Study. The goal of this commentary is to describe the stakeholder engagement practices used in the conceptualization and start-up of the SISTER Study.
MAIN TEXT: The research team, including Black endometrial cancer survivors, developed a grant proposal, grounded in engagement values derived from the Patient-Centered Outcomes Research Institute[®] and the Public Health Critical Race Praxis. The team implemented values-aligned stakeholder engagement activities, including the creation of an advisory board charter, structuring meetings and roles, incorporating stakeholder input into study material and protocols, establishing an external advisory board, and developing an engagement evaluation plan. Overall, we learned that it is possible to design and operationalize a community-engaged pragmatic randomized controlled trial in alignment with a racial equity social justice research methodology and patient-centered outcomes research engagement practices. We describe other lessons learned, including operational challenges to implementing our engagement practices and our approaches to addressing these challenges, and promising practices to replicate in future studies or partnerships.
CONCLUSION: The SISTER Study is an example of establishing principled methods of stakeholder engagement within an area of study and population that has been underrepresented in stakeholder-engaged research. The engagement practices within the SISTER Study can inform community-academic partnership practices in health equity research.}, }
@article {pmid40781068, year = {2025}, author = {Kelnhofer-Millevolte, LE and Smith, JR and Nguyen, DH and Wilson, LS and Lewis, HC and Arnold, EA and Brinkley, MR and Shin, K and Ahn, JH and Kim, ET and Kulej, K and Geballe, AP and Ramachandran, S and Avgousti, DC}, title = {Human cytomegalovirus induces neuronal gene expression through IE1 for viral maturation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7316}, pmid = {40781068}, issn = {2041-1723}, support = {GM133441//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AI145945//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; GM133434//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Cytomegalovirus/physiology/genetics/metabolism ; *Immediate-Early Proteins/metabolism/genetics ; Histones/metabolism/genetics ; *Neurons/metabolism/virology ; *Cytomegalovirus Infections/virology/genetics/metabolism ; *Virus Assembly/genetics ; Host-Pathogen Interactions/genetics ; Gene Expression Regulation ; }, abstract = {Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes occur in the context of host gene regulation is still emerging. Histone variant macroH2A1 is both important for maintaining nuclear integrity and functions to promote herpes simplex virus infection. Therefore, we hypothesized it may also function in cytomegalovirus infection. Here, we discovered that macroH2A1 is necessary for HCMV-induced cellular reorganization and formation of infectious progeny. Using RNA-seq in infected cells, we find that while all viral genes are highly expressed in the absence of macroH2A1, many HCMV-induced host genes are not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with a neuronal signature. Further, we find that HCMV immediate early protein, IE1, is both necessary and sufficient to induce these neuronal genes, providing a mechanism of activation. Together, our findings demonstrate that HCMV hijacks a dormant neuronal secretory pathway through chromatin manipulation for efficient virion maturation.}, }
@article {pmid40779734, year = {2025}, author = {Wang, L and Xu, H and Simons, RL and Beach, SRH and Lei, MK and Ong, ML and Philibert, RA and Mielke, MM and Sun, Y and Lu, Y and Chiang, CWK and Darst, BF and Ye, K}, title = {Associations of Longitudinal Changes in Blood Biomarkers of Dementia With the Proportion of Genetically Inferred African Ancestry.}, journal = {Neurology}, volume = {105}, number = {5}, pages = {e213976}, doi = {10.1212/WNL.0000000000213976}, pmid = {40779734}, issn = {1526-632X}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Alzheimer Disease/blood/genetics ; Biomarkers/blood ; *Black or African American/genetics ; Cross-Sectional Studies ; *Dementia/blood/genetics/ethnology ; *Glial Fibrillary Acidic Protein/blood ; Longitudinal Studies ; *Neurofilament Proteins/blood ; *tau Proteins/blood ; }, abstract = {BACKGROUND AND OBJECTIVES: African American individuals have a higher risk of Alzheimer disease (AD) and related dementia (ADRD) than non-Hispanic White individuals. Some cross-sectional studies with self-reported race and ethnicity have reported racial differences in circulating ADRD biomarkers, including phosphorylated tau181 (p-Tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). We aimed to examine the associations of genetically inferred African ancestry proportion with the longitudinal changes in these biomarkers and to evaluate the associations of previously identified ADRD-related genetic factors in European cohorts with these biomarkers in an African American cohort.
METHODS: This study used longitudinal data from the Family and Community Health Study, which was initiated in 1996, recruited and followed 889 African American families residing in Georgia and Iowa. Circulating p-Tau181, GFAP, and NfL were measured in serum samples collected in 2008 (wave 5) and 2019 (wave 8). Closely related individuals, genetically inferred to be third-degree relatives or closer, were excluded. Genetic ancestry proportions were inferred using the ADMIXTURE analysis. Multivariable regression analyses were performed to test the associations of African ancestry proportion with cross-sectional biomarker levels and their longitudinal changes over 11 years. We also tested the associations of selected genetic variants, polygenic scores, and APOE ε4 status with these biomarkers.
RESULTS: Our cross-sectional sample included 573 participants (mean age = 55.1 years; 69% female), whereas our longitudinal sample included 225 (57.2 years; 80% female). African ancestry proportion was not associated with cross-sectional biomarker levels but was inversely associated with the longitudinal change in p-Tau181 (β = -14.50 pg/mL, p = 0.02). The significant inverse association was robust to adjustment for age, sex, APOE ε4, socioeconomic status, physical activity, smoking, subjective cognitive decline, and various cardiovascular risk factors and comorbidities. Finally, genetic factors associated with AD and biomarkers in European cohorts were not associated with the 3 biomarkers in our African American cohort.
DISCUSSION: We found suggestive evidence that a higher African ancestry proportion is associated with an attenuated increase in the blood p-Tau181 level over time. More research is needed to characterize the longitudinal dynamics of ADRD biomarkers across ancestry and the driving biological or sociocultural factors.}, }
@article {pmid40779330, year = {2025}, author = {Wang, Q and Duerr, A and Gao, F}, title = {Addressing Population Heterogeneity for HIV Incidence Estimation Based on Recency Test.}, journal = {Statistics in medicine}, volume = {44}, number = {18-19}, pages = {e70216}, doi = {10.1002/sim.70216}, pmid = {40779330}, issn = {1097-0258}, support = {R01AI177078/NH/NIH HHS/United States ; R01DA032106/NH/NIH HHS/United States ; R37AI029168/NH/NIH HHS/United States ; ISR-US-20-10990//Gilead/ ; }, mesh = {Humans ; *HIV Infections/epidemiology ; Incidence ; Cross-Sectional Studies ; Computer Simulation ; Models, Statistical ; }, abstract = {Cross-sectional HIV incidence estimation leverages recency test results to determine the HIV incidence of a population of interest, where recency test uses biomarker profiles to infer whether an HIV-positive individual was "recently" infected. This approach possesses an obvious advantage over the conventional cohort follow-up method since it avoids longitudinal follow-up and repeated HIV testing. In this manuscript, we consider the extension of cross-sectional incidence estimation to estimate the incidence of a different target population, addressing potential population heterogeneity. We propose a general framework that incorporates two scenarios: one when the target population is a subset of the population with cross-sectional recency testing data and the other with an external target population. In addition, we propose estimators to incorporate HIV subtypes, a special type of covariate that modifies the properties of recency tests, into our framework. Through simulation studies and a data application, we demonstrate the performance of the proposed methods. We conclude with a discussion on sensitivity analysis and future work to improve our framework.}, }
@article {pmid40779102, year = {2025}, author = {Ramos, M and Shepherd, L and Sheffield, NC and Mahmoud, A and Pagès, H and Wokaty, A and Righelli, D and Risso, D and Davis, S and Oh, S and Waldron, L and Morgan, M and Carey, V}, title = {Bioconductor's Computational Ecosystem for Genomic Data Science in Cancer.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2932}, number = {}, pages = {1-46}, pmid = {40779102}, issn = {1940-6029}, mesh = {*Neoplasms/genetics ; *Genomics/methods ; Humans ; *Software ; *Computational Biology/methods ; Databases, Genetic ; *Data Science/methods ; }, abstract = {The Bioconductor project enters its third decade with over two thousand packages for genomic data science, over 100,000 annotation and experiment resources, and a global system for convenient distribution to researchers. Over 60,000 PubMed Central citations and terabytes of content shipped per month attest to the impact of the project on cancer genomic data science. This report provides an overview of cancer genomics resources in Bioconductor. After an overview of Bioconductor project principles, we address exploration of institutionally curated cancer genomics data such as TCGA. We then review genomic annotation and ontology resources relevant to cancer and then briefly survey analytical workflows addressing specific topics in cancer genomics. Concluding sections cover how new software and data resources are brought into the ecosystem and how the project is tackling needs for training of the research workforce. Bioconductor's strategies for supporting methods developers and researchers in cancer genomics are evolving along with experimental and computational technologies. All the tools described in this report are backed by regularly maintained learning resources that can be used locally or in cloud computing environments.}, }
@article {pmid40778818, year = {2025}, author = {Neill, NJ and Satpathy, S and Krug, K and Meena, JK and Ramesh Babu, N and Calderon, C and Reed, D and Weber, MJ and Dobrolecki, LE and Lewis, A and Sallas, C and Anurag, M and Holloway, KR and Huang, C and Vasaikar, S and Cardenas, MF and Kim, BJ and Chan, DW and Avanessian, SC and Tyagi, S and Orellana, M and Mao, S and Li, H and Gong, F and Kurley, SJ and Meerbrey, KL and Olson, CM and Nair, A and Sun, T and Chung, HC and Bowling, EA and Wang, JH and Zhang, P and Xiao, P and Yang, D and Stossi, F and Polley, MC and Saltzman, AB and Mundt, F and Mani, DR and Gillette, MA and Hilsenbeck, SG and Miles, G and Gutierrez, C and Osborne, CK and Lin, CY and Gray, NS and Sun, J and Wheeler, DA and Perou, CM and Malovannaya, A and Lewis, MT and Zhang, B and Ellis, MJ and Carr, SA and Westbrook, TF}, title = {Integrative proteogenomics and forward genetics reveals a novel mitotic vulnerability in triple-negative breast cancer.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-23-1173}, pmid = {40778818}, issn = {2159-8290}, abstract = {Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent with the mitotic stress caused by PTPN12 inactivation in TNBC cell lines, tumors harboring loss of PTPN12 exhibit heightened sensitivity to taxane chemotherapy. Collectively, this data suggests that PTPN12 inactivation may drive chromosomal instability and favorable MTA response in TNBC; two prominent features of the disease with unclear mechanistic etiology.}, }
@article {pmid40778675, year = {2025}, author = {Razzo, BM and Midha, S and Portuguese, AJ and Grajales-Cruz, AF and De Menezes Silva Corraes, A and Costello, P and Liu, Y and Sperling, AS and Nadeem, O and Dima, D and Banerjee, R and Cowan, AJ and Afrough, A and Anderson, LD and Lieberman-Cribbin, A and Kaur, G and Goyal, A and Atrash, S and Ferreri, CJ and Voorhees, PM and Pasvolsky, O and Lee, HC and Patel, KK and Julian, KL and Forsberg, PA and Herr, MM and Chhabra, S and Parrondo, RD and Lin, Y and Chen, A and Susanibar-Adaniya, SP and Khouri, J and Raza, S and Anwer, F and Vazquez-Martinez, M and Castaneda Puglianini, O and Sborov, DW and Davis, JA and Rossi, A and Shune, L and Bhurtel, J and Hwang, WT and Hansen, DK and Sidana, S and Garfall, AL and Richard, S}, title = {Real-World Experience with Teclistamab for Relapsed/Refractory Multiple Myeloma from the US Myeloma Immunotherapy Consortium.}, journal = {Blood cancer discovery}, volume = {}, number = {}, pages = {OF1-OF11}, doi = {10.1158/2643-3230.BCD-24-0354}, pmid = {40778675}, issn = {2643-3249}, support = {T32CA009615//Center for Cancer Research (CCR)/ ; //Leukemia and Lymphoma Society (LLS)/ ; }, abstract = {UNLABELLED: Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of postapproval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin.
SIGNIFICANCE: T cell-engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response.}, }
@article {pmid40778089, year = {2025}, author = {Thonglert, K and Greer, MD and Schaub, SK and Bowen, SR and Menghini, AM and Nyflot, MJ and Grassberger, C and Tsai, J and Zaki, P and Kim, EY and Wong, T and Apisarnthanarax, S}, title = {Simultaneous integrated boost and protection proton beam therapy approach for hepatocellular carcinoma.}, journal = {Clinical and translational radiation oncology}, volume = {54}, number = {}, pages = {101008}, pmid = {40778089}, issn = {2405-6308}, abstract = {PURPOSE: Although simultaneous integrated boost and protection with proton beam therapy (SIB-PBT) facilitates tumor dose escalation while maintaining organ-at-risk (OAR) dose constraints, clinical outcomes are limited. This study assessed the safety and efficacy of using the SIB-PBT technique in hepatocellular carcinoma (HCC) patients.
METHODS: We reviewed 47 patients with HCC who underwent SIB-PBT between 2014-2021. The radiation dose ranged from 36-67.5 Gy(RBE) in 15 fractions. SIB-PBT was used for the following reasons: minimize high-dose exposure to organs-at-risk (OARs) (n = 22, 47 %), treat targets with different dose levels (n = 6, 13 %), or both (n = 19, 40 %). Survival, local control, and toxicities were assessed using Kaplan-Meier, Fine-Gray cumulative incidence, and descriptive statistics, respectively.
RESULTS: Forty-one patients (87 %) had tumors located ≤2 cm from luminal gastrointestinal (GI) OARs. The median tumor diameter was 9.2 cm (range, 2.0-21.5 cm). The median EQD2 D50%, D95% and D99% of gross tumor volume were 79.8 (range, 51.1-85.9), 66.7 (range, 36.9-84.6) and 50.2 (range, 34.1-83.6) Gy(RBE)10, respectively. Most patients (91 %) received a D0.5 cc of <45 Gy(RBE) to luminal GI OARs. At a median follow-up of 22 months (range, 0.8-77.0 months), the 2-year cumulative incidence of local failure was 12 %. The 2-year progression-free survival and overall survival rates were 12 % (95 % CI 4.7-23.4 %), and 49 % (95 % CI, 33.2-63.2 %), respectively. One patient experienced grade 3 acute nausea/vomiting. No GI bleeding/ulcers or grade 4 + toxicity were observed. CP + 2 occurred in 5 patients.
CONCLUSION: SIB-PBT enables OAR protection along with heterogeneous tumor dose escalation and is a safe and effective treatment for HCC tumors.}, }
@article {pmid40766464, year = {2025}, author = {Holland, M and Ahmed, M and Young, JM and McFadyen, S and Drurey, JR and Ostrowski, EA and Levin, TC}, title = {Hypermutable hotspot enables the rapid evolution of self/non-self recognition genes in Dictyostelium.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766464}, issn = {2692-8205}, support = {R01 GM074108/GM/NIGMS NIH HHS/United States ; R35 GM150681/GM/NIGMS NIH HHS/United States ; }, abstract = {Cells require highly polymorphic receptors to perform accurate self/non-self recognition. In the amoeba Dicytostelium discoideum, polymorphic TgrB1 & TgrC1 proteins are used to bind sister cells and exclude cheaters, but it remains unknown how cells continually generate this extreme genetic diversity. Here, we created a collection of chromosome-length, whole genome sequences from 10 Dictyostelium discoideum isolates and sister species to understand the evolution of the large tgr gene family. Our dataset includes AX2-214, a widely used D. discoideum lab strain, as well as complete genomes for two Chlamydia-like endosymbionts harbored within amoebae. We find that tgrB1 and C1 lie in a hypermutational hotspot, with haplotypes that undergo repeated intralocus recombination, duplications, transpositions, and inversions. These structural dynamics are highly localized adjacent to tgrB and C, resulting in the gain and loss of dozens of genes. The tgrBC genes themselves frequently duplicate and recombine, leading to the rapid generation of unique tgrBC repertoires. In the broader tgr gene family, some genes (e.g. tgrN) are single copy and syntenic across all the genomes, whereas others (e.g. tgrA) prolifically duplicate at similar rates to Dictyostelium transposons. Thus, the tgr genes are among the most rapidly evolving families genome-wide. We propose that the intense diversification within the tgrBC locus can help explain how these genes acquire such extreme levels of polymorphism, with parallels to the MHC immune genes in mammals and other allorecognition systems. This collection of amoeba genomes is also an ideal dataset for comparative genomics and molecular evolution in Amoebozoa.}, }
@article {pmid40766138, year = {2025}, author = {Harmon, LM and Hattig, ZS and Huang, YP and Beckford, C and Farrar, J and Pollard, JA and Zarnegar-Lumley, S and Ma, X and Ries, RE and Meshinchi, S and Godley, LA and Triche, TJ}, title = {Germline Variant Burden Warrants Universal Genetic Testing in Pediatric Myeloid Leukemia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40766138}, support = {F99 CA294248/CA/NCI NIH HHS/United States ; R03 CA290259/CA/NCI NIH HHS/United States ; }, abstract = {Causal germline genetic variants are frequently detected in young (under age 40) patients presenting with myelodysplastic syndromes (MDS) or bone marrow failure (BMF), where progression to acute myeloid leukemia (AML) contributes substantially to mortality in these patients. We reasoned that de novo pediatric AML, which shares clinical and biological characteristics, might also share germline genetic risk variants. We investigated germline variants in a large cohort (n=365) of pediatric AML patients with whole-genome sequencing (WGS), 29 with matched marrow-derived stromal cells, and 336 with matched remission marrow samples. Variants were deemed "likely germline" based on variant allele frequency (VAF) across available samples. Following American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guidelines, we annotated pathogenic/likely pathogenic (P/LP) variants in 555 genes linked to leukemia risk. P/LP variants were identified in 5.5% (95% CI: (3.3%,7.9%)) of patients in genes linked to familial myeloid malignancy and an additional 3.3% (95% CI: (1.6%,5.2%)) of patients in genes conferring risk to lymphoid malignancy or solid tumors. The large cohort enabled burden testing, which we employed by comparing loss-of-function variants between patients and 2504 control subjects from the 1000 Genomes Project. There was a 6.9-fold (95% CI: (3.1,14.9)) increase in loss-of-function variants in genes implicated in myeloid malignancy risk, a 2.4-fold (95% CI: (1.7,3.2)) increase in candidate risk genes, and a 1.6-fold (95% CI: (1.1,2.3)) increase in randomly-selected genes. We then assembled cohorts totaling 4,622 pediatric and adult patients with acute leukemia or MDS from 10 published studies, and compared P/LP variant burdens across age and diagnosis. The prevalence of germline variants in myeloid malignancies across age groups exceeds 5% consistently and with high confidence. Because the National Comprehensive Cancer Network recommends that all patients receive screening if their pre-test germline variant probability exceeds 5%, our results support germline genetic variant testing as an integral component of diagnostic work-up for myeloid malignancies, including donor selection for stem cell transplantation.}, }
@article {pmid40775447, year = {2025}, author = {Chang, YH and Bresnahan, ST and Taylor Head, S and Harrison, TA and Yu, Y and Huff, CD and Pasaniuc, B and Lindström, S and Bhattacharya, A}, title = {Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {40775447}, issn = {1532-1827}, support = {CA293419//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {BACKGROUND: Integrating genome-wide association study (GWAS) and transcriptomic datasets can identify mediators for genetic risk of cancer. Traditional methods often are insufficient as they rely on total gene expression measures and overlook alternative splicing, which generates different transcript-isoforms with potentially distinct effects.
METHODS: We integrate multi-tissue isoform expression data from the Genotype Tissue-Expression Project with GWAS summary statistics (all N > ~20,000 cases) to identify isoform- and gene-level associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total).
RESULTS: Directly modeling isoforms using transcriptome-wide association studies (isoTWAS) significantly improves discovery of genetic associations compared to gene-level approaches, identifying 164% more significant associations (6163 vs. 2336) with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes. isoTWAS tags transcriptomic associations at 52% more independent GWAS loci across the six cancers. Isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression. We highlight several isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast).
CONCLUSION: These results underscore the importance of modeling isoforms to maximize discovery of genetic risk mechanisms for cancers.}, }
@article {pmid40774832, year = {2025}, author = {Sheppard, DP and Psutka, SP and Hunter, H}, title = {Prehabilitation: Cognitive considerations.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.06.017}, pmid = {40774832}, issn = {1873-2496}, abstract = {Urologic cancers and their treatments confer risk for cognitive dysfunction, which can have significant impact on quality of life and overall well-being during survivorship. Current approaches to ameliorate cognitive dysfunction in urologic and other cancers emphasize post-treatment rehabilitation methods of cognitive compensatory strategies or training-based restorative practice. Prehabilitation involves supporting resilience prior to treatment initiation and has demonstrated promise for supporting various clinical outcomes in urologic cancers. However, there is a paucity of studies that have utilized prehabilitation approaches to support cognitive functioning, and few existing prehabilitation studies in urologic cancers have examined cognitive functioning endpoints. The objectives of this literature review are to describe: (1) common cognitive findings in urologic cancers, (2) contemporary evidence for cognitive rehabilitation in cancer populations, (3) existing cognitive prehabilitation approaches that have yet to be implemented in urologic cancers, and (4) prehabilitation efforts addressing physical activity, nutrition, and mood/mental health that could be used in the future to support and study cognitive endpoints. A model for cognitive prehabilitation is proposed to guide future research in urologic cancers.}, }
@article {pmid40774326, year = {2025}, author = {Triplette, M and Aldrich, MC}, title = {Lung Cancer in Special Populations.}, journal = {Seminars in respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2657-9494}, pmid = {40774326}, issn = {1098-9048}, abstract = {Lung cancer is the leading cause of cancer deaths worldwide, claiming more lives than other age-related and screen-detectable cancers. Cigarette smoking remains the most important risk factor. However, despite common perceptions, risk is not related solely to cigarette smoking. Several vulnerable and special populations experience a disproportionate burden of lung cancer, often complicated by overlapping medical issues, diagnostic challenges, and treatment limitations. This review highlights four populations (people with HIV, persons who are immunocompromised, lung cancer in nonsmoking women, and individuals with interstitial lung disease [ILD]) who experience unique risks that impact early detection, diagnosis, and management of lung cancer. Three of these populations are frequently underrepresented in clinical trials, yet they may be at elevated risk due to chronic inflammation, immune dysregulation, or previous medical therapies. Individuals with HIV have a significantly increased incidence of lung cancer, often presenting at younger ages and with more advanced disease. Similarly, patients who are immunocompromised following organ or stem cell transplantation are at heightened risk due to prolonged immune dysfunction and prior exposures to toxic therapies. Individuals with ILD, especially idiopathic pulmonary fibrosis (IPF), have an increased risk of developing lung cancer, which is challenging to detect with imaging given architectural distortion and even more challenging to treat given limited pulmonary reserve. We also highlight women, as there has been a striking trend of rising incidence of lung cancer among women worldwide, particularly among those who have never smoked. The intersection of these risks with traditional lung cancer risk factors like tobacco smoking highlights a critical need for increased awareness, improved risk stratification, and adapted screening strategies that take these complexities into account. In this review, we explore the epidemiology, clinical presentation, and early detection and management challenges unique to each population, underscoring the necessity of precision approaches to support individualized care.}, }
@article {pmid40773733, year = {2025}, author = {Minalga, B and Feuer, C}, title = {Addressing Transgender Erasure in HIV Clinical Trials: The Scorecard for Transgender and Gender-Diverse Inclusion.}, journal = {American journal of public health}, volume = {}, number = {}, pages = {e1-e10}, doi = {10.2105/AJPH.2025.308134}, pmid = {40773733}, issn = {1541-0048}, abstract = {We sought to offer a structured framework for evaluating transgender and gender-diverse (TGD) inclusion in HIV clinical trials, with actionable criteria for trial design and conduct, and to quantify and characterize TGD inclusion in pivotal HIV studies as supporting evidence of the need for this framework. We devised a tool (scorecard) consisting of 14 scoreable indicators for TGD-responsive HIV research with input from global TGD communities. We tested the scorecard in a cross-sectional review of 41 randomized controlled HIV biomedical efficacy trials to measure TGD responsiveness. Studies were selected to represent the spectrum of groundbreaking HIV therapeutic and prevention studies enrolling participants in countries around the world from 1991 to 2023. We found that TGD individuals represent a reported 2532 (1.4%) of 178 893 participants in the selected HIV clinical trials. Scorecard indicators reveal a dearth of HIV research responsive to the needs of TGD communities. The lack of TGD representation in HIV clinical trials indicates a historical erasure of TGD communities with potential public health consequences. The scorecard might guide future HIV research to be more responsive to the needs of TGD people. (Am J Public Health. Published online ahead of print August 7, 2025:e1-e10. https://doi.org/10.2105/AJPH.2025.308134).}, }
@article {pmid40773709, year = {2025}, author = {Yuen, K and Meagher, M and Mercer, J and Yilma, B and Stoppler, M and Fragkogianni, S and Mar, N and Kalebasty, AR and Gupta, S and Grivas, P and Bagrodia, A and Mckay, R and Stewart, T and Salmasi, A}, title = {Comprehensive Comparison of Somatic, Germline, and Immune Cell Profiles in Upper Tract and Bladder Urothelial Carcinoma.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500289}, doi = {10.1200/PO-25-00289}, pmid = {40773709}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/genetics/immunology/pathology ; Retrospective Studies ; Female ; Male ; Aged ; Middle Aged ; Microsatellite Instability ; *Carcinoma, Transitional Cell/genetics/immunology ; Germ-Line Mutation ; Aged, 80 and over ; Mutation ; DNA Mismatch Repair ; *Ureteral Neoplasms/genetics/immunology ; }, abstract = {PURPOSE: Molecular characterization of anatomically distinct urothelial carcinoma in the upper tract (UTUC) and bladder (UCB) has been challenging because of the rarity of UTUC. However, recent advances in real-world data curation have facilitated the generation of larger UTUC cohorts. In this study, we investigated the somatic, germline, and immunologic landscapes of UTUC compared with UCB.
METHODS: From the Tempus Database, we retrospectively analyzed 505 UTUC and 2,416 UCB cases. Tumors were sequenced using Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration, tumor mutational burden (TMB), PD-L1, microsatellite instability (MSI), and mismatch repair (MMR) were evaluated. Potential germline alterations were assessed in 46 genes for patients with tumor/normal matched sequencing (UTUC, n = 285; UCB, n = 1,359).
RESULTS: Alterations in TERT, TP53, RB1, ERBB2, and CDKN1A were more frequent in UCB, whereas KMT2D, FGFR3, CDKN2B, KRAS, and MYC were more frequent in UTUC. Germline variants were found in 4.8% of UCB and 5.6% of UTUC, with trends toward higher Lynch syndrome-associated gene alterations (MLH1, MSH2, MSH6, PMS2) in UTUC (0.6% v 1.8%, P = .059). The prevalence of TMB ≥10 mut/Mb was higher in UCB (17% v 11%, P < .001). UCB had higher PD-L1 positivity (P = .013), whereas UTUC had more MSI-high (UTUC = 3.2% v UCB = 1%, P = .001) and MMR-deficient (P = .020) cases. CD4[+] and regulatory T-cell infiltrates were similar in both.
CONCLUSION: By comprehensive molecular characterization of UC, we observed distinct genomic alterations and tumor microenvironment patterns in UTUC and UCB. Further research is warranted to elucidate the clinical implications of these findings. We compared the genetic and immune features of upper tract and bladder cancers. Our study found key differences that could affect treatment decisions, such as specific gene changes and immune markers. These insights may help doctors personalize therapies and improve patient care.}, }
@article {pmid40773210, year = {2025}, author = {Yeh, JM and Ward, ZJ and Leisenring, W}, title = {Childhood Cancer Survivor Risk Estimates and Age, Overdispersion, and Social Context-Reply.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.2424}, pmid = {40773210}, issn = {2374-2445}, }
@article {pmid40772965, year = {2025}, author = {Venkatesh, H and Fong, L}, title = {CD4+ T cell dysfunction in cancer.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {9}, pages = {}, doi = {10.1084/jem.20241417}, pmid = {40772965}, issn = {1540-9538}, support = {R35CA253175/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/immunology/therapy/pathology ; *CD4-Positive T-Lymphocytes/immunology ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Immunotherapy ; }, abstract = {While the importance of CD8+ T cells in successful cancer immunotherapy is well-established, CD4+ T cells are increasingly recognized as key mediators of effective anti-tumor immunity. However, the mechanisms underlying the functional impairment of CD4+ T cells in tumors are not as well characterized as in CD8+ T cells. In this review, we will explore how CD4+ T cells are altered in tumor-bearing hosts, compare these changes to those observed in CD8+ T cells, and discuss how these changes impact tumor control. Approaches that counteract functional impairment in tumor-reactive CD4+ T cells may further enhance the efficacy of cancer immunotherapy.}, }
@article {pmid40772634, year = {2025}, author = {Cohen, SA and Aushev, VN and Laliotis, G and Jabbal, IS and Nagarajan, A and Wang, C and Fakih, M and Sharif, S and Alyunis, F and Tejani, MA and Alqahtani, A and Marshall, J and Chang, J and Botta, G and Manage, K and George, GV and Sharma, S and Malhotra, M and Chandana, S and Mehler, S and Somer, BG and Babadi, E and Wu, C and Hanna, D and Chidharla, A and Kasi, A and Vosoughi, E and Dayyani, F and Pedersen, K and Briski, RE and Azzi, G and Katiyar, V and Chan, A and Sharma, V and Shreenivas, A and Chakrabarti, S and Fuqua, J and Malla, M and Polite, B and Bent, AH and Rabinowitz, M and Jurdi, A and Liu, MC and Aleshin, A and Kopetz, S}, title = {Real-world Monitoring of ctDNA Reliably Predicts Cancer Recurrence and Treatment Efficacy in Patients with Resected Stages I-III Colon Cancer.}, journal = {Annals of surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/SLA.0000000000006887}, pmid = {40772634}, issn = {1528-1140}, abstract = {OBJECTIVE: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application.
SUMMARY BACKGROUND DATA: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment.
METHODS: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes.
RESULTS: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients.
CONCLUSIONS: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.}, }
@article {pmid40772450, year = {2025}, author = {Webster, RT and Mirzaei, S and Bhatia, S and Srivastava, DK and Mostoufi-Moab, S and Dixon, SB and Chow, EJ and Armstrong, GT and Krull, KR and van der Plas, E}, title = {Diabetes mellitus and neurocognition: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {131}, number = {16}, pages = {e70011}, doi = {10.1002/cncr.70011}, pmid = {40772450}, issn = {1097-0142}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; }, mesh = {Humans ; Female ; Male ; *Cancer Survivors/psychology ; Adult ; *Neoplasms/complications/therapy ; Cardiovascular Diseases/epidemiology ; Child ; *Diabetes Mellitus/epidemiology ; Adolescent ; Young Adult ; Risk Factors ; *Cognitive Dysfunction/epidemiology/etiology ; }, abstract = {BACKGROUND: The objective of this research was to examine associations between diabetes mellitus (DM) and neurocognitive impairment in survivors of childhood cancer while exploring mechanistic associations with treatment exposures and moderating associations with cardiovascular disease (CVD) and risky lifestyle factors.
METHODS: Survivors of the Childhood Cancer Survivor Study (N = 16,196; mean ± standard deviation age, 32.9 ± 7.9 years; 50.2% female; N = 615 with DM) self-reported neurocognitive functioning, risky drinking, physical inactivity, and tobacco use. Medical data were collected from chart review. Multivariable regression determined the association of DM with neurocognitive impairment while adjusting for relevant treatment exposures. Interactions between DM and treatment, risky lifestyle, and cardiovascular predictors on impairment were explored. Path analysis was used to examine the effects of treatment exposures through DM and CVD on impairment. Among survivors with DM, multivariable regressions examined predictors of neurocognitive change over time (mean, 11.21 years).
RESULTS: Survivors with DM had an increased risk of impairment relative to survivors without DM (task completion: odds ratio [OR], 1.5; 95% confidence limits [CI], 1.2-1.9; emotion regulation: OR, 1.4; 95% CI, 1.1-2.0; and organization: OR, 1.5; 95% CI, 1.1-2.0). The effects of cranial radiation on neurocognition were mediated by DM, including task completion (β = 0.02), emotion regulation (β = 0.02), memory (β = 0.01), and organization (β = 0.02; all p < .01). Among survivors with DM, CVD was associated with declines in task completion (estimate = 0.44; p < .01) and organization (estimate = 0.27; p = .03).
CONCLUSIONS: Survivors with DM are at increased risk of neurocognitive impairment. Although CVD did not exacerbate concurrent risk for impairment, it was associated with a decline in neurocognitive functioning over time in survivors with DM. Preventing/managing CVD in survivors with DM could mitigate additional neurocognitive decline.}, }
@article {pmid40770768, year = {2025}, author = {Wu, L and Zhu, X and Liu, Y and Zhao, D and Yu, BC and Wei, Z and Lin, X and Qi, LS}, title = {Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {233}, pmid = {40770768}, issn = {1474-760X}, support = {R21AG077193//NIH National Institute of Aging/ ; no. 2046650//the National Science Foundation CAREER award/ ; }, mesh = {Humans ; *Cellular Senescence/genetics ; *Inflammation/genetics ; *Aging/genetics ; Genome-Wide Association Study ; Mesenchymal Stem Cells/metabolism/cytology ; *CRISPR-Cas Systems ; Genomics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome, Human ; }, abstract = {BACKGROUND: Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
RESULTS: We perform multiple genome-wide CRISPR interference (CRISPRi) screenings in human primary mesenchymal stem cells derived from adipose tissue during either replicative senescence or inflammation-induced senescence. These screens reveal distinct sets of potential novel regulators specific to each senescence pathway. Combining our perturbation-based functional genomic data with 405 genome-wide association study datasets, including 50 aging-related studies, we find that the inflammatory aging signatures identified from CRISPRi screenings are significantly associated with diverse aging processes, suggesting novel molecular signatures for analyzing and predicting aging status and aging-related disease.
CONCLUSIONS: The signatures verified through comprehensive functional genomics and genetic analyses may provide new targets for modulating the aging process and enhancing the quality of cell therapy products.}, }
@article {pmid40766494, year = {2025}, author = {Shih, RM and Arimura, Y and Konishi, HA and Funabiki, H}, title = {IMPACTS OF DNA METHYLATION ON H2A.Z DEPOSITION AND NUCLEOSOME STABILITY.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766494}, issn = {2692-8205}, abstract = {In eukaryotes with DNA methylation, the histone variant H2A.Z and DNA methylation are maintained in mutually exclusive sections of the genome. How this antagonism is established, however, remains an open question. Here, we examined the impacts of DNA methylation on both the intrinsic stability of H2A.Z nucleosomes and chaperone-mediated H2A.Z deposition. Cryo-EM and endonuclease accessibility analyses show that H2A.Z nucleosomes with methylated DNA are more open and accessible compared to their unmethylated counterparts. In Xenopus laevis, H2A.Z preferentially associates with unmethylated DNA in both the fibroblast cell line XTC-2 and sperm pronuclei formed in the transcriptionally silent egg extract. The proportion of H2A.Z that colocalizes with methylated DNA, however, is higher in sperm pronuclei than in XTC-2. By monitoring nucleosome assembly on synthetic DNA constructs in Xenopus egg extracts, we find that the H2A.Z bias for unmethylated substrates is dependent on the SRCAP complex, the major H2A.Z deposition chaperone. Consistently, recruitment of the SRCAP complex to DNA is suppressed by DNA methylation. Altogether, we propose that the SRCAP complex is the major determinant for preferential H2A.Z enrichment on unmethylated DNA, whereas DNA methylation destabilizes DNA wrapping in H2A.Z-containing nucleosomes.}, }
@article {pmid40769720, year = {2025}, author = {Nicoletti, C and Massenet, J and Pintado-Urbanc, AP and Connor, LJ and Nicolau, M and Sundar, S and Xu, M and Schmitt, A and Zhang, W and Fang, Z and Chan, TCI and Wang, YX and Tapscott, SJ and Cheung, TH and Simon, MD and Caputo, L and Puri, PL}, title = {MYOD represses gene expression from non-E-box motifs.}, journal = {Genes & development}, volume = {}, number = {}, pages = {}, doi = {10.1101/gad.352708.125}, pmid = {40769720}, issn = {1549-5477}, abstract = {We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell trans-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory elements of expressed genes, invariably leading to reduced chromatin accessibility and gene repression. At variance with conventional E-box-driven increased chromatin accessibility and H3K27 acetylation at previously silent loci of MYOD-activated genes, MYOD-mediated chromatin compaction and repression of transcription was associated with high occurrence of non-E-box motifs and did not lead to reduced levels of H3K27ac but coincided with reduced levels of H4 acetyl-methyl lysine modification (Kacme). Using MYOD mutants, we dissected the molecular mechanism of MYOD-mediated repression, whereby repression of mitogen-responsive and growth factor-responsive genes occurred via promoter binding, which requires a conserved domain within the first helix; conversely, repression of cell of origin/alternative lineage genes occurred via binding and decommissioning of distal regulatory elements such as superenhancers (SEs), required either the N-terminal activation domain or the two chromatin remodeling domains, and coincided with reduced strength of CTCF-mediated chromatin interactions. These data extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator. They also reveal an unprecedented functional versatility arising from alternative chromatin recruitment through E-box or non-E-box sequences, whereby genetic determinants dictate differential usage of MYOD functional domains.}, }
@article {pmid40769632, year = {2025}, author = {Arter, ZL and Park, C and Deng, L}, title = {MET Tyrosine Kinase Domain Mutations in NSCLC: Expanding the Landscape of Acquired Resistance in Oncogene-Driven Tumors.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {8}, pages = {998-1000}, doi = {10.1016/j.jtho.2025.05.001}, pmid = {40769632}, issn = {1556-1380}, }
@article {pmid40769150, year = {2025}, author = {Durfey, SL and Kapnadak, SG and Pena, T and Willmering, MM and Godwin, JD and Teresi, ME and Heltshe, SL and Vo, AT and Villacreses, RA and Aliukonyte, I and Boyken, L and Stroik, MR and Morgan, SJ and Wang, GM and Betts, HL and Zhang, S and Goss, CH and Clancy, JP and Aitken, ML and Steele, C and Feder, AF and Esther, CR and Tiddens, HAWM and Woods, JC and Stoltz, DA and Singh, PK}, title = {Pseudomonas infections persisting after CFTR modulators are widespread throughout the lungs and drive lung inflammation.}, journal = {Cell host & microbe}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chom.2025.07.009}, pmid = {40769150}, issn = {1934-6069}, abstract = {Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve the physiological defect causing cystic fibrosis, but the lungs of most people remain infected and inflamed. A leading hypothesis implicates damaged segments as the cause of persistent infection and predicts that mildly diseased segments within an individual's lungs will clear after treatment, whereas severely diseased segments will not. Our findings contradict this hypothesis. We used bronchoscopy to sample the least- and most-damaged lung segments in Pseudomonas aeruginosa (Pa)-infected individuals before modulators and returned to these same segments after 1.5 years. Surprisingly, we find an "all-or-none" infection clearance response: the most-diseased segments clear if any other lung segment in that person clears, and the least-diseased segments remain infected if others in that person do. Furthermore, neutrophilic inflammation completely resolves where Pa clears but remains elevated where Pa persists. These data indicate that post-modulator infections are not limited to severely diseased segments and that Pa infections drive persistent lung inflammation after modulators.}, }
@article {pmid40769077, year = {2025}, author = {Goya, S and Nunley, EB and Longley, PC and Mathis, JR and Varela, CG and Kim, DY and Nurik, M and Naccache, SN and Greninger, AL}, title = {Phylodynamics of human metapneumovirus and evidence for a duplication-deletion model in G gene variant evolution.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {180}, number = {}, pages = {105848}, doi = {10.1016/j.jcv.2025.105848}, pmid = {40769077}, issn = {1873-5967}, abstract = {BACKGROUND: In December 2024, human metapneumovirus (hMPV) gained global attention amid rising cases in Chinese hospitals, prompting a World Health, Organization (WHO) statement indicating case numbers remained within expected ranges. To assess whether a variant of public health concern was emerging and to examine global hMPV phylodynamics, we conducted a genomic surveillance study in western Washington State.
STUDY DESIGN: We sequenced hMPV genomes from inpatient and outpatient samples collected between 2021 and 2025 in western Washington State and constructed phylogenomic and phylodynamic trees.
RESULTS: We obtained 60 hMPV-A and 39 hMPV-B genomes, including 13 from November 2024 to January 2025. Following COVID-19 pandemic disruptions, hMPV seasonality returned to typical patterns after 2023. Genomic analysis showed hMPV-A predominance since 2022-23, with co-circulation of A2b1, A2b2, B1, and B2 sublineages. The A2b2 sublineage was most prevalent and all genomes carried a 111-nt G gene duplication. Phylogenetic evidence suggests the 111-nt variant evolved from a prior 180-nt duplication via a 69-nt deletion rather than through independent duplication events. Most sublineages showed multiple co-circulating clades, except A2b1. Phylodynamics showed recovery of global diversity after pandemic-related declines and a higher evolutionary rate in hMPV-A compared to hMPV-B. No distinct evolutionary features of heightened concern were detected.
CONCLUSIONS: Despite recent concerns, our findings indicate that hMPV circulation in, the USA follows expected seasonal patterns, with ongoing introductions of diverse viral variants from preexisting sublineages rather than emergence of a novel variant. Continued genomic surveillance is essential, particularly as vaccine development progresses.}, }
@article {pmid40767935, year = {2025}, author = {Brennan, MA and Plichta, JK and Rozenblit, M and Flanagan, MR}, title = {Surgeon Attitudes on the Management of de novo Oligometastatic Breast Cancer.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {40767935}, issn = {1534-4681}, }
@article {pmid40767528, year = {2025}, author = {Lee, HJ and Gulati, R and Sayar, E and Patel, RA and Itagi, P and Richards, HM and Persse, T and Arora, S and Coleman, I and Adil, M and Schuster, SL and Shokri, F and Wright, JL and Yu, EY and True, LD and Chambers, M and Hawley, JE and Cheng, HH and Schweizer, MT and Grivas, P and Nelson, PS and Montgomery, RB and Hsieh, AC and Vakar-Lopez, F and Morrissey, C and Lam, HM and Ha, G and Tretiakova, MS and Haffner, MC and Raychaudhuri, R}, title = {Patterns of HER2 Expression in Metastatic Prostate and Urothelial Cancers: Implications for HER2-Targeted Therapies.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-25-0069}, pmid = {40767528}, issn = {2767-9764}, abstract = {HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. While HER2-directed therapies like fam-trastuzumab deruxtecan (T-DXd) are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer (PC) and urothelial carcinoma (UC) remains inadequately characterized. We evaluated HER2 protein expression in metastatic PC and UC using a validated immunohistochemistry assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the PC cohort (n=52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only 5 (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy number gains was observed in some tumors but did not correlate with HER2 protein expression (p=0.2). In UC (n=20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in 6 (30%) cases and 3+ expression observed in 3 (15%) cases in at least one tumor. UC samples showed less heterogeneity, with more consistent expression across metastases. HER2 over-expression is rare and heterogeneous in metastatic PC, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in UC. These findings underscore the importance of comprehensive HER2 assessment in advanced UC and suggests success of HER2-directed therapies in PC will require careful case selection.}, }
@article {pmid40765894, year = {2025}, author = {Naifeh, JA and Edwards, ER and Bentley, KH and Gildea, SM and Kennedy, CJ and King, AJ and Kleiman, EM and Luedtke, A and Nassif, TH and Nock, MK and Sampson, NA and Zainal, NH and Stein, MB and Capaldi, VF and Ursano, RJ and Kessler, RC}, title = {Predicting suicide attempts among US Army soldiers using information available at the time of periodic health assessments.}, journal = {Nature. Mental health}, volume = {3}, number = {2}, pages = {242-252}, pmid = {40765894}, issn = {2731-6076}, support = {U01 MH087981/MH/NIMH NIH HHS/United States ; }, abstract = {The value of population screening for suicide risk remains unclear. The U.S. Army's annual medical examination, the Periodic Health Assessment (PHA), screens for suicidality and other mental and physical health problems. This 2014-2019 cohort study used PHA and Army administrative data (n=1,042,796 PHAs from 452,473 soldiers) to develop a model to predict 6-month nonfatal and fatal suicide attempts (SAs). The model was designed to establish eligibility for a planned high-risk SA prevention intervention. The PHA suicide risk screening questions had limited value, as 95% of SAs occurred among soldiers who denied suicidality. However, a simple lasso penalized regression model that included a wide range of administrative predictors had good test sample discrimination (0.794 [SE=0.009] area under the receiver operating characteristic curve) and calibration (0.0001 integrated calibration index). The 25% of soldiers at highest predicted risk accounted for 69.5% of 6-month SAs, supporting use of the model to target preventive interventions.}, }
@article {pmid40765672, year = {2025}, author = {Heit, M and Cohen, SA}, title = {Contemporary Use of ctDNA for the Colorectal Surgeon.}, journal = {Clinics in colon and rectal surgery}, volume = {38}, number = {5}, pages = {334-338}, pmid = {40765672}, issn = {1531-0043}, abstract = {While advances in treatment and diagnostics have improved prognosis in colorectal cancer (CRC), room for advancement remains, highlighting the importance of improving tools for early detection and treatment guidance. Current national guidelines rely on stage-based treatment recommendations but fail to identify patients with lower stage disease who have a higher likelihood of recurrence or those for whom additional therapy may not be beneficial. Circulating tumor DNA (ctDNA) is an emerging noninvasive blood-based assay, which can inform cancer status as a single time point and/or longitudinal biomarker. ctDNA can be used for the diagnosis of cancer, detection of minimal/molecular residual disease, molecular profiling, and assessing treatment response. In patients for whom operative management is indicated, detectable ctDNA is associated with worse survival outcomes. This review highlights the expanding field of ctDNA in CRC, underlining pivotal data and areas with the need for more research that are key for colorectal surgeons to understand.}, }
@article {pmid40764319, year = {2025}, author = {Wilcox-King, A and Wan, YH and Scharffenberger, SC and Chhan, CB and Davis, AR and Homad, LJ and Seydoux, E and MacPhee, KJ and Siddaramaiah, LK and Melo, M and Dosenovic, P and Irvine, DJ and Hyrien, O and Stamatatos, L and McGuire, AT}, title = {Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {185}, pmid = {40764319}, issn = {2059-0105}, support = {P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; UM1AI144462//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; INV-032929/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; }, abstract = {VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunogens capable of initiating VRC01-class B cell response. Among these, we developed an anti-idiotypic monoclonal antibody (ai-mAb)-derived VRC01 class targeting immunogen. Because it is distinct from Env, we speculated that the ai-mAb will selectively engage naive VRC01 class B cells while limiting B cell responses directed at off-target epitopes on Env during prime-boost regimens. Here, we evaluated the serum and B cell responses to ai-mAb prime/Env boost, and Env-prime/Env boost regimens in a murine adoptive transfer model where VRC01 precursor B cells are present at physiological levels. We found that the Env-Env regimen led to the greatest expansion of on-target VRC01 B cells, drove larger VRC01-class GC responses, and elicited higher titers of circulating antibodies despite also eliciting substantial off-target Env-specific responses. Single-cell sorting experiments revealed that the ai-mAb was driving off-track somatic mutations. IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth.}, }
@article {pmid40764177, year = {2025}, author = {Raychaudhuri, R and Khaki, AR and Redman, MW and Baker, KK and Ng, K and Chen, X and Mao, J and Woo, B and Lin, A and Hannochka, A and Conrad, N and Kahugu, M and Panlasigui, P and Haffner, MC and Hsieh, AC and Lam, HM and Vakar-Lopez, F and Yezefski, T and Schweizer, MT and Montgomery, RB and Yu, EY and Dash, A and Psutka, SP and Lin, DW and Schade, GR and Gore, JL and Wright, JL and Grivas, P}, title = {Neoadjuvant Pembrolizumab and Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Nonurothelial Histologic Subtypes of Muscle-invasive Bladder Cancer: A Phase 2 Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.07.002}, pmid = {40764177}, issn = {1873-7560}, abstract = {Muscle-invasive bladder cancer (MIBC) with histologic subtypes represents a clinical challenge because of poor responses to conventional therapies and under-representation in clinical trials. This single-center phase 2 trial evaluated the combination of neoadjuvant pembrolizumab and accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) chemotherapy in patients with pure or predominant nonurothelial histologies. Seventeen patients were enrolled, with squamous differentiation being the most common variant. The primary endpoint, a pathologic complete response (pCR), was achieved in nine of 17 patients (53%), with an additional patient achieving ypTisN0 (downstaging rate 59%) and another achieving a clinical complete response. Grade ≥3 toxicities were observed in 47% of patients, primarily attributable to aMVAC. At median follow-up of 35 mo (range 11-48) the estimated 2-yr event-free survival (EFS) and overall survival rates were 64% (95% confidence interval 32-84%) and 79% (95% confidence interval 47-93%), respectively. Preliminary biomarker analysis did not reveal significant correlations between immune-cell subsets at baseline and pCR or EFS. These findings suggest that chemoimmunotherapy is a very promising approach for MIBC with histology subtypes. Larger studies are warranted to further refine therapeutic strategies.}, }
@article {pmid40763299, year = {2025}, author = {Gauderman, WJ and Fu, Y and Queme, B and Kawaguchi, E and Wang, Y and Morrison, J and Brenner, H and Chan, A and Gruber, SB and Keku, T and Li, L and Moreno, V and Pellatt, AJ and Peters, U and Samadder, NJ and Schmit, SL and Ulrich, CM and Um, C and Wu, A and Lewinger, JP and Drew, DA and Mi, H}, title = {Pathway polygenic risk scores (pPRS) for the analysis of gene-environment interaction.}, journal = {PLoS genetics}, volume = {21}, number = {8}, pages = {e1011543}, doi = {10.1371/journal.pgen.1011543}, pmid = {40763299}, issn = {1553-7404}, abstract = {A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will dilute the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N = 78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p = 0.41) is observed, a significant pPRS x NSAIDs interaction (p = 0.0003) is identified based on SNPs within the TGF-β/ gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.}, }
@article {pmid40763029, year = {2025}, author = {McGuire, DJ and Akondy, RS and Yang, S and Edupuganti, S and Nagar, S and Michael, G and De Rosa, SC and Newell, EW and Farber, DL and Kissick, HT and McElrath, MJ and Ahmed, R}, title = {Regulation of CD45 isoforms during human effector and memory CD8 T cell differentiation: Implications for T cell nomenclature.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {32}, pages = {e2322982122}, doi = {10.1073/pnas.2322982122}, pmid = {40763029}, issn = {1091-6490}, support = {U19 AI057266/AI/NIAID NIH HHS/United States ; U19 AI057266-S1//HHS | NIH | NIAID | Division of Intramural Research (DIR, NIAID)/ ; }, mesh = {Humans ; *Leukocyte Common Antigens/immunology/metabolism/genetics ; *CD8-Positive T-Lymphocytes/immunology/cytology/metabolism ; *Immunologic Memory/immunology ; *Cell Differentiation/immunology ; Protein Isoforms/immunology ; *Memory T Cells/immunology ; Receptors, CCR7 ; SARS-CoV-2/immunology ; Yellow Fever Vaccine/immunology ; COVID-19/immunology ; Yellow fever virus/immunology ; }, abstract = {This study examines the expression of CD45 isoforms on human yellow fever virus vaccine (YFV-17D) specific CD8 T cells longitudinally after vaccination. As expected, effector CD8 T cells at day 14 express CD45RO but within 4 to 6 wk these virus-specific CD8 T cells become CD45RA positive and remain CD45RA for >10 y. The journey for these YFV-specific CD8 T cells goes from naive (CD45RA+ CCR7+) to effector/effector memory (CD45RO+ CCR7-) to Temra (CD45RA+ CCR7-) to stem-cell memory (CD45RA+ CCR7+). These YFV-specific CD8 T cells rarely acquire the canonical Tcm phenotype (CD45RO+ CCR7+). This CD45RO to RA switch coincides with clearance of YFV, so we hypothesized that antigen may be playing a role in regulating CD45 expression. We addressed this issue by ex vivo analysis and provide evidence that this switch is indeed regulated by antigen. Sorted YFV-specific CD45RO effector CD8 T cells reexpress CD45RA when cultured ex vivo in the absence of antigen and retain CD45RO in the presence of cognate peptide. We also extended these ex vivo analysis to human cytomegalovirus (CMV)-specific CD8 T cells and show that CD45RO cells transition to CD45RA in the absence of antigen and CD45RA cells become CD45RO when stimulated with CMV peptide. We then show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific CD8 T cells can repeatedly undergo the same CD45RA to RO to RA transition in vivo after the SARS-CoV-2 mRNA vaccination. Again, the canonical Tcm phenotype spike-specific memory CD8 T cells were not readily detectable. These studies warrant a reevaluation of how human memory CD8 T cells are defined.}, }
@article {pmid40762835, year = {2025}, author = {Duffy, AM and Goenka, A and Azeem, MI and Taz, A and Potdar, SV and Scott, SA and Marin, E and Kaufman, JL and Hofmeister, CC and Joseph, NS and Gupta, VA and Lonial, S and Nooka, AK and Dhodapkar, MV and Dhodapkar, KM}, title = {Early CD4+ T-cell proliferative burst and chronic T-cell engagement impact myeloma outcomes following T-cell engager therapy.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI192927}, pmid = {40762835}, issn = {1558-8238}, }
@article {pmid40762207, year = {2025}, author = {Thiruvengadam, SK and Ahn, KW and Patel, J and Lian, Q and Hertzberg, M and Epperla, N and Metheny, L and Hong, S and Jain, T and Aljurf, M and Beitinjaneh, A and Vaughn, J and Gopal, A and Iqbal, M and Wirk, B and Manjappa, S and Oliver, C and Mohty, R and Shadman, M and Turtle, C and Hamadani, M and Herrera, AF}, title = {CD19 Directed CAR T Therapy for Transformed Follicular Lymphoma: A CIBMTR Analysis.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70027}, pmid = {40762207}, issn = {1096-8652}, abstract = {Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19-directed chimeric antigen receptor T-cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30-86) and median prior lines of therapy was 4 (range: 1-18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow-up of 25 months (range: 1-72) from CAR T infusion, the 2-year overall survival (OS) was 57% (95% CI: 53-60) and progression-free survival (PFS) was 43% (95% CI: 40-47). The 2-year cumulative incidences of relapse or progression (rel/prog) and non-relapse mortality (NRM) were 47% (95% CI: 44-51) and 9% (95% CI: 7-11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell-associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.}, }
@article {pmid40759764, year = {2025}, author = {Talbert, PB and Henikoff, S}, title = {Centromeres drive and take a break.}, journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology}, volume = {33}, number = {1}, pages = {17}, pmid = {40759764}, issn = {1573-6849}, mesh = {*Centromere/genetics/metabolism ; Animals ; Humans ; DNA Replication ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA, Satellite/genetics ; Meiosis ; Kinetochores/metabolism ; Evolution, Molecular ; }, abstract = {The identification of CENPA, CENPB, and CENPC by Earnshaw and Rothfield 40 years ago has revealed the remarkable diversity and complexity of centromeres and confirmed most seed plants and animals have centromeres comprised of complex satellite arrays. The rapid evolution of centromeres and positive selection on CENPA and CENPC led to the centromere drive model, in which competition between tandem satellite arrays of differing size and centromere strength for inclusion in the egg of animals or megaspore of seed plants during female meiosis drives rapid evolution of centromeres and kinetochore proteins. Here we review recent work showing that non-B-form DNA structures in satellite centromeres make them sites of frequent replication fork stalling, and that repair of collapsed forks by break-induced replication rather than unequal sister chromatid exchange is likely the primary mode of satellite expansion and contraction, providing the variation in satellite copy number that is the raw material of centromere drive. Centromere breaks at replication, rather than errors at mitosis, can account for most centromere misdivisions that underlie aneuploidies in cancer.}, }
@article {pmid40758946, year = {2025}, author = {Nilius, H and Sinitsa, E and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, AE and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Nagler, M}, title = {Outcomes of Patients with Suspected Heparin-Induced Thrombocytopenia in a Contemporary Multicenter Cohort.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016639}, pmid = {40758946}, issn = {2473-9537}, abstract = {Managing patients with suspected heparin-induced thrombocytopenia (HIT) poses significant clinical challenges. Limited evidence exists on how management decisions impact clinical outcomes, leading to treatment recommendations based on low-certainty evidence. This study aimed to evaluate the treatment strategies and clinical outcomes of patients with suspected heparin-induced thrombocytopenia (HIT) in a contemporary multicenter cohort. We conducted a prospective, multicenter cohort study including consecutive patients with suspected HIT from 11 centers. Patients were stratified into three groups: (a) HIT confirmed, (b) HIT-negative but heparin/PF4 antibody-positive, and (c) HIT-negative without antibodies. Clinical and laboratory data were systematically collected. HIT was diagnosed using the washed-platelet heparin-induced platelet activation (HIPA) test as the reference standard. Among 1,393 patients (46% female, median age 67), HIT was confirmed in 119 (8.5%). Most patients were in intensive care (37%) or had undergone cardiac surgery (32%). Argatroban was the predominant treatment (70%), and platelet recovery occurred in 77% of HIT patients. Among patients with HIT, subsequent venous thromboembolism occurred in 23%, arterial thromboembolism in 9%, major bleeding in 12.6%, and mortality in 18%, with no significant differences between anticoagulants. Treatment with argatroban, bivalirudin, or direct oral anticoagulants (DOACs) significantly reduced arterial thromboembolism risk. Outcomes did not differ between HIT-negative patients with or without heparin/PF4 antibodies. HIT, as well as the mere suspicion of HIT, remains a serious condition with a high risk of adverse outcomes, including death. Our findings provide further evidence supporting the effectiveness of DOACs, argatroban, and bivalirudin in reducing arterial thromboembolism risk.}, }
@article {pmid40758858, year = {2025}, author = {Vasconcelos, AG and Johnson, M and Cai, Y and Hsu, L and Franceschini, N and Auer, PL and Kooperberg, C and Raffield, LM and Reiner, AP}, title = {Methylation profile of individuals with sickle cell trait.}, journal = {Epigenetics}, volume = {20}, number = {1}, pages = {2539234}, pmid = {40758858}, issn = {1559-2308}, mesh = {Humans ; *DNA Methylation ; *Sickle Cell Trait/genetics ; Female ; Male ; Adult ; Black or African American/genetics ; Middle Aged ; CpG Islands ; Epigenesis, Genetic ; Genome-Wide Association Study ; beta-Globins/genetics ; Epigenome ; White ; }, abstract = {Sickle cell trait (SCT) is due to heterozygosity for the β-globin sickle cell mutation. SCT recently has been associated with increased risk of various adverse health outcomes. DNA methylation (DNAm) is one potential mechanism by which SCT may impact disease risk. To identify DNAm sites associated with SCT, we conducted an epigenome-wide association (EWAS) meta-analysis using whole blood Illumina EPIC array data available in a total of 3,677 African American participants (including 1,071 with SCT) from the Women's Health Initiative and Jackson Heart Study. We identified 103 differentially methylated CpGs and 119 differentially methylated regions associated with SCT. The strongest signals were hypermethylated cis loci within predicted regulatory elements within or near the β-globin gene cluster on chromosome 11. Beyond the globin locus, SCT-associated DMPs were enriched in genes involved in redox regulation and oxidative stress. We also demonstrate an association of SCT with differences in biological age and epigenetic age acceleration, though the pattern and strength of association differ according to the epigenetic clock used. Specifically, more recent epigenetic clocks that incorporate clinical phenotypes or laboratory biomarkers related to adverse health outcomes are associated with accelerated aging among individuals with SCT compared to African American controls. Our results lay the groundwork for future study of the role of DNAm in biologic aging and related health outcomes among individuals with SCT.}, }
@article {pmid40758381, year = {2025}, author = {Kumar, R and Hwang, S and Antony, M and Valenzuela, RFP and Kumar, M}, title = {Musculoskeletal Myeloid Sarcoma: Clinical, Imaging, Management, and Outcomes in 41 Adult Patients.}, journal = {Journal of computer assisted tomography}, volume = {}, number = {}, pages = {}, doi = {10.1097/RCT.0000000000001788}, pmid = {40758381}, issn = {1532-3145}, abstract = {OBJECTIVE: To analyze symptoms, imaging features, management, and outcomes of musculoskeletal myeloid sarcoma in adult leukemic patients.
MATERIALS AND METHODS: This is a retrospective analysis of clinical symptoms, imaging features, management, and outcomes in 41 adult leukemic patients with biopsy-proven myeloid sarcomas of bones and muscles.
RESULTS: Nineteen patients had acute, and 15 had chronic myeloid leukemia. Additional 5 previously treated leukemia patients included 1 with chronic myeloid leukemia, 3 with myelofibrosis, and 1 with myelodysplastic syndrome. The remaining 2 patients had isolated myeloid sarcoma with normal marrow without a history of hematologic disorder. Twenty-nine patients had bone tumors only, 3 muscle tumors only, 8 both bone and soft tissue tumors, and 1 intraarticular synovial tumor of an ankle. Of the 71 focal bone tumors, 68 were lytic and 3 were sclerotic. In addition, diffuse sclerotic bone lesions were present in 1 patient, and diffuse mixed lytic/sclerotic bone lesions in 2 patients. Most tumors were asymptomatic and were discovered incidentally on imaging. Local pain, mass, and pathologic fractures were the most common complaints when present. Vertebral bone and paravertebral soft tissue tumors caused neurological symptoms. Muscle tumors became symptomatic when they involved adjoining bone, nerve, or spinal cord. Only 3 among 13 muscle tumors presented as palpable masses. The imaging features of these musculoskeletal tumors were nonspecific. On MRI, both muscle and lytic bone MSs were hypo-to-iso-intense on T1WI, hyperintense on fat-suppressed T2WI, and enhanced on post-contrast fat-suppressed T1WI. A synovial myeloid sarcoma of the ankle showed diffusely thickened synovium on MRI. F-18 FDG PET-CT was helpful in the detection, monitoring of treatment response, and post-treatment surveillance in 5 patients. All patients were treated with cytarabine-based systemic anti-leukemic treatment and optional radiation, surgical resection, bone marrow transplant, and/or a combination of these. The known mean survival time of 35 dead patients after the appearance of musculoskeletal MS was 12.1 months.
CONCLUSIONS: Musculoskeletal myeloid sarcoma, which can occasionally precede it, is a rare complication of AML. Most tumors are asymptomatic. Imaging, particularly MRI and 18-F FDG PET-CT, plays a crucial role in detecting and monitoring treatment response, as well as post-treatment surveillance. The disease has poor clinical outcomes and short-term survival.}, }
@article {pmid40757857, year = {2025}, author = {Shi, Z and Tsuge, M and Collier, N and Takeuchi, Y and Uchida, T and Rutter, CM and Teraoka, Y and Uprichard, SL and Ishida, Y and Tateno, C and Ozik, J and Dahari, H and Chayama, K}, title = {Modeling of hepatitis B virus infection spread in primary human hepatocytes.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0092725}, doi = {10.1128/jvi.00927-25}, pmid = {40757857}, issn = {1098-5514}, abstract = {Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHHs) over 32 days post-inoculation (p.i.) and modified our in-vivo agent-based modeling (ABM) to gain insights into the HBV lifecycle and spread in vitro. Parallel PHH cultures were mock-treated or treated with HBV entry inhibitor Myr-preS1 (6.25 µg/mL) was initiated 24 h p.i. In untreated PHH, three viral DNA kinetic patterns were identified: (i) an initial decline, followed by (ii) rapid amplification and (iii) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 h. After the eclipse phase, the viral production rate increased over time, starting with a slow production cycle of 1 virion per day, which gradually accelerated to 1 virion per hour after 3 days. Approximately 4 days later, virion production reached a steady state production rate of 4 virions/h. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar to those predicted in uPA/SCID mice with human livers.IMPORTANCEWhile primary human hepatocytes (PHHs) are the most physiologically relevant culture system for studying HBV infection in vitro, a comprehensive understanding of HBV infection kinetics and spread in PHH is lacking. In this study, we characterize HBV viral kinetics and modify our in vivo agent-based modeling (ABM) to provide quantitative insights into the HBV production cycle and viral spread in PHH. The ABM provides an estimate of the HBV eclipse phase duration, HBV production cycles, and Myr-preS1 efficacy in blocking HBV spread in PHH. The results resemble those predicted in uPA/SCID mice with human livers, demonstrating that estimated HBV infection kinetic parameters in PHH in vitro mirror those observed in the in vivo HBV infection chimeric mouse model.}, }
@article {pmid40757627, year = {2025}, author = {Truong, L and Adams, AK and Bishop, S and Dupuis, V and Garza, L and Quigley, T and Hassell, L and Drain, PK and Ibarra, G and Sorrell, AW and Warne, T and Gregor, C and Webber, E and Ko, LK}, title = {"It's not about me. It's about what's best for my community": Factors impacting COVID-19 vaccine uptake among Native Americans and Latinos from two agricultural communities.}, journal = {The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association}, volume = {41}, number = {3}, pages = {e70057}, doi = {10.1111/jrh.70057}, pmid = {40757627}, issn = {1748-0361}, support = {/GM/NIGMS NIH HHS/United States ; /TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/administration & dosage/therapeutic use ; *COVID-19/prevention & control/ethnology ; Male ; Female ; Adult ; Focus Groups ; Middle Aged ; *Rural Population/statistics & numerical data ; *Hispanic or Latino/psychology/statistics & numerical data ; Montana/epidemiology ; Washington/epidemiology ; SARS-CoV-2 ; Aged ; *Patient Acceptance of Health Care/ethnology ; *Indians, North American/psychology/statistics & numerical data ; Qualitative Research ; White ; }, abstract = {PURPOSE: While SARS-CoV-2 significantly impacts rural Native American and Latino communities, COVID-19 vaccines offer an effective and safe mitigation strategy. Vaccine uptake is disproportionately lower in rural communities than in urban communities across the nation. This study examined barriers and motivators of COVID-19 vaccine uptake in two Native American and Latino rural agricultural communities in eastern Washington and Montana.
METHODS: We conducted 28 key informant interviews with trusted community members and six community focus groups with 39 participants from May 2021 to June 2021. Participants were from the Yakima Valley (WA) and Flathead Reservation (MT). The Social Cognitive Theory and Social Context Framework informed development of the interview and focus group moderator guides. We used deductive and inductive approach to code transcripts and thematic analysis to generate themes.
FINDINGS: Barriers to COVID-19 vaccine uptake were misconceptions about COVID-19 vaccines shaped by misinformation, politicization of vaccines, historical trauma and mistrust in government, and structural barriers in rural agricultural communities. Having access to accurate and understandable COVID-19 vaccine information and receiving information from trusted sources were motivators of COVID-19 vaccine uptake. Protecting families, children, elders, and the community, and striving to return to normal life were also noted as motivators.
CONCLUSIONS: Understanding the community's perceptions and experiences around the COVID-19 vaccine is critical for successful implementation of strategies to increase vaccine uptake during future public health emergencies. Strategies for vaccine uptake among communities in the Flathead Reservation and Yakima Valley need to address barriers and highlight motivators of COVID-19 vaccine uptake.}, }
@article {pmid40754387, year = {2025}, author = {Moosavi, D and Mullens, DA and Davidson, LA and Fan, YY and Goldsby, JS and Ivanov, IV and Levy, L and Kahsai, OJ and Curtis, KR and Raftery, D and Purcell, HJ and Mather, E and Ammar, H and Randolph, T and Issaka, RB and Navarro, SL and Lampe, JW and Hullar, MA and Chapkin, RS}, title = {Gut microbial community and host intestinal gene expression with combined fish oil and soluble corn fiber compared with corn oil and maltodextrin: A randomized crossover trial in healthy older individuals.}, journal = {The American journal of clinical nutrition}, volume = {122}, number = {2}, pages = {396-412}, doi = {10.1016/j.ajcnut.2025.04.031}, pmid = {40754387}, issn = {1938-3207}, mesh = {Humans ; *Fish Oils/pharmacology/administration & dosage ; *Gastrointestinal Microbiome/drug effects ; Middle Aged ; Cross-Over Studies ; Aged ; Male ; *Polysaccharides/pharmacology/administration & dosage ; Female ; *Dietary Fiber/administration & dosage/pharmacology ; *Corn Oil/administration & dosage/pharmacology ; Feces/microbiology ; *Intestines/microbiology/drug effects ; }, abstract = {BACKGROUND: Concurrent consumption of dietary fiber and n-3 polyunsaturated fatty acids reduces colon tumor formation. However, their combined effects on colorectal cancer risk remain unexplored in human trials.
OBJECTIVES: This study investigated the synergistic effects of fish oil (FO) and fermentable fiber on the gut transcriptional profiles and microbiome composition in older adults.
METHODS: In a randomized controlled crossover pilot study, 30 adults (ages 50-75 y), received fermentable fiber (33 g/d soluble corn fiber; SCF) plus eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA as FO, 7.7 g/d) or a comparator (similar doses of maltodextrin plus corn oil; MD + CO) for 30 d, followed by a 60-d washout period before crossing over to the alternate intervention. Serum phospholipid fatty acids, stool exfoliome [ribonucleic acid sequencing (RNAseq)], microbiome (16S ribosomal ribonucleic acid gene sequencing), butyrate kinase (but) gene abundance (digital droplet polymerase chain reaction), and fecal short-chain fatty acids were analyzed. Linear mixed models were used for the majority of outcome analyses. Differential expression and pathway enrichment analyses were applied to RNAseq data, whereas microbiome diversity was assessed using α and β diversity.
RESULTS: Serum EPA and DHA concentrations were higher after SCF + FO than MD + CO supplementation [EPA: β = 0.51; 95% confidence interval: 0.31, 0.72; DHA: β = 0.18; 95% confidence interval: 0.10, 0.27; P < 0.0001]. Analysis of host gut transcriptional networks revealed that SCF + FO supplementation inhibited the glucose-insulin receptor-phosphatidylinositol-3 kinase-signaling axis. Microbiome analysis revealed significant intervention differences in β-diversity (F = 4.4, R[2] = 0.08, P = 0.001), and 27 of 73 genera analyzed, several known short-chain fatty acid producers, differed between the 2 interventions (false discovery rate <0.05). Abundance of the but gene from Roseburia sp (P < 0.001) and the genera Roseburia (P = 0.006) were lower in the SCF + FO compared to MD + CO intervention, although fecal butyrate concentrations did not differ.
CONCLUSIONS: Thirty-day supplementation of SCF + FO compared with MD + CO showed significant shifts in intestinal cell pathways relevant to colorectal cancer with concomitant differences in gut microbial community structure and butyrate-producing taxa.}, }
@article {pmid40754223, year = {2025}, author = {Nadiminti, KV and Ahn, KW and Patel, J and Lian, Q and Bezerra, E and Chen, A and Ganguly, S and Gergis, U and Hashmi, H and Kharfan-Dabaja, MA and Kuruvilla, J and Lekakis, L and Locke, FL and Murthy, H and Mousthafa, MA and Perales, MA and Pophali, P and Riedell, PA and Shah, NN and Wang, T and Pasquini, M and Hamadani, M and Turtle, CJ and Herrera, AF and Shadman, M}, title = {Chimeric Antigen Receptor T-cell Therapy for Richter Transformation: A CIBMTR analysis.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.07.021}, pmid = {40754223}, issn = {2666-6367}, abstract = {Relapsed and/or refractory Richter transformation (RT) is generally associated with poor response to available therapies and short survival time. As RT patients were excluded from participating in the pivotal studies of chimeric antigen receptor T cell therapy (CAR-T) for large B-cell lymphoma, there is paucity of information about the efficacy of CAR-T in RT. Therefore, through the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed data from 140 RT patients who received anti-CD19 CAR-T between 2018 and 2023. Patients had received a median of 3 lines of therapy for RT (range:1-8), with nearly 43% being exposed to a Bruton's tyrosine kinase inhibitor and/or venetoclax. Axicabtagene ciloleucel (axi-cel) (65%) and tisagenlecleucel (tisa-cel) (28%) were the commonly prescribed products. Grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 9.4 % and 20%, respectively. After a median follow-up of 25 months (range: 1.8-61.5) from CAR-T infusion, 2-year progression-free and overall survival were 32.5% (95%CI, 24-41) and 46.6% (95%CI, 38-58), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality were 58.8% (95% CI, 50 - 67), and 8.7% (95% CI, 4 - 14%), respectively. Poor performance status and refractory disease before CAR-T infusion were predictive of inferior survival and disease progression. Our results show that anti-CD19 CAR-T can function as an effective treatment modality for a proportion of RT patients.}, }
@article {pmid40754035, year = {2025}, author = {Jafari, O and Ma, S and Lam, BD and Jiang, JY and Zhou, E and Ranjan, M and Ryu, J and Bandyo, R and Maghsoudi, A and Peng, B and Amos, CI and Oluyomi, A and Fillmore, NR and La, J and Li, A}, title = {Development and Validation of VTE-BERT Natural Language Processing Model for Venous Thromboembolism.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtha.2025.07.021}, pmid = {40754035}, issn = {1538-7836}, abstract = {BACKGROUND: Accurate and rapid phenotyping of venous thromboembolism (VTE) in longitudinal studies is important. A natural language processing (NLP) tool externally validated in representative patients is lacking.
METHODS: We designed a novel NLP platform, NLPMed, to assist thrombosis researchers with data preprocessing, phenotype annotation, language model finetuning, and NLP application. Utilizing clinical notes, discharge summaries, and radiology reports in patients with cancer from two healthcare institutions, we finetuned Bio_ClinicalBERT to develop VTE-BERT. The new model was trained to detect acute VTE events and their anatomical locations longitudinally. We internally and externally validated the model's performance in two randomly sampled cohorts of patients with advanced cancer.
RESULTS: The training cohort consisted of 715 patients and 14,013 annotated notes with ≥1 VTE keyword from the Harris Health System (HHS). The internal validation cohort included 400 additional patients with 7,190 VTE keyword-containing notes from HHS. The external validation cohort included 400 patients with 7,371 VTE keyword-containing notes from the National Veterans Affairs Healthcare System. VTE-BERT was trained until it reached a precision of 95% and recall of 98% on the patient level. Using independent datasets, the model achieved precision and recall of 95% and 91% in internal validation and of 85% and 92% in external validation.
CONCLUSIONS: We trained and externally validated an efficient NLP model to detect incident VTE events longitudinally. We believe its adoption will accelerate thrombosis research by improving VTE detection at scale and decreasing the time and expense involved with manual chart review in big data epidemiological studies.}, }
@article {pmid40753019, year = {2025}, author = {Selukar, S and Yin, V and Othus, M}, title = {Synthetic control arms and other uses of external data in clinical trials for hematological malignancies.}, journal = {Blood reviews}, volume = {}, number = {}, pages = {101324}, doi = {10.1016/j.blre.2025.101324}, pmid = {40753019}, issn = {1532-1681}, abstract = {Clinical trialists have been debating the use of data external to the study for decades. In this review, we develop concepts for interested readers to consider the use of external data in clinical trials, and we provide perspectives on the real-world usage of external data in phase 2 and 3 clinical trials for hematological malignancies across US academic cancer clinical trial networks. Only a minority of these studies have included external data (beyond use in establishing outcome benchmarks) in recent years, but improvements in data sharing and advances in methodologies may lead to more sources of potentially high-quality data for the broader clinical trials community. Identifying appropriate external data specific to the clinical trial and developing plans to adequately address differences between study and external data will remain key considerations for including external data in clinical trials.}, }
@article {pmid40709277, year = {2025}, author = {Cao, J and Ferguson, M and Sun, J and Shen, M and Small, R and Hippe, DS and Zhao, X and Zhang, D and Watase, H and Yuan, C and Gao, P and DeMarco, JK and Nicosia, RF and Wang, Y and Li, H and Li, Z and Wang, Y and Kohler, T and Hatsukami, T and Sui, B}, title = {Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40709277}, issn = {2693-5015}, abstract = {BACKGROUND: The clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging.
OBJECTIVES: The aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients.
METHODS: Carotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 μm thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallory's trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups.
RESULTS: A total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools (β=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; β=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH (β=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001).
CONCLUSIONS: The histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach.}, }
@article {pmid40672332, year = {2025}, author = {Williamson, C and Moodley, C and Magaret, CA and Giorgi, EE and Rolland, M and Westfall, DH and Yssel, A and Deng, W and Rossenkhan, R and Mkhize, NN and Chen, L and Zhao, H and Bhattacharya, T and Pankow, A and Murrell, B and York, T and Gwashu-Nyangiwe, A and Ndabambi, N and Thebus, R and Cohen, P and Lambson, B and Kaldine, H and Bhebhe, S and Juraska, M and Bai, H and deCamp, AC and Ludwig, J and Molitor, C and Beaume, N and Matten, D and Huang, Y and Zhang, L and Reeves, DB and Mayer, B and Karuna, ST and Hural, JA and Morris, L and Montefiori, D and Bumgarner, RE and Moore, PL and Edlefsen, PT and Edupuganti, S and Mgodi, N and McElrath, MJ and Cohen, MS and Corey, L and Gilbert, PB and Mullins, JI}, title = {Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672332}, issn = {2692-8205}, abstract = {In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-Δpol (2.5 kb) and 53,088 rev-env-Δnef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in ~38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1μg/ml) and resistant viruses (IC80>3μg/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01.}, }
@article {pmid40752589, year = {2025}, author = {Ng, SK and Flaherty, PW and Ancheta, M and Tindbaek, KA and Sekhon, MK and Huang, JJ and Portuguese, AJ and Albittar, A and Kopmar, NE and Cowan, AJ and Shadman, M and Hirayama, AV and Till, BG and Cassaday, RD and Turtle, CJ and Liu, C and Xie, H and Leisenring, WM and Gauthier, J and Liang, EC and Hill, JA}, title = {Opportunities to improve antibiotic stewardship, and identification of blood biomarkers associated with bacteremia following CAR-T cell therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.07.022}, pmid = {40752589}, issn = {2666-6367}, abstract = {BACKGROUND: Cytokine release syndrome (CRS) is frequent after chimeric antigen receptor T-cell therapy (CAR-T). CRS and bacteremia share clinical features, making it difficult to distinguish between the two and deliver targeted treatment. As a result, most patients with CRS receive empiric broad-spectrum antibiotics that may adversely impact long-term outcomes.
OBJECTIVES: The objectives of this study were to identify blood biomarkers that distinguish between CRS and bacteremia in the first month after CAR-T. We also describe the utilization of empiric antibiotics to identify opportunities for improved antimicrobial stewardship.
STUDY DESIGN: We identified patients who received CAR-T for hematologic malignancies between July 2013 and April 2024. We calculated the cumulative incidences of CRS and bacteremia within 30 days post-CAR-T. In a matched case control analysis, where three patients with CRS and no bacteremia (controls) were matched to each patient with bacteremia (cases), we described the clinical characteristics of CRS, bacteremia, and antibiotic exposure. We then assessed the levels and kinetics of six biomarkers (C-reactive protein [CRP], interleukin-6, ferritin, fibrinogen, lactate dehydrogenase, and D-dimer) for their ability to discriminate between bacteremia and CRS using Mann-Whitney U tests and generalized estimating equation (GEE) models.
RESULTS: Among 694 CAR-T recipients, 517 (75%; 95% confidence interval [CI], 71-78%) developed CRS. Bacteremia occurred in 19 patients with a cumulative incidence of 2.7% (95% CI, 1.7-4.2%) within 30 days and 1.4% (95% CI, 0.7-2.6%) within 14 days of CAR-T. The median time from blood culture to positive result was one day (interquartile range [IQR], 1-1). Among the 57 matched controls, CRS occurred a median of four days (IQR, 1-5) post-CAR-T, all were hospitalized for fevers, and 92% of CRS events were treated with empiric antibiotics for a median of seven days (IQR, 5-8). As a result, for every patient with bacteremia treated with antibiotics within the first 14 days, an estimated 52 patients with CRS and no serious bacterial infection received empiric antibiotics. The levels and kinetics of biomarkers were similar among cases and controls within 14 days after CAR-T. Beyond day +14, CRP, D-dimer, and ferritin levels were significantly higher among patients with bacteremia and distinguished cases from controls with moderate discrimination (area under the curve of 0.77, 0.77, and 0.81, respectively). In addition, increasing CRP and fibrinogen ≥ 14 days post-CAR-T were significantly associated with bacteremia (odds ratio [OR], 1.46; 95% CI, 1.07-2.01 and OR, 4.32; 95% CI, 1.28-14.61 per 0.25 log10 increase in biomarker level per day, respectively).
CONCLUSION: We demonstrate that most CAR-T recipients who developed CRS received empiric broad-spectrum antibiotics, but bacteremia was rare. Although blood biomarkers were unable to distinguish between CRS and bacteremia early after CAR-T, higher CRP, D-dimer, and ferritin and rising levels of CRP and fibrinogen ≥14 days post-CAR-T were associated with bacteremia and can facilitate earlier targeted interventions. These data highlight opportunities for improved antibiotic stewardship in the context of CRS, which is critical given the association between broad-spectrum antibiotic exposure, gut microbiome dysbiosis, and worse outcomes after CAR-T.}, }
@article {pmid40751436, year = {2025}, author = {Samandari, T and Achola, M and Hutter, JN and Mboya, G and Otieno, W and Kee, JJ and Huang, Y and Aponte, JJ and Ockenhouse, CF and Lee, CK and Polakowski, L and Yacovone, M and Tapley, A and Dadabhai, S and Mkhize, NN and Kaldine, H and Bhebhe, S and Moore, PL and Hural, J and Garrett, N and Kublin, JG}, title = {Plasmodium falciparum Parasitemia Does Not Diminish Neutralizing Antibody Responses After mRNA COVID-19 Booster Vaccination in HIV-infected Adults.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf398}, pmid = {40751436}, issn = {1537-6613}, abstract = {mRNA vaccines have emerged as powerful tools for the prevention of infectious diseases, but subclinical malaria may reduce vaccine immunogenicity. We evaluated neutralizing antibody responses in asymptomatic HIV-infected adults with and without PCR-confirmed Plasmodium falciparum who received either monovalent mRNA-1273 or bivalent mRNA-1273.222 (WA-1 and BA.4/5) booster vaccines. In previous studies, a 50% pseudovirus inhibitory dose neutralizing antibody (ID50) titer of 1,000 correlated with 96% efficacy in preventing COVID-19. We observed ID50 geometric mean titers >22,000 in both parasitemic and non-parasitemic participants one month after boosting. We conclude that COVID-19 mRNA vaccine antibody responses are unimpaired by concurrent asymptomatic parasitemia.}, }
@article {pmid40750774, year = {2025}, author = {Domingo-Domènech, E and Pro, B and Illidge, T and Horwitz, S and Trumper, L and Iyer, S and Advani, R and Bartlett, NL and Christensen, JH and Kim, WS and Feldman, T and Choi, I and Gritti, G and Belada, D and Shustov, A and Illes, A and Zinzani, PL and Hüttmann, A and Trneny, M and Le Gouill, S and Jagadeesh, D and Friedberg, JW and Little, M and Dong, C and Fanale, M and Fenton, K and Savage, KJ}, title = {Brentuximab vedotin plus chemotherapy for the treatment of front-line systemic anaplastic large cell lymphoma: subgroup analysis of the ECHELON-2 study at 5 years' follow-up.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {129}, pmid = {40750774}, issn = {2044-5385}, mesh = {Humans ; *Brentuximab Vedotin/administration & dosage/therapeutic use/adverse effects ; *Lymphoma, Large-Cell, Anaplastic/drug therapy/mortality/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Follow-Up Studies ; Female ; Male ; Middle Aged ; Aged ; Adult ; Treatment Outcome ; }, abstract = {ClinicalTrials.gov number: NCT01777152.}, }
@article {pmid40750760, year = {2025}, author = {Golmohammadi, M and Raza, S and Albayyadhi, M and Sholehrasa, H and Khouri, J and Williams, L and Hansen, DK and Moradi, A and Xu, X and Albliwi, M and Ali, AH and Dima, D and Anwer, F and Paul, B and Jaberi-Douraki, M}, title = {Comprehensive assessment of adverse event profiles associated with bispecific antibodies in multiple myeloma.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {130}, pmid = {40750760}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy ; *Antibodies, Bispecific/adverse effects/therapeutic use ; B-Cell Maturation Antigen/immunology ; Male ; *Antineoplastic Agents, Immunological/adverse effects/therapeutic use ; Female ; Aged ; }, abstract = {Bispecific antibodies (BsAbs) have shown promise in the management of relapsed/refractory multiple myeloma (MM). Despite its efficacy, this class of drugs is associated with significant toxicities. In this study, we conducted a pooled analysis of the available clinical trials on BsAbs for the treatment of MM, including full publications and abstracts until April 2025. BsAbs were classified into two groups: B-cell maturation antigen (BCMA), and GPRC5D/FcRH5 BsAbs. Welch's t-test was performed to compare the safety profiles of each agent. For clustering, we used principal component analysis (PCA). Our study analyzed 22 trials involving 2374 patients with MM from early 2023 to April 2025. Among these, 1276 patients received BCMA BsAbs, 841 treated with GPRC5D/FcRH5 BsAbs, 157 received teclistamab + talquetamab, and 65 patients received a talquetamab + daratumumab, and 35 patients received talquetamab + pomalidomide. The median follow-up for all groups was 11.83 months. Among all-grade hematologic adverse events (AEs), neutropenia occurred in 40.4%, anemia in 39.2%, thrombocytopenia in 21.4%, lymphopenia in 19.2%, infections in 45.8%, and cytokine release syndrome (CRS) in 65%. For grade 3/4 AEs, infections occurred in 20.3%, CRS in 1.5%, neutropenia in 35.2%, anemia in 24.5%%, thrombocytopenia in 13.5%, and lymphopenia in 17.7%. CRS and the need for tocilizumab were significantly less frequent with BCMA BsAbs vs GPRC5D/FcRH5 BsAbs, (P < 0.002). Skillings Mack (Generalized Friedman's) findings emphasized substantial distinctions between BCMA and GPRC5D/FcRH5×CD3 in both overall and severe grade 3/4 AEs (p ≤ 0.0002). PCA revealed agents with all grades and grade 3/4 showed similar clustering patterns except for three agents. Overall, our findings demonstrated the excellent efficacy on the use of BsAbs in MM; however, these agents have been linked to a unique AE profile. GPRC5D/FcRH5 are associated with less grade 3/4 hematologic toxicity whereas BCMA BsAbs were associated with lower grade 3/4 CRS rates, compared to GPRC5D/FcRH5. These insights are crucial for guiding treatment decisions and developing strategies to improve patient outcomes.}, }
@article {pmid40749169, year = {2025}, author = {Dhakal, B and Akhtar, OS and Fandrei, D and Jensen, A and Banerjee, R and Pan, D and Richard, S and Friend, R and Rees, MJ and Costello, P and Vazquez Martinez, MA and Pasvolsky, O and Wagner, CB and Davis, JA and Castaneda Puglianini, OA and Reshef, R and Afrough, A and Dima, D and Bhutani, M and Nadeem, O and Parrondo, RD and Freeman, CL and Mikkilineni, L and Raza, S and Anderson, LD and Kapoor, P and Hosoya, H and Chhabra, S and Grajales-Cruz, A and Gaballa, MR and Midha, S and Alsina, M and Sborov, DW and Patel, KK and Lin, Y and Ferreri, CJ and Gagelmann, N and Kumar, AD and Hansen, DK and Cowan, AJ and Costa, LJ and Merz, M and Sidana, S}, title = {Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025029773}, pmid = {40749169}, issn = {1528-0020}, abstract = {Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two BCMA-directed chimeric antigen receptor T cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma (RRMM); however, the 6-8 weeks manufacturing time risks disease progression or death in up to 10% of patients, highlighting the need for effective bridging strategies. Talquetamab, a GPRC5D-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 US, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n=98 cilta-cel, n=21 ide-cel). Reasons for not proceeding (n=15) included progression (n=7), manufacturing failure (n=6), or patient decision (n=2). Median age was 65 years; patients had received a median 5 prior lines of therapy. High-risk cytogenetics and extramedullary disease were present in 44% and 41% respectively. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days (82% at 0.8 mg/kg biweekly). Toxicity was manageable: no grade ≥3 CRS, 2% grade 3 ICANS and grade 1-2 Talq unique toxicities (70% oral, 38% skin, 17% nail; 60% resolved). Talquetamab achieved 71% response rate. Post CAR-T 88% responded (54% complete response), with low-grade toxicities (2 grade≥3 CRS, 1 grade 3 ICANS and 5% grade≥3 infections). Two cases of facial palsy and one AML occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe enabling the majority of difficult to treat patients to successfully proceed to BCMA CAR-T therapy.}, }
@article {pmid40749165, year = {2025}, author = {McManus, D and Copsel, SN and Pfeiffer, BJ and Wolf, D and Barreras, H and Ma, S and Khodor, A and Komai, S and Burgos da Silva, M and Hazime, H and Gallardo, M and Lime, SGR and van den Brink, MRM and Park, JH and Abreu, MT and Hill, GR and Perez, VL and Levy, RB}, title = {Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues, ameliorating GVHD post-HSCT.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025028418}, pmid = {40749165}, issn = {1528-0020}, abstract = {The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the TNF superfamily receptor TNFRSF25 and the high affinity IL-2 receptor with a TL1A-Ig fusion protein and low dose IL-2, respectively was used to pre-treat recipient mice prior to allogeneic-HSCT (aHSCT). Pre-treatment induced Treg expansion persisting 1-2 weeks post-HSCT leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in the frequency of stable and active Tregs creating a suppressive tissue environment in the colon, liver and eye. Importantly, pre-treatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria outgrowth and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, it was found that the increased tissue Treg frequency included resident CD69+CD103+FoxP3+ hepatic Tregs. In contrast to infusion of donor Treg cells, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient prior to the receipt of donor allo-reactive T cells and successful perseveration of GVL responses. We posit strategies that circumvent the need of producing large numbers of Tregs ex-vivo through manipulating this recipient compartment in vivo, can provide translational approaches to improve aHSCT outcomes.}, }
@article {pmid40748320, year = {2025}, author = {Ziller, SG and Blew, RM and Roe, DJ and Odegaard, A and Chen, Z and Caan, BJ and Luo, J and Manson, JE and Neuhouser, ML and Rohan, TE and Bea, JW}, title = {Dual-energy X-ray absorptiometry derived adiposity and colorectal cancer incidence and mortality in postmenopausal women.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0581}, pmid = {40748320}, issn = {1538-7755}, abstract = {BACKGROUND: Determine if dual-energy X-ray absorptiometry (DXA) derived adiposity was associated with colorectal cancer (CRC) incidence and mortality in postmenopausal women from the Women's Health Initiative (WHI) DXA Cohort.
METHODS: Whole-body DXA scans estimated adiposity. Women with cancer history (except non-melanoma skin cancer) or missing baseline DXA were excluded. For 27 years of follow-up, outcomes and death were adjudicated. Descriptive statistics by CRC status were calculated. Fine and Gray's competing risks regression was used to estimate sub-hazard ratios (SHR) and 95% confidence intervals (CI). Observation time was from enrollment to first CRC event or competing risk (other cancer, other cause of death); women without cancer at last follow-up were censored. Covariates included sociodemographic, clinical, and study characteristics.
RESULTS: After exclusions, 9,950 women were included, with 191 first-incident CRC and 88 CRC-related deaths identified. At baseline, mean (±SD) age was 63.3 (±7.4) years, and body mass index was 28.2 (±5.7) kg/m2. In adjusted models, baseline continuous abdominal visceral adipose tissue (VAT) (per 100cm2) and android fat (per kg) were significantly associated with a higher risk of first-incident CRC: SHR (95% CI) 1.23 (1.04-1.45) and 1.15 (1.01-1.31), respectively. There were no significant associations between adiposity and CRC mortality.
CONCLUSIONS: Higher amounts of abdominal VAT and android fat were associated with a higher risk of CRC incidence in postmenopausal women.
IMPACT: Associations between VAT and CRC, independent of BMI, support clinical assessment of body composition across weight categories. A head-to-head comparison of VAT and BMI for CRC prediction is recommended in future research.}, }
@article {pmid40748144, year = {2025}, author = {Flamand, L and Arbuckle, J and Bonnafous, P and Descamps, V and Hill, JA and Jarrett, R and Jerome, K and Kaufer, BB and Koide, R and Komaroff, AL and Medveczky, P and Miura, H and Mori, Y and Parrish, N and Pellett, PE and Wood, M and Yoshikawa, T and Zerr, DM}, title = {Endogenous human herpesviruses 6A/B.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0105425}, doi = {10.1128/jvi.01054-25}, pmid = {40748144}, issn = {1098-5514}, abstract = {Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called "endogenous HHV-6A/B (eHHV-6A/B)." Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using "eHHV-6A/B" for inherited forms and reserving "chromosomally integrated" for somatic integrations only.}, }
@article {pmid40748049, year = {2025}, author = {Xia, B and Kim, AR and Liu, F and Han, M and Stoneburner, E and Makdissi, S and Di Cara, F and Mohr, SE and Ring, A and Perrimon, N}, title = {Phage-displayed synthetic library and screening platform for nanobody discovery.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40748049}, issn = {2050-084X}, support = {NIH NIGMS P41 GM132087/NH/NIH HHS/United States ; NIH 5R24OD035556/NH/NIH HHS/United States ; 2021R1A6A3A14039622//National Research Foundation/ ; }, mesh = {*Single-Domain Antibodies/isolation & purification/immunology/genetics ; Animals ; *Peptide Library ; Cell Surface Display Techniques ; Drosophila Proteins/immunology ; Drosophila ; }, abstract = {Nanobodies, single-domain antibodies derived from camelid heavy-chain antibodies, are known for their high affinity, stability, and small size, which make them useful in biological research and therapeutic applications. However, traditional nanobody generation methods rely on camelid immunization, which can be costly and time-consuming, restricting their practical feasibility. In this study, we present a phage-displayed synthetic library for nanobody discovery. To validate this approach, we screened nanobodies targeting various Drosophila secreted proteins. The nanobodies identified were suitable for applications such as immunostaining and immunoblotting, supporting the phage-displayed synthetic library as a versatile platform for nanobody development. To address the challenge of limited accessibility to high-quality synthetic libraries, this library is openly available for non-profit use.}, }
@article {pmid40746155, year = {2025}, author = {Dong, M and Thakral, A and Byrne, KS and Bosse, Y and Zhou, H and Zhang, Y and Atkins, J and Haycock, P and Brown, MC and Murison, K and Timens, W and Sin, DD and Kothari, J and Gabriel, AAG and Zaridze, D and Savic, M and Lissowska, J and Świątkowska, B and Janout, V and Holcatova, I and Mukeria, A and Fernandez-Tardon, G and Davies, MPA and Triplette, M and Schabath, MB and Andrew, AS and Chen, C and Taylor, F and Field, JK and Tardon, A and Shete, SS and Brennan, P and Landi, MT and McKay, J and Amos, CI and Lin, X and Christiani, DC and Hung, RJ and Liu, G and Xu, W}, title = {Genome-wide association study of early-stage non-small cell lung cancer prognosis: a pooled analysis in the International Lung Cancer Consortium.}, journal = {Carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/carcin/bgaf031}, pmid = {40746155}, issn = {1460-2180}, abstract = {Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale genome-wide association prognostic study using data from the International Lung Cancer Consortium (ILCCO) through a two-phase analysis. Phase 1 includes the discovery of genome-wide association studies analysis using a multivariable Cox PH model on 3428 NSCLC patients of European ancestry from 10 ILCCO participating studies to identify genetic variants associated with overall survival and validation analysis for genome-wide significant variants (P-value ≤5 × 10-8) using the Cancer Genome Atlas (TCGA). Phase 2 aims to identify causal variants using functional analyses of genome-wide significant and suggestive variants (P-value ≤1 × 10-5), including variant-epigenetic functional annotation (FAVOR), CHIP-seq data, variant-gene expression association, and colocalization analysis. We identified two significant variants; of those, a locus at 9q21.31 (rs117979484) was significant at the genome-wide level (P = 3.67 × 10-8) and validated in TCGA (P = 0.03). Three suggestive variants were found to have a putative epigenetic function: intronic variants rs149281784 (BCL7B gene) and rs148031766 (POM121 gene) both located at 7q11.23 and in moderate linkage disequilibrium with each other; and variant rs2471630 (SRCIN1 gene; 17q12). Specifically, variants rs149281784 and rs148031766 have potential regulatory roles in the transcriptional activation of the BCL7B gene and POM121 gene. Exploratory survival analyses in the squamous cell carcinomas subgroup also identified a significant variant, rs138467404 (GRHL-2 gene; 8q22.3) at a genome-wide level (P = 4.75 × 10-8) and validated by TCGA (P = 0.02). These new findings indicate potential novel pathways associated with early-stage NSCLC prognosis. Future research may validate additional genome-wide suggestive variants as being relevant for lung cancer outcomes.}, }
@article {pmid40742241, year = {2025}, author = {Graham, LS and Yu, EY}, title = {Early and Precise: Treating HRR Alterations in Hormone-Sensitive Prostate Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-2359}, pmid = {40742241}, issn = {1557-3265}, abstract = {Patients with prostate cancer and HRR alterations face worse outcomes. Early use of PARP inhibitors, especially in BRCA-mutated cancers is promising. However, optimal timing, sequencing, and benefits for non-BRCA alterations remain unclear, underscoring the need for well-designed clinical trials and personalized treatment discussions.}, }
@article {pmid40742180, year = {2025}, author = {Tang, G and Carr, AV and Perez, C and Ramos Sarmiento, K and Levy, L and Lampe, JW and Diener, C and Gibbons, SM}, title = {Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization.}, journal = {mSystems}, volume = {}, number = {}, pages = {e0098425}, doi = {10.1128/msystems.00984-25}, pmid = {40742180}, issn = {2379-5077}, abstract = {Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, quantitative polymerase chain reaction (qPCR), or spike-ins, can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read count ratios. We compared B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. B:H ratios in stool were correlated with bacterial-to-diet (B:D) read count ratios, but B:D ratios exhibited a substantial number of outlier points. Host read depletion methods reduced the total number of human reads in a given sample, but B:H ratios were strongly correlated before and after host read depletion, indicating that host read depletion did not reduce the utility of B:H ratios. B:H ratios showed expected variation between health and disease states and were generally stable in healthy individuals over time. Finally, we showed how B:H and B:D ratios can be used to track antibiotic treatment response and recovery. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning, enabling robust absolute biomass estimates directly from stool metagenomic data.IMPORTANCEIn this study, we asked whether normalization by host reads alone was sufficient to estimate absolute bacterial biomass directly from stool metagenomic data, without the need for synthetic spike-ins, additional experimental biomass measurements, or training data. The approach assumes that the contribution of host DNA to stool is more constant or stable than biologically relevant fluctuations in bacterial biomass. We find that host read normalization is an effective method for detecting variation in gut bacterial biomass. Absolute bacterial biomass is a key metric that often gets left out of gut microbiome studies, and empowering researchers to include this measure more broadly in their metagenomic analyses should serve to improve our understanding of host-microbiota interactions.}, }
@article {pmid40740737, year = {2025}, author = {Bulosan, H and Nunez, YC and Wu, B and George, E and Cogen, AL}, title = {A patient with a purple, edematous great toe.}, journal = {JAAD case reports}, volume = {62}, number = {}, pages = {113-115}, pmid = {40740737}, issn = {2352-5126}, }
@article {pmid40740502, year = {2025}, author = {Nolan, CT and Campbell, I and Farrell-Sherman, A and Briones Ortiz, BA and Yang, C and Naish, KA and Di Stilio, VS and Kaldy, JE and Donoghue, C and Ruesink, JL and Imaizumi, T}, title = {Florigen and antiflorigen gene expression correlates with reproductive state in a marine angiosperm, Zostera marina.}, journal = {iScience}, volume = {28}, number = {8}, pages = {113082}, pmid = {40740502}, issn = {2589-0042}, abstract = {Florigen and antiflorigen genes within the phosphatidylethanolamine-binding protein (PEBP) family regulate flowering in angiosperms. In eelgrass (Zostera marina), an estuarine foundation species, flowering, and seed production are crucial for population resilience. Yet, the molecular mechanism underpinning flowering remains unknown. Among 13 PEBP genes in Z. marina (ZmaPEBP), we showed that four genes (ZmaFT2, ZmaFT4, ZmaFT9, and ZmaTFL1a) altered flowering time when overexpressed in Arabidopsis. We analyzed gene expression in different tissues and throughout the growth season from perennial and annual populations in Willapa Bay and Yaquina Bay, USA. Across six sites exhibiting different degrees of population genetic structure, ZmaFT2 and ZmaFT4 were expressed in leaves of vegetative and reproductive shoots and in rhizomes of reproductive shoots. ZmaFT9 was solely expressed in leaves of vegetative shoots, while ZmaTFL1a levels increased after flowering shoots developed. Our results suggest that ZmaFT2 and ZmaFT4 may promote flowering, while ZmaFT9 may inhibit flowering in eelgrass.}, }
@article {pmid40739416, year = {2025}, author = {Shin, MB and Vu, T and Masud, M and Duran, MC and Escoffery, NC and Bishop, S and Winer, RL and Ko, LK}, title = {Evaluation of an implementation support program for rural communities using a two-tiered, embedded framework.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40739416}, issn = {1573-7225}, support = {U48 DP006398 and U48 DP006377//Division of Cancer Prevention and Control, the National Center for Chronic Disease Prevention and Health Promotion of the Centers for Disease Control and Prevention, U.S. Department of Health and Human Services/ ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {PURPOSE: Evaluate the impact of Implementation Studio (the "Studio") on community-based organizations' (CBOs) EBI implementation, including changes in breast and colorectal (CRC) cancer screening status among Hispanic/Latino/a EBI recipients.
METHODS: A two-tiered, embedded framework consisted of 1) surveys (n = 38) comparing up-to-date breast and CRC screening status among EBI recipients pre/post-EBI delivery (Tier 1); and semi-structured interviews (n = 13 total; n = 7 leaders, n = 6 community health workers) with CBO staff assessing EBI implementation outcomes using rapid qualitative analysis methods (Tier 2) guided by Proctor's Implementation Research Outcomes Framework. Surveys and interviews were conducted in Spanish/English by phone/virtually September 2022-September 2023.
RESULTS: Up-to-date screening status increased by 16.6% for breast and 19.3% for CRC screening pre/post-EBI implementation, albeit not statistically significant overall (p = 0.168). CBOs reported that implementing EBIs cultivated their confidence and enhanced CBOs' workforce capacity (acceptability). CHWs (the primary EBI implementers) proficiently used the Studio tools to adapt the EBIs to improve fit and implement them in the rural Hispanic/Latino/a communities (appropriateness). Remote delivery increased the EBI accessibility for the community (feasibility). Key drivers of costs were CHWs' time to adapt and implement EBIs (costs). CBOs expressed the need to address clients' social needs to maintain EBI's impact (sustainability).
CONCLUSION: CBOs successfully implemented CHW-led EBIs, and their efforts increased up-to-date cancer screening among rural Hispanic/Latino/a community members. These findings demonstrate that Studio is a promising strategy for building CBOs' capacity to implement EBIs and increase cancer screening.}, }
@article {pmid40739193, year = {2025}, author = {Trejo, MJ and Floyd, JS and Massera, D and Daviglus, M and Garcia-Bedoya, O and Cai, J and Talavera, GA and Tamayo-Murillo, DE and Labovitz, D and Kaplan, R}, title = {Association of liver related biomarkers with incident cardiovascular disease and all-cause mortality in the Hispanic community health study/study of Latinos (HCHS/SOL), a population-based cohort study.}, journal = {BMC gastroenterology}, volume = {25}, number = {1}, pages = {543}, pmid = {40739193}, issn = {1471-230X}, support = {1R01DK134672/DK/NIDDK NIH HHS/United States ; N01-HC65236/HL/NHLBI NIH HHS/United States ; N01-HC65236/HL/NHLBI NIH HHS/United States ; N01-HC65233/HL/NHLBI NIH HHS/United States ; N01-HC65237/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; 1R01AG085320//National Institute of Aging/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Cardiovascular Diseases/mortality/blood/ethnology/epidemiology ; Biomarkers/blood ; *Hispanic or Latino/statistics & numerical data ; *Alanine Transaminase/blood ; Aged ; *Aspartate Aminotransferases/blood ; Young Adult ; Adolescent ; Incidence ; Cohort Studies ; *Fatty Liver/blood/ethnology/complications ; United States/epidemiology ; Cause of Death ; White ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) increases risk of cardiovascular disease (CVD). Despite the high prevalence of MASLD among Hispanic populations, there is a scarcity of research on the associations between non-invasive markers of liver disease and incident CVD and all-cause mortality. In this study we investigated the association of liver related biomarkers with CVD events and all-cause mortality in a population based Hispanic/Latino cohort.
METHODS: We included 15,216 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 years with no pre-existing CVD. The composite outcome combined incident CVD and all-cause mortality. Having "elevated ALT/AST" was defined as ALT > 40 IU/mL or AST > 37 IU/mL for males, and ALT or AST > 31 IU/mL for females. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) relating our composite outcome to elevated ALT/AST, FIB-4 and MASLD. Using interaction terms, we assessed whether the relationship between elevated ALT/AST and the composite outcome differed by MASLD status.
RESULTS: The study population was 40 years old on average, 52.7% female and had 740 CVD or all-cause mortality events. Elevated FIB-4 had the strongest association with incident CVD or all-cause mortality (comparing FIB-4 > 2.67 versus ≤ 2.67, HR:3.47; CI:2.34-5.14). Elevated AST was found to be associated with incident CVD or all-cause mortality (HR:1.53; CI:1.14-2.05). MASLD was not associated with incident CVD or all-cause mortality (HR:1.14; CI: 0.94-1.40), but it was associated with incident CVD alone (HR:1.69; CI:1.19-2.39). The relationship between elevated ALT/AST and incident or all-cause mortality was modified by MASLD, such that the strongest association between elevated ALT/AST and incident CVD or all-cause mortality was in the absence of MASLD (HR:1.95; CI:1.20-3.18).
CONCLUSIONS: Among Hispanic adults FIB-4 was strongly associated with CVD or all-cause mortality and among persons without MASLD, elevated ALT/AST were associated with CVD or all-cause mortality.}, }
@article {pmid40738478, year = {2025}, author = {Murakami, N and Blosser, CD and Webber, AB and Gupta, G and Singh, N and Boppana, S and Master, S and Parasuraman, R and Campagnaro, EL and Java, A and Sprangers, B and Bhasin-Chhabra, B and Lum, E and Khirfan, D and Alexander, P and Molnar, MZ and Benes, B and Thakur, AK and Bumma, N and Karam, S and Hultcrantz, M and Bridoux, F and Sanchorawala, V and Leung, N and Landau, H}, title = {Management recommendations for kidney transplantation in patients with plasma cell dyscrasia.}, journal = {Kidney international}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.kint.2025.07.011}, pmid = {40738478}, issn = {1523-1755}, abstract = {Patients with plasma cell dyscrasias (PCD), including multiple myeloma, AL amyloidosis, and monoclonal gammopathy of renal significance (MGRS), face a high burden of end-stage kidney disease (ESKD), limiting survival and quality of life. While kidney transplantation offers potential benefits, it is underutilized due to high risk of recurrence and historically poor outcomes. A multidisciplinary panel of transplant nephrologists, hematologists/oncologists, and pathologists convened to evaluate contemporary evidence and evolving strategies in kidney transplant for PCD-ESKD. Advances in PCD therapies are improving survival and expanding kidney transplant eligibility. Key challenges remain, including optimizing hematologic response pre-kidney transplant, immunosuppression management to mitigate recurrence and avoid infection complications. Ongoing research and multidisciplinary collaboration are essential to refine transplant selection, integrate biomarkers for risk stratification, and develop tailored post-kidney transplant surveillance. These efforts may increase access to kidney transplant and improve outcomes for patients with PCD-ESKD.}, }
@article {pmid40737820, year = {2025}, author = {VoPham, T and Liu, T and Cortez, M and Karasaki, S and Falkenberg, NF and Zewdie, HY and Lin, J and Nondin, C and Chao, SLS and Knowlton, T and Quennehen, B and Mendoza, JA and Ioannou, GN and Berry, K and Adamkiewicz, G and Li, CI and Hart, JE}, title = {Exposure to outdoor air pollution, wildfires, and cancer survival in the United States.}, journal = {Cancer epidemiology}, volume = {98}, number = {}, pages = {102899}, doi = {10.1016/j.canep.2025.102899}, pmid = {40737820}, issn = {1877-783X}, abstract = {BACKGROUND: Climate change has led to an increase in wildfires, a major source of air pollution, which may be particularly harmful to individuals diagnosed with cancer. The objective of this study was to examine the relationships of air pollution and wildfires with mortality risk among cancer survivors.
METHODS: Surveillance, Epidemiology, and End Results (SEER) cancer registries provided information on 7,051,014 patients diagnosed with cancer from 2000 to 2021 in the United States. Cox regression was used to calculate adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) for the associations between exposures to particulate matter < 2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone (O3), and wildfires (estimated using high-resolution geospatial datasets) with all-cause and cause-specific mortality risk.
RESULTS: There were 3,452,593 deaths, including 2,369,364 from cancer, 525,409 from cardiopulmonary, and 557,820 from other causes. Among cancer survivors, higher exposure to PM2.5 and wildfires (but not NO2 or O3) were associated with increased risk for all-cause, cancer, and other mortality. The association between PM2.5 and cancer mortality was stronger in counties more heavily impacted by wildfires (HR per 10 μg/m[3] in counties with ≥ median 0.39 wildfires per year: 1.17, 95 % CI 1.04-1.33) vs. no wildfires (HR 1.06, 95 % CI 0.97-1.15) (p interaction = 0.0064).
CONCLUSIONS: Among patients diagnosed with cancer, PM2.5 air pollution, particularly in areas heavily impacted by wildfires, is associated with increased risk for mortality.}, }
@article {pmid40737539, year = {2025}, author = {Rangarajan, HG and Satwani, P and Herr, MM and Chen, M and Martens, MJ and Wudhikarn, K and John, S and Fabrizio, VA and Hsieh, EM and Kelkar, AH and Doherty, E and Marks, DI and Ringden, O and Friend, BD and Kelly, MS and Farhadfar, N and Prestidge, T and Hossain, NM and Liu, H and Hashmi, S and Modi, D and Winestone, LE and El Boghdadly, Z and Murthy, HS and Perales, MA and Chemaly, RF and Dandoy, CE and Hill, JA and Huppler, AR and Riches, M and Auletta, JJ}, title = {Real-World Outcomes of Infections Following Tisagenlecleucel in Patients with B-Cell ALL: A CIBMTR Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016149}, pmid = {40737539}, issn = {2473-9537}, abstract = {Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications through 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In multivariable analysis, receipt of ≥3 lines of therapy prior to tisa-cel (hazard ratio [HR] 1.86, 95% CI 1.13-3.08, p=0.015), any grade cytokine release syndrome (HR 1.78, 95% CI 1.17-2.71, p=0.007), and lack of neutrophil recovery (HR 2.63, 95% CI 1.47-4.69, p=0.001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections with the addition of younger age as an adverse risk (<6 vs. 6-15 years HR 2.38, 95% CI 1.23-4.61, p=0.01). Risk factors for viral infections included increasing age (1-year increase HR 1.05, 95% CI 1.01-1.09, p=0.016), prior history of any infection (HR 2.76, 95% CI 1.40-5.46, p=0.004), and prior hematopoietic cell transplant (HR 2.10, 95% CI 1.18-3.71, p=0.011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI 0.0-0.8%). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.}, }
@article {pmid40737504, year = {2025}, author = {Nascimento De Lima, P and Bartholomew, L and May, FP and Coronado, GD and Rutter, CM}, title = {The triple-effect of colorectal cancer screening: reducing deaths, government spending and mortality disparities.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf202}, pmid = {40737504}, issn = {1460-2105}, abstract = {Colorectal cancer (CRC) screening accounts for over 60% of cancer screening costs in the US, prompting recurrent debates about its value. Yet CRC screening remains the main tool to curb overall CRC incidence, mortality, and disparities that affect Black Americans. Using the race-specific CRC-SPIN microsimulation model, we show that CRC screening in the United States simultaneously achieves three goals: it saves lives by preventing 24 deaths per 1,000 Black Americans screened with fecal immunochemical test (FIT) and 26 screened with colonoscopy; saves tax dollars by shifting costs from Medicare to private payers; and reduces racial incidence and mortality disparities, helping offset disparities in CRC survival. Both FIT and colonoscopy screening are cost-effective relative to no screening, with annual FIT remaining the most-cost-effective option. Changes to policy requiring coverage of preventive care services must avoid compromising the effectiveness of CRC screening-arguably the greatest equalizer of cancer disparities.}, }
@article {pmid40737434, year = {2025}, author = {Parks, KR and Moodie, Z and Allen, MA and Yen, C and Furch, BD and MacPhee, KJ and Ozorowski, G and Heptinstall, J and Hahn, WO and Zheng, Z and Lu, H and Grant, S and Domin, E and Duff, MO and Seese, A and Marini-Macouzet, C and Ballweber-Fleming, L and Lee, WH and Cottrell, CA and Liguori, A and Georgeson, E and Alavi, N and Kubitz, M and Phelps, N and Seaton, KE and Cohen, KW and Anderson, MA and Mondal, K and Laufer, DS and Kublin, JG and Ward, AB and Hyrien, O and De Rosa, SC and Himansu, S and Leav, B and Reuter, C and Tomaras, GD and Montefiori, D and Walsh, SR and Frank, I and Sobieszczyk, ME and Goepfert, PA and Stephenson, KE and Baden, LR and Van Tieu, H and Keefer, MC and Clark, J and Riddler, SA and Schief, WR and McElrath, MJ}, title = {Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial.}, journal = {Science translational medicine}, volume = {17}, number = {809}, pages = {eady6831}, doi = {10.1126/scitranslmed.ady6831}, pmid = {40737434}, issn = {1946-6242}, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *AIDS Vaccines/immunology/adverse effects ; *RNA, Messenger/genetics ; *Vaccination ; *env Gene Products, Human Immunodeficiency Virus/immunology ; Female ; Male ; Adult ; *HIV Antibodies/immunology ; HIV Infections/immunology/prevention & control ; HIV-1/immunology ; *Protein Multimerization ; Middle Aged ; }, abstract = {mRNA technology might accelerate development of an urgently needed preventive human immunodeficiency virus (HIV) vaccine. We evaluated the safety and immunogenicity of three mRNA-encoded envelope trimers, including two doses of soluble and membrane-anchored forms, in a randomized, open-label, phase 1 clinical trial. Vaccines were generally well tolerated, although 6.5% (7 of 108) of participants developed urticaria, a higher proportion than seen with other mRNA vaccines. mRNA-encoded trimers induced strong envelope-specific B and T cell responses. Immunization with membrane-anchored trimers, intended to obscure epitopes at the trimer base targeted by nonneutralizing antibodies, reduced the frequency of base-binding serum antibodies in comparison with soluble trimers. Three immunizations elicited autologous tier 2 serum neutralizing antibodies in 80% of vaccinees receiving the membrane-anchored trimers, in contrast to only 4% receiving the soluble trimer. Thus, with demonstration of more favorable safety, mRNA-encoded membrane-anchored HIV envelope trimers represent a promising platform for HIV vaccine clinical development.}, }
@article {pmid40666976, year = {2025}, author = {Johnson, MM and Sung, K and Haddox, HK and Vora, AA and Araki, T and Victora, GD and Song, YS and Fukuyama, J and Matsen, FA}, title = {Nucleotide context models outperform protein language models for predicting antibody affinity maturation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666976}, issn = {2692-8205}, abstract = {Antibodies play a crucial role in adaptive immunity. They develop as B cell receptors (BCRs): membrane-bound forms of antibodies that are expressed on the surfaces of B cells. BCRs are refined through affinity maturation, a process of somatic hypermutation (SHM) and natural selection, to improve binding to an antigen. Computational models of affinity maturation have developed from two main perspectives: molecular evolution and language modeling. The molecular evolution perspective focuses on nucleotide sequence context to describe mutation and selection; the language modeling perspective involves learning patterns from large data sets of protein sequences. In this paper, we compared models from both perspectives on their ability to predict the course of antibody affinity maturation along phylogenetic trees of BCR sequences. This included models of SHM, models of SHM combined with an estimate of selection, and protein language models. We evaluated these models for large human BCR repertoire data sets, as well as an antigen-specific mouse experiment with a pre-rearranged cognate naive antibody. We demonstrated that precise modeling of SHM, which requires the nucleotide context, provides a substantial amount of predictive power for predicting the course of affinity maturation. Notably, a simple nucleotide-based convolutional neural network modeling SHM outperformed state-of-the-art protein language models, including one trained exclusively on antibody sequences. Furthermore, incorporating estimates of selection based on a custom deep mutational scanning experiment brought only modest improvement in predictive power. To support further research, we introduce EPAM (Evaluating Predictions of Affinity Maturation), a benchmarking framework to integrate evolutionary principles with advances in language modeling, offering a road map for understanding antibody evolution and improving predictive models.}, }
@article {pmid40737329, year = {2025}, author = {Yeh, KB and Bahnfleth, WP and Bradforda, E and Cardona, C and Coleman, KK and Hudson, PJ and Dadonaite, B and Hutchins, RJ and Maresso, A and MacIntyre, CR and Scotch, M}, title = {Three things we can do now to reduce the risk of avian influenza spillovers.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {31}, pages = {e2503565122}, doi = {10.1073/pnas.2503565122}, pmid = {40737329}, issn = {1091-6490}, support = {89233218CNA000001//DOE | NNSA | Los Alamos National Laboratory (LANL)/ ; }, }
@article {pmid40736449, year = {2025}, author = {Brenner, AT and Odebunmi, OO and Waters, AR and Wangen, M and Marciniak, MW and Ferrari, RM and Wheeler, SB and Shah, PD}, title = {It's a good idea, but are they willing? Assessing pharmacist willingness to deliver colorectal cancer screening.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0275}, pmid = {40736449}, issn = {1538-7755}, abstract = {BACKGROUND: Accessibility, expanding scope of practice, and a rapidly changing policy landscape make US community pharmacies a promising delivery setting for colorectal cancer (CRC) screening. It is not clear, however, whether community pharmacists are willing to incorporate CRC screening into their pharmacy practice, what potential drivers of willingness are, and, if unwilling, under what conditions pharmacists would be willing to provide PharmFIT™.
METHODS: From September 2022 to January 2023, we surveyed 578 currently practicing community pharmacists. We assessed willingness to provide a pharmacy-based CRC screening program (PharmFIT™). We used multiple linear regression to identify correlates of perceived implementation complexity and multiple logistic regression to explore overall willingness to implement PharmFIT™ Results: Most pharmacists (80%) were willing to implement PharmFIT™. The most common reasons for unwillingness were that results needed to be reported to the patients' PCPs (52%), that appropriate training in delivering CRC screening be provided (48%) and that care coordination with PCPs be clear (46%). Perceived complexity of the intervention decreased as years in practice increased (β= 0.013; CI95%: 0.01-0.02) and as level of knowledge about CRC screening increased (β= 0.085; CI95%: 0.01-0.16). Respondents' willingness to implement PharmFIT™ increased as perceived complexity decreased (OR:5.68, CI95%: 3.96-8.15).
CONCLUSIONS: Most community pharmacists in the US would be willing to integrate PharmFIT™ into their current workflows. Training in how to deliver FIT and preparation for the coordination of test results and follow up care should be completed prior to implementing PharmFIT™.
IMPACT: Community pharmacies are a viable venue for delivering CRC screening.}, }
@article {pmid40736255, year = {2025}, author = {Andrews, A and Harrar, DB and Zelleke, T and Zhang, J and Zhang, B and Barber, J and Dasan, R and Amoah, N and Findorff, O and Krieger, S and Barrett, E and O'Brien, N and Fuller, CE and Moxon, CA and Taylor, TE and Griffiths, MJ and Ray, STJ and Postels, DG}, title = {Electroencephalogram Features Distinguish Cases of Cerebral Malaria Among Malawian Children With Fever and Coma.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf316}, pmid = {40736255}, issn = {1537-6591}, support = {R03NS124536//US National Institutes of Health/ ; }, abstract = {BACKGROUND: In febrile comatose patients living in malaria-endemic areas, overlapping symptoms and limited laboratory capacity make it difficult to distinguish parasitic, bacterial, and viral central nervous system infections. We evaluated electroencephalography (EEG) as a biomarker to differentiate the microbiologic etiology of pediatric febrile coma at a major referral center in Malawi.
METHODS: This was a retrospective case-control study comparing EEG recordings of Malawian children with cerebral malaria to those with febrile coma of nonmalarial cause (bacterial meningitis, viral encephalitis, or unknown cause). Participants were admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2013 and 2021. Inclusion criteria were fever, coma (Blantyre Coma Score ≤2), and coma etiology (malarial or nonmalarial) defined by laboratory testing. Four supervised machine learning algorithms were used to train a balanced ensemble classifier, SuperLearner, generating test characteristics of the diagnostic ability of EEG features.
RESULTS: Two hundred three children with cerebral malaria and 87 children with nonmalarial coma were included. Univariate analysis of qualitative (visual) EEG interpretations revealed higher voltage, slower background frequency, more sleep elements, less variability, more abnormal organization, and less continuity in cerebral malaria. Quantitative waveform analysis showed greater power in cerebral malaria. Both quantitative and qualitative EEG interpretation distinguished coma etiology (area under the receiver operating characteristic curve [AUROC] = 0.85 and 0.86, respectively). Combining qualitative and quantitative interpretation methods, the test characteristic improved (AUROC = 0.90).
CONCLUSIONS: EEG features distinguish malarial from nonmalarial coma in febrile Malawian children. This technology may aid in distinguishing the microbiologic etiology of febrile coma in malaria-endemic areas.}, }
@article {pmid40735070, year = {2025}, author = {Sarfraz, Z and Maharaj, A and Venur, VA and Lathia, JD and Odia, Y and Ahluwalia, MS}, title = {Immunotherapy in Glioblastoma: An Overview of Current Status.}, journal = {Clinical pharmacology : advances and applications}, volume = {17}, number = {}, pages = {185-209}, pmid = {40735070}, issn = {1179-1438}, abstract = {Glioblastoma (GB) is an aggressive brain tumor with standard therapies offering limited but measurable survival benefit. Immunotherapy is expanding the treatment landscape for GB. Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have shown benefit in several cancers and are being studied in GB, with ongoing efforts to address the tumor's immunosuppressive environment. Chimeric Antigen Receptor (CAR) T-cell therapies are also being explored, with new approaches designed to overcome antigen variability and improve access across the blood-brain barrier. Cancer vaccines, especially dendritic cell-based platforms like DCVax-L, have shown promising survival outcomes in clinical trials. Advances in biomarker analysis and genomics are supporting more personalized immunotherapy approaches. In addition, combination strategies involving ICIs, CAR T-cells, vaccines, and oncolytic viruses are being developed to enhance immune response. This review outlines current immunotherapy approaches in GB, focusing on their mechanisms, clinical development, and future directions.}, }
@article {pmid40730903, year = {2025}, author = {Peters, Q and Prlic, M}, title = {Six degrees of TGFβ.}, journal = {Nature immunology}, volume = {26}, number = {8}, pages = {1221-1222}, pmid = {40730903}, issn = {1529-2916}, }
@article {pmid40730902, year = {2025}, author = {Devi, KSP and Wang, E and Jaiswal, A and Konieczny, P and Kim, TG and Nirschl, CJ and Verma, A and Liu, Y and Milczanowski, J and Christo, SN and Gandolfo, LC and Haitz, K and Vardam, TD and Wu, P and King, SL and Tse, SW and Pradhan, K and Jiang, X and Tian, T and Fuhlbrigge, RC and Schmults, CD and Clark, RA and Kupper, TS and Freeman, GJ and Mackay, LK and Naik, S and Newell, EW and Elemento, O and Suarez-Farinas, M and Anandasabapathy, N}, title = {PD-1 is requisite for skin TRM cell formation and specification by TGFβ.}, journal = {Nature immunology}, volume = {26}, number = {8}, pages = {1339-1351}, doi = {10.1038/s41590-025-02228-1}, pmid = {40730902}, issn = {1529-2916}, support = {R01 AR083208/AR/NIAMS NIH HHS/United States ; }, mesh = {*Programmed Cell Death 1 Receptor/metabolism/immunology/genetics ; Animals ; *Transforming Growth Factor beta/metabolism/immunology ; *Skin/immunology/cytology ; Mice ; Humans ; *Immunologic Memory ; *CD8-Positive T-Lymphocytes/immunology ; Mice, Inbred C57BL ; Signal Transduction/immunology ; *Memory T Cells/immunology ; Mice, Knockout ; Cell Differentiation/immunology ; Female ; }, abstract = {Tissue-resident memory T (TRM) cells provide infectious, cancer and vaccine-trained immunity across barrier sites. TRM cells are implicated in autoimmunity, successful response to immune checkpoint blockade in the tumor microenvironment and toxicities that occur after immune checkpoint blockade in peripheral tissues. Here, we identified that signaling through the immune checkpoint programmed death receptor 1 (PD-1) strongly impacts the early specification of CD8[+] TRM cells in the skin. PD-1 is expressed broadly across mouse and human skin TRM cells, in the absence of persistent infection, and is retained on skin TRM cells in aged mice. PD-1 supports early TRM cell colonization, skin-specific programming and silencing of other differentiation programs and promotes TGFβ responsivity and skin engraftment. Thus, PD-1 signaling mediates skin TRM cell specification during immune initiation. These findings may inform therapeutic PD-1 agonist and antagonist use to modulate successful peripheral memory.}, }
@article {pmid40730747, year = {2025}, author = {Marchi, F and Shastri, VM and Marrero, RJ and Nguyen, NHK and Öttl, A and Schade, AK and Landwehr, M and Krali, O and Nordlund, J and Ghavami, M and Sckaff, F and Mansinghka, VK and Cao, X and Slayton, W and Starostik, P and Cogle, CR and Ribeiro, RC and Rubnitz, JE and Klco, J and Elsayed, A and Gamis, AS and Triche, TJ and Ries, R and Kolb, EA and Aplenc, R and Alonzo, T and Pounds, S and Meshinchi, S and Lamba, JK}, title = {Epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6961}, doi = {10.1038/s41467-025-62005-4}, pmid = {40730747}, issn = {2041-1723}, support = {R01CA132946//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA270120//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; SAP 21-061-01//American Cancer Society (American Cancer Society, Inc.)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/diagnosis/mortality ; Prognosis ; DNA Methylation/genetics ; *Epigenomics/methods ; Adult ; Child ; Female ; Male ; Adolescent ; Machine Learning ; CpG Islands/genetics ; Middle Aged ; Child, Preschool ; Young Adult ; Epigenesis, Genetic ; Cohort Studies ; }, abstract = {Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation on patient samples confirms high concordance between epigenomic signatures and genomic lesions, though uniquely rare karyotypes remained challenging due to limited available training data. These results unveil the potential for increased affordability, speed, and accuracy for patients in need of complex molecular diagnosis and prognosis.}, }
@article {pmid40730678, year = {2025}, author = {Hagan, CE and Sheehan, VM and Rezanka, CM and Li, MA and Martínez-Escardó, L and Campbell, KJ and Snyder, AG and Headley, M and Oberst, A}, title = {Apoptotic cells promote circulating tumor cell survival and metastasis.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1121}, doi = {10.1038/s42003-025-08541-7}, pmid = {40730678}, issn = {2399-3642}, support = {T32GM007270//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; U01CA289564//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {*Neoplastic Cells, Circulating/pathology/metabolism ; *Apoptosis ; Humans ; Animals ; Cell Survival ; Mice ; Cell Line, Tumor ; *Lung Neoplasms/secondary ; Neoplasm Metastasis ; Female ; Thromboplastin/metabolism ; Phosphatidylserines/metabolism ; Blood Coagulation ; }, abstract = {During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.}, }
@article {pmid40729824, year = {2025}, author = {Yoshida, Y and Nguyen, NQ and Moon, EH and Rebholz, C and Skali, H and Arthur, V and Echouffo-Tcheugui, JB and Ballantyne, C and Selvin, E and Shah, A and Kaplan, R and Rodriguez, CJ and Qi, Q and Cheng, S and Yu, B}, title = {A Metabolomics Study of Cardiac Dysfunction in Hyperglycemia-Findings From the Atherosclerosis Risk in Communities (ARIC) Study and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc25-0730}, pmid = {40729824}, issn = {1935-5548}, support = {1P20GM152305/GM/NIGMS NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; R01 HL104199/HL/NHLBI NIH HHS/United States ; R01HL141824/HL/NHLBI NIH HHS/United States ; R01HL168683/HL/NHLBI NIH HHS/United States ; 7-23-JDFWH-10//American Diabetes Association/ ; }, abstract = {OBJECTIVE: Hyperglycemic states (prediabetes and diabetes) are associated with heart failure (HF) risk. We aimed to identify distinct metabolites for subclinical cardiac dysfunction, a precursor of HF, in hyperglycemic or euglycemic individuals.
RESEARCH DESIGN AND METHODS: We conducted cross-sectional and prospective analyses of 2,492 HF-free participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5, 2011-2013. A total of 1,297 participants were hyperglycemic (assessed on the basis of hemoglobin A1c >5.7%, fasting glucose >100 mg/dL, use of diabetes medication, or diagnosis), and 1,195 were euglycemic. We used logistic regression for analysis of association between 790 metabolites and cardiac dysfunction, defined according to echocardiographic abnormalities (left ventricular hypertrophy, systolic or diastolic dysfunction) or elevated NT-proBNP or troponin T, in two glycemic groups separately. We used Cox regression for prospective association between cardiac dysfunction-related metabolites identified in the prior step and HF risk, adjusting for clinical risk factors. Analyses were replicated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n = 5,167).
RESULTS: Microvascular disease-related metabolites (e.g., pseudouridine, N6-carbamoylthreonyladenosine, N6-acetyllysine, N2,N5-diacetylornithine) were associated with cardiac dysfunction in hyperglycemic individuals. Carbohydrate and cofactor-derived metabolites (e.g., gulonate, erythrocyte) were associated with cardiac dysfunction in euglycemic individuals. These cardiac dysfunction-related metabolites were prospectively associated with HF risk in the two glycemic groups (follow-up 7.5 years, 137 and 94 HF cases, per-SD increase hazards ratios range 1-1.9 and 1.1-2.9), respectively. HCHS/SOL results were consistent with those from ARIC.
CONCLUSIONS: Metabolites known for microvascular complications were associated with cardiac dysfunction in hyperglycemic individuals but not among their euglycemic counterparts, supporting the premise that microvascular dysfunction contributes to HF pathogenesis in diabetes.}, }
@article {pmid40728846, year = {2025}, author = {Kamp, KJ and Hendrickson, K and Iqbal, A and Saad, K and Clark-Snustad, K and Dey, N and Gui, X and Lee, S}, title = {Correlation of Fecal, Plasma, Serum, and Salivary Calprotectin to Endoscopic and Histologic Outcomes in Patients With Crohn's Disease: A Pilot Study.}, journal = {Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates}, volume = {48}, number = {4}, pages = {265-270}, pmid = {40728846}, issn = {1538-9766}, mesh = {Humans ; *Leukocyte L1 Antigen Complex/analysis/blood/metabolism ; *Crohn Disease/pathology/metabolism/diagnosis/blood ; Pilot Projects ; *Feces/chemistry ; Female ; Male ; Adult ; *Saliva/chemistry ; Biomarkers/analysis/blood ; Colonoscopy ; Middle Aged ; Severity of Illness Index ; Young Adult ; }, abstract = {Easily obtained, noninvasive biomarkers are needed for Crohn's disease monitoring. This pilot study compared associations between calprotectin levels in stool, saliva, and blood to assess their correlation with endoscopic and histologic outcomes among patients with Crohn's disease. Participants recruited from an Inflammatory Bowel Disease center provided stool, blood, and saliva samples prior to undergoing scheduled colonoscopy (n = 17). We collected participant demographics and clinical disease activity. Endoscopic disease was assessed with the Simple Endoscopic Score. Histologic disease was assessed with the Robarts Histological Index. The mean age of the sample was 32.3 (SD 7.5) years. Correlations with endoscopic disease activity were 0.83 for fecal calprotectin, 0.26 for plasma calprotectin, 0.24 for serum calprotectin, and 0.02 for salivary calprotectin. Correlations with histologic disease activity were 0.80 for fecal calprotectin, 0.55 for plasma calprotectin, 0.15 for serum calprotectin, and -0.03 for salivary calprotectin. Fecal calprotectin had the strongest correlations with endoscopic and histologic disease outcomes, but fecal calprotectin levels were lower among those with ileal disease. For blood-based calprotectin, plasma calprotectin had a higher correlation with histology than serum, and plasma calprotectin levels were higher among those with ileal disease.}, }
@article {pmid40666929, year = {2025}, author = {Kumar, S and Jiang, J and Donald-Paladino, MS and Chen, J and Gutierrez, A and Federation, AJ and Szulzewsky, F and Holland, EC and Ferguson, FM and Nabet, B}, title = {Development of PROTACs for targeted degradation of oncogenic TRK fusions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666929}, issn = {2692-8205}, abstract = {Chromosomal translocations leading to the fusion of tropomyosin receptor kinases (TRK) with diverse partner proteins have been identified as oncogenic drivers in many adult and pediatric cancers. While first-generation TRK kinase inhibitors, such as entrectinib and larotrectinib, have shown positive responses in TRK fusion-positive cancers, resistance mutations against these inhibitors in the kinase domain limit their efficacy. Second-generation inhibitors are in clinical evaluation, highlighting a need for novel therapeutic modalities to achieve durable suppression of the oncogenic activity of TRK fusions. Here, we developed heterobifunctional small molecule degraders (PROTACs) to achieve targeted degradation of TRK fusions. By conjugating entrectinib to thalidomide, we identified JWJ-01-378 as a potent and selective CRBN-recruiting degrader of the TPM3-TRKA fusion. JWJ-01-378 induced TPM3-TRKA degradation through the ubiquitin-proteasome system and proteomics analysis confirmed the acute selectivity of JWJ-01-378 for achieving TPM3-TRKA degradation with minimal off-target effects. While JWJ-01-378 was also able to degrade wild-type TRK, it was unable to degrade TRK inhibitor resistant mutants and ALK fusions. Importantly, TPM3-TRKA degradation by JWJ-01-378 suppressed downstream signaling and reduced cancer cell viability, with improved responses compared to heterobifunctional control compounds that cannot degrade TPM3-TRKA. Together, our study expands the toolbox of compounds for evaluating targeted degradation of TRK fusions in cancer.}, }
@article {pmid40728034, year = {2025}, author = {Horne, DJ and Zifodya, JS and Shapiro, AE and Church, EC and Kreniske, JS and Kay, AW and Scandrett, K and Steingart, KR and Takwoingi, Y}, title = {Xpert MTB/RIF Ultra assay for pulmonary tuberculosis and rifampicin resistance in adults and adolescents.}, journal = {The Cochrane database of systematic reviews}, volume = {7}, number = {}, pages = {CD009593}, pmid = {40728034}, issn = {1469-493X}, mesh = {Humans ; *Rifampin/therapeutic use/pharmacology ; *Tuberculosis, Pulmonary/diagnosis/drug therapy/microbiology ; Adolescent ; Adult ; Sensitivity and Specificity ; *Mycobacterium tuberculosis/drug effects/genetics/isolation & purification ; *Antibiotics, Antitubercular/therapeutic use/pharmacology ; Bias ; Randomized Controlled Trials as Topic ; Child ; *Drug Resistance, Bacterial/genetics ; }, abstract = {BACKGROUND: Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.
OBJECTIVES: To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.
SEARCH METHODS: We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov and the WHO ICTRP) to 16 October 2023 without language restrictions. A WHO Public Call for ongoing and unpublished studies was made between 30 November 2023 and 15 February 2024.
SELECTION CRITERIA: We included cross-sectional studies, cohort studies, and randomised controlled trials that provided data on the diagnostic accuracy of Xpert Ultra using respiratory specimens in adolescents (aged 10 to 14 years) and adults (aged 15 years and older) with presumptive pulmonary tuberculosis. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based phenotypic drug susceptibility testing with or without whole genome sequencing.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardised form. We assessed risk of bias using QUADAS-2. We performed meta-analyses using a bivariate model to produce summary sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarised Xpert Ultra trace-positive results.
MAIN RESULTS: Pulmonary tuberculosis detection For detection of pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity against culture were 90.7% (95% confidence interval (CI) 88.2 to 92.7) and 94.8% (95% CI 92.8 to 96.3) (32 studies, 12,529 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss nine cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 47. In people living with HIV, Xpert Ultra summary sensitivity and specificity were 87.7% (82.0 to 91.7) and 95.3% (92.2 to 97.2) (11 studies, 1164 participants). Amongst people with smear-negative, culture-positive pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity were 80.7% (75.4 to 85.0) and 94.0% (91.3 to 95.9) (16 studies, 6460 participants). In people with a history of tuberculosis, Xpert Ultra summary sensitivity and specificity were 84.8% (78.2 to 89.7) and 86.2% (78.9 to 91.3) (9 studies, 809 participants). The proportion of Ultra trace-positive results that were true positives compared to the microbiological reference standard was 38.8%. Reclassifying trace-positive results as Xpert Ultra-negative led to a reduction in sensitivity and modest increase in specificity. Rifampicin resistance detection For detection of rifampicin resistance, Xpert Ultra summary sensitivity and specificity were 95.8% (93.2 to 97.4) and 98.3% (97.0 to 99.0) (10 studies, 1644 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss four cases. The number of people wrongly diagnosed with rifampicin resistance would be 16 out of the 900 who do not have rifampicin resistance. Xpert Ultra performed similarly, for rifampicin resistance, in people with smear-positive and smear-negative tuberculosis.
AUTHORS' CONCLUSIONS: Xpert Ultra has high sensitivity and specificity for detection of pulmonary tuberculosis rifampicin resistance. Xpert Ultra for the detection of pulmonary tuberculosis has lower sensitivity in people with smear-negative/culture-positive tuberculosis and lower sensitivity and specificity in people with a history of tuberculosis. Xpert Ultra trace-positive results were common. Strengths of this review include the approach to identifying relevant studies, the number of studies and participants included in this systematic review, and that most studies were at low risk of bias. The small number of studies (six) and participants who were adolescents is a limitation to our accuracy estimates in this age group. Xpert Ultra testing provides accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multiple-drug-resistant tuberculosis.
FUNDING: The WHO supported this systematic review. Liverpool School of Tropical Medicine hosted the Cochrane Infectious Diseases Group (CIDG) editorial base, which supported the authors in the development of this review update. The Foreign, Commonwealth and Development Office funded the CIDG.
REGISTRATION: Generic protocol available on Open Science Framework via https://osf.io/26wg7/wiki/home/. Previous protocol and review versions available via DOI 10.1002/14651858.CD009593 and DOI 10.1002/14651858.CD009593.pub5.}, }
@article {pmid40727571, year = {2025}, author = {Vega, P and Newby, R and Bender Ignacio, RA and Fisher, CE and Oken, E and Harbell, JW and Mour, GK and Shubeilat, J and Ng, YH and Li, M and Bhattacharya, R and Bakthavatsalam, R and Sibulesky, L and Vikram, HR and Rakita, RM and Tayyar, R}, title = {Donor-Derived Tuberculosis in 3 Solid Organ Transplant Recipients From the Same Donor.}, journal = {Open forum infectious diseases}, volume = {12}, number = {7}, pages = {ofaf372}, pmid = {40727571}, issn = {2328-8957}, abstract = {Donor-derived tuberculosis is a rare complication following solid organ transplantation, and tuberculosis screening is not a current transplant prerequisite for most donors. Donor-derived tuberculosis usually presents sooner than reactivation tuberculosis, and the most common finding is fever. We present 3 cases of donor-derived tuberculosis in the recipients of 2 kidneys and 1 liver from the same donor, who presented with unexplained fevers occurring 4-5 weeks after transplantation. Initial antibacterial therapy failed in all 3 patients, leading to further testing, which identified Mycobacterium tuberculosis by culture and molecular studies. All recipients successfully received tuberculosis therapy but had significant morbidity and prolonged hospital stays. Donor-derived tuberculosis should be among the differential diagnoses of unexplained fever in solid organ transplant recipients in the first few months after transplantation. Screening protocols should be implemented for donors with an epidemiologic risk of tuberculosis, with special emphasis on deceased donors.}, }
@article {pmid40723216, year = {2025}, author = {Powles, T and Sridhar, SS and Bellmunt, J and Sternberg, CN and Grivas, P and Hunter, E and Salter, M and Powell, R and Dring, A and Green, J and Akoulitchev, A and Ronen, R and Dutkowski, J and Amezquita, R and Huang, CH and Fernandez, D and Nameki, R and Ching, KA and Pu, J and Saul, M and Deng, S and di Pietro, A and Davis, CB}, title = {Blood-Epigenetic Biomarker Associations with Tumor Immunophenotype in Patients with Urothelial Carcinoma from JAVELIN Bladder 100.}, journal = {Cancers}, volume = {17}, number = {14}, pages = {}, doi = {10.3390/cancers17142332}, pmid = {40723216}, issn = {2072-6694}, support = {N/A//Merck (CrossRef Funder ID: 10.13039/100009945) and was previously conducted under an alliance between Merck and Pfizer./ ; }, abstract = {BACKGROUND/OBJECTIVES: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment.
METHODS: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden.
RESULTS: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation.
CONCLUSIONS: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays.}, }
@article {pmid40723206, year = {2025}, author = {Gang, M and Othus, M and Olix, AC and Markey, KA and Stirewalt, DL and Connelly-Smith, LS and Lee, SJ and Milano, F and Walter, RB}, title = {CD34+ Cell Dose, Measurable Residual Disease, and Outcome After Myeloablative HLA-Matched Peripheral Blood Hematopoietic Cell Transplantation for Adults with Acute Myeloid Leukemia.}, journal = {Cancers}, volume = {17}, number = {14}, pages = {}, doi = {10.3390/cancers17142323}, pmid = {40723206}, issn = {2072-6694}, support = {P01-CA078902//National Cancer Institute/National Institutes of Health/ ; P01-CA018029//National Cancer Institute/National Institutes of Health/ ; P30-CA015704//National Cancer Institute/National Institutes of Health/ ; T32-HL007093//NIH/National Heart, Lung, and Blood Institute/ ; }, abstract = {Background: The impact of donor graft cell composition on post-HCT outcomes in AML remains controversial. Furthermore, it is unknown whether this interacts with pre-HCT MRD status. We evaluated the impact of CD34+ and CD3+ cell doses on outcomes of myeloablative conditioning (MAC) HCT in patients with myelodysplastic neoplasm (MDS)/AML or AML with and without detectable MRD in pre-HCT bone marrow specimens. Methods: We utilized an electronic database to identify all adults ≥18 years with MDS/AML or AML who underwent MAC and received 10/10 HLA-matched sibling or unrelated donor mobilized PBSC allografts in first morphologic remission between 2006 and 2023 at the University of Washington/Fred Hutchinson Cancer Center. Results: Among 385 adults, we found a progressive decrease in relapse incidence and improved survival with increasing CD34+ doses up to a threshold of 5.61 × 10[6]/kg, above which the relapse risk no longer decreased. After multivariable adjustment, a low CD34+ dose was associated with increased risk of relapse as well as lower overall and relapse-free survival. Similar results were obtained for patients with and without pre-HCT MRD. Higher CD3+ doses were linearly associated with an increased incidence of moderate-severe chronic GVHD. Conclusions: Our data identify a non-linear relationship between CD34+ cell dose and relapse risk in AML patients undergoing myeloablative allogeneic HCT, with no apparent added benefit beyond a CD34+ dose threshold. Our findings suggest that donor graft composition impacts outcomes in adults with AML undergoing allogeneic HCT after MAC, independent of pre-HCT MRD status; however, additional studies are needed for other donor cell scenarios.}, }
@article {pmid40721534, year = {2025}, author = {Grosely, R and Alvarado, C and Ivanov, IP and Nicholson, OB and Puglisi, JD and Dever, TE and Lapointe, CP}, title = {eIF1 and eIF5 dynamically control translation start site fidelity.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40721534}, issn = {1545-9985}, abstract = {Human translation initiation requires accurate recognition of translation start sites. While AUG codons are canonical start sites, non-AUG codons are also used, typically with lower efficiency. The initiator tRNA and initiation factors eIF1 and eIF5 control recognition. How they distinguish different start sites yet allow flexible recognition remains unclear. Here we used real-time single-molecule assays and an in vitro reconstituted human system to reveal how eIF1 and eIF5 direct start site selection. eIF1 binds initiation complexes in two modes: stable binding during scanning, followed by transient, concentration-dependent rebinding after start site recognition. Termination of eIF1 rebinding requires transient and concentration-dependent binding by eIF5, which allows the formation of translation competent ribosomes. Non-AUG start sites differentially stabilize eIF1 and destabilize eIF5 binding, blocking initiation at multiple points. We confirmed these opposing effects in human cells. Collectively, our findings uncover that eIF1 and eIF5 directly compete to bind initiation complexes and illuminate how their dynamic interplay tunes the fidelity of start site recognition, which has broad connections to health and disease.}, }
@article {pmid40721386, year = {2025}, author = {Ferguson-Steele, ZO and Kilgore, MR and Lam, DL}, title = {Ovarian Cancer Metastasis to the Breast: Radiologic-Pathologic Correlation.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbaf029}, pmid = {40721386}, issn = {2631-6129}, abstract = {Ovarian metastasis to the breast is extremely rare. The clinical and radiologic presentation of metastasis to the breast is nonspecific and can mimic primary breast cancers. The most common mammographic findings of ovarian metastasis are superficial, circumscribed, high-density masses without architectural distortion. Compared with other malignancies that metastasize to the breast, ovarian cancer can more frequently show microcalcifications. On US, these masses can be hypoechoic or have heterogeneous echogenicity with posterior acoustic enhancement. Less commonly, ovarian metastasis can present similarly to inflammatory breast cancer, demonstrating diffuse skin thickening on mammography and US. Immunohistochemistry is useful in differentiating ovarian metastasis from primary breast lesions. Ovarian and breast markers, including Wilm's tumor, paired box 8, cancer antigen 125, GATA binding protein 3, and gross cystic disease fluid protein 15, are particularly helpful. Overall, metastatic ovarian cancer to the breast provides a diagnostic challenge requiring close radiologic and pathologic correlation to reach the correct diagnosis.}, }
@article {pmid40716572, year = {2025}, author = {Hong, L and Di Federico, A and Liu, B and Cooper, AJ and Alessi, JV and Clark, P and Rinsurongkawong, W and Young, C and Li, H and Qin, K and Aminu, M and Elamin, Y and Sepesi, B and Lewis, J and Gibbons, DL and Vaporciyan, AA and Lee, JJ and Le, X and Wu, J and Roy-Chowdhuri, S and Routbort, MJ and Futreal, PA and Heymach, JV and Awad, MM and Schoenfeld, AJ and Zhang, J and Ricciuti, B and Deng, L and Vokes, NI}, title = {Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multi-Center Retrospective Study.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2025.07.121}, pmid = {40716572}, issn = {1556-1380}, abstract = {BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare non-small cell lung cancer (NSCLC) subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared to other NSCLC subtypes.
PATIENTS AND METHODS: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).
RESULTS: We analyzed 4,841 patients including 165 PSC cases treated with ICI-based therapy from three institutions, and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1,138 (75.1%) LUAD, and 312 (20.6%) LUSC. PSC patients were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for PSC patients compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37%-43% of patients with PSC who received ICIs were responders, compared to 26%-29% in LUAD and 22%-46% in LUSC (P < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared to LUAD/LUSC, and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared to LUAD. Case observation showed relatively better outcomes to ICI than targeted therapies in PSC patients with MET exon 14 skipping or KRAS G12C.
CONCLUSION: PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.}, }
@article {pmid40720905, year = {2025}, author = {Bricker, JB and Santiago-Torres, M and Mull, KE and Sullivan, BM and Mehrotra, R}, title = {Population-Level Dissemination of a Smoking Cessation Smartphone App: Quasi-Experimental Comparison of Values-Based Messages in Social Media Advertisements.}, journal = {JMIR mHealth and uHealth}, volume = {13}, number = {}, pages = {e71619}, doi = {10.2196/71619}, pmid = {40720905}, issn = {2291-5222}, abstract = {BACKGROUND: Cigarette smoking is prevalent in many countries worldwide, especially in low- and middle-income countries (LMICs), presenting an urgent public health challenge. Disseminating freely available smoking cessation treatments that effectively decrease cigarette smoking globally is urgently needed.
OBJECTIVE: Identify the highest impact and most cost-effective values-based social media advertisements to disseminate our smoking cessation smartphone app, "iCanQuit", among adults living in 7 major cities of India. Values represented in the advertisements included family, relationships, self-care, health, and self-control. Using a quasi-experimental design, we aimed to determine (1) which values-based advertisements had the highest smoking cessation app dissemination reach, as measured by click-through rate (CTR), app installs, and app usage metrics; and (2) which values-based message advertisements were more cost-effective as measured by cost-per-impression, cost-per-click, and cost-per-install. The study population included a selected media market of individuals living in 7 metro cities of India - Delhi, Mumbai, Kolkata, Chennai, Bengaluru, Hyderabad, and Pune - who were exposed to one of 6 social media advertisements from January 16 to May 5, 2024.
METHODS: The advertisement campaign design for each of the identified values, based on previous smoking cessation trial data, followed a collaborative iterative process. Advertisements ran sequentially for 16 weeks. Advertisement exposure and app usage data were objectively collected via Google's Display & Video 360 advertisements campaign management and Firebase app development platforms. Advertisement exposure impact on app engagement was measured via several metrics, including click-through rate (CTR, ie, the likelihood of user clicks on an advertisement after seeing it), the number of app installs (ie, a user opening the app for the first time after downloading it), and the number of app sessions (ie, app usage). Cost efficiency was measured via cost per click and cost per install for each ad.
RESULTS: Overall, the CTR was 5%. The app was installed 5111 times. The average cost per click and cost per app install across all advertisements were US $ 0.006 and US $ 6.43, respectively. The advertisements with the lowest cost per install (range: US $4.83-US $5.16) and highest CTR (between 6% and 9%) focused on the values of family, health, and self-control. Advertisements focused on the values of relationships and self-care had modestly higher levels of engagement.
CONCLUSIONS: Advertisements focusing on the values of family, health, and self-control had the highest potential reach at the lowest cost. Overall, these findings provide insights into the reach and cost-effectiveness of values-based messages in social media advertisements, guiding future outreach efforts for population-level dissemination of smoking cessation apps.}, }
@article {pmid40719521, year = {2025}, author = {Rillamas-Sun, E and Woods, NF and Pike, KC and LaCroix, AZ and Zaslavsky, O and Dobra, A and Stefanick, ML and Cochrane, BB}, title = {Latent Class Analysis of Well-Being in Older Women.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1177/15409996251363398}, pmid = {40719521}, issn = {1931-843X}, abstract = {Background: Previous efforts to assess well-being and health focused on individual indicators of hedonic, evaluative, or eudaemonic measures or summated scores reflecting all dimensions. The objectives of this study were to develop profiles that preserve distinct dimensions of hedonic, evaluative, and eudemonic well-being while permitting its exploration as a predictor of health endpoints. Methods: A total of 81,148 Women's Health Initiative (WHI) participants with well-being measures collected in 2011-2012 (mean age = 76.4 years) were included. Women were recruited to the WHI Clinical Trial and Observational Cohort, continued participation in WHI Extensions (2005-2010 and 2010-2015), and completed the 2011-2012 questionnaire. Classes were identified from hedonic (life enjoyment, happiness, life satisfaction, quality of life) and eudaemonic (personal growth, purpose in life, environmental mastery, self-mastery, self-control) measures using latent class analysis. Characteristics were described by classes, and associations with all-cause mortality were examined using logistic regression. Results: Four well-being classes were identified. Class 2 (17.8%) had the lowest (worst) well-being scores, and class 4 (53.9%) had the highest (best) well-being scores in all dimensions. Class 1 (6.4%) had high hedonic and moderate eudaemonic with low life enjoyment. Class 3 (21.9%) had high hedonic and moderate eudaemonic scores with low self-mastery. Women in class 4 were younger, more educated, reported higher annual incomes, least likely to smoke, and most likely to drink alcohol daily. Relative to class 4, odds ratios (95% confidence interval) of all-cause mortality were 1.33 (1.24-1.43), 1.75 (1.67-1.84), and 1.26 (1.20-1.31) for classes 1, 2, and 3, respectively, even after adjustment for demographic and behavioral confounders. Conclusion: Latent class analysis identified groups by levels of hedonic and eudaemonic indicators, preserving information about well-being dimensions while supporting interpretation of relationships with well-being important to older women and health research.}, }
@article {pmid40713931, year = {2025}, author = {Akaike, T and Ch'en, PY and Hippe, DS and Gilmour, MW and Gong, E and Fu, A and Singh, N and Cahill, K and Gunnell, L and Vohra, N and Hall, E and Bhatia, S and Lipson, EJ and Blosser, CD and Nghiem, PT}, title = {Merkel Cell Carcinoma in Solid Organ Transplant Recipients: Prognosis and Response to Immunotherapy.}, journal = {The British journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1093/bjd/ljaf304}, pmid = {40713931}, issn = {1365-2133}, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with an increased risk of occurrence in immunocompromised patients, including solid organ transplant recipients (SOTR). As the number of SOTR rises worldwide, MCC cases in this population are also expected to increase. While anti-programmed death-(ligand)1 (anti-PD-(L)1) immunotherapy generates durable tumor responses in ∼50% of immunocompetent (IC) patients with advanced MCC, its efficacy and safety in SOTR remain uncertain as these patients have been excluded from most clinical trials.
OBJECTIVES: To compare baseline characteristics and outcomes among SOTR and IC patients with MCC, and to evaluate efficacy and toxicity of anti-PD-(L)1 in SOTR.
METHODS: We queried a MCC registry from our institution (April 1988-May 2024), extracting data on demographics, anti-PD-(L)1 response, immunosuppression regimens, and incidence of allograft rejection and failure for analysis.
RESULTS: We identified 1214 MCC patients (37 SOTR and 1177 IC patients); 8 of 37 SOTR received anti-PD-(L)1. The median time from solid organ transplant to MCC diagnosis was 10 years (range 0.4-43). The proportion of patients with advanced MCC (≥ stage III) was 76% in SOTR compared to 51% in IC patients (p=0.004). SOTR status was associated with worse outcomes, including higher rates of disease progression (adjusted hazard ratio [aHR] 2.3), MCC-specific mortality (aHR 3.0), and overall mortality (aHR 3.9; all p<0.001). The median time to death due to MCC for SOTR was 2.7 years; 24% of SOTR died within one year of diagnosis, in contrast to just 4% of IC patients. The median time to MCC progression for SOTR was 8.6 months vs 12 years for IC patients. Among SOTR, 70% developed distant metastases within 2 years versus 25% of IC patients. All eight MCC SOTR treated with anti-PD-(L)1 were kidney transplant recipients, with 5 (63%) experiencing an objective response (CR: 2, PR: 3). However, 2 (29%) patients experienced irreversible graft failure within 9 weeks.
CONCLUSIONS: SOTR status is a significant independent risk factor of a worse prognosis for MCC. This study represents the largest cohort evaluating the efficacy and safety of anti-PD-(L)1 in SOTR with advanced MCC, highlighting the potential benefits in this population.}, }
@article {pmid40713377, year = {2025}, author = {Safyan, RA and Chiorean, EG}, title = {Updates on molecular targets and clinical trials with targeted therapies for pancreatic cancer.}, journal = {Surgical oncology}, volume = {}, number = {}, pages = {102268}, doi = {10.1016/j.suronc.2025.102268}, pmid = {40713377}, issn = {1879-3320}, abstract = {Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. KRAS mutations are present in 90 % of PDA, while 10 % are KRAS wild type and are potentially targetable with epidermal growth factor receptor (EGFR) blockade. KRAS[G12C] inhibitors have shown activity in G12C mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. Fewer than 1 % of PDA harbor microsatellite instability high (MSI-High) status and are susceptible to immune checkpoint blockade. Albeit rare, and occurring in KRAS wild type PDAs, BRAF V600E mutations, HER2 amplification, and RET, NTRK, and NRG1 fusions are targetable with cancer agnostic FDA approved therapies. In this review, we highlight clinically relevant molecular alterations and clinical trials with focus on targeted therapies that can improve pancreatic cancer patients' outcomes through precision medicine.}, }
@article {pmid40667331, year = {2025}, author = {Hu, C and Popchock, AR and Latino, AA and Asbury, CL and Biggins, S}, title = {Direct observation of interdependent and hierarchical kinetochore assembly on individual centromeres.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667331}, issn = {2692-8205}, abstract = {Kinetochores are megadalton protein machines that harness microtubules to segregate chromosomes during cell division. The kinetochores must assemble after DNA replication during every cell cycle onto specialized regions of chromosomes called centromeres, but the order and regulation of their assembly remains unclear due to the complexity of kinetochore composition and the difficulty resolving individual kinetochores in vivo. Here, by adapting a prior single-molecule method for monitoring kinetochore assembly in budding yeast lysates, we identify a sequential order of assembly and uncover previously unknown interdependencies between subcomplexes. We show that inner kinetochore assembly depends partly on outer kinetochore components, and that outer kinetochore branches do not assemble independently of one another. Notably, Mif2 assembly is a rate-limiting step that can be accelerated by binding to the Mtw1 subcomplex, thereby promoting rapid assembly of many inner and outer kinetochore components. The importance of controlling kinetochore assembly kinetics is supported by a Mif2 mutant lacking both autoinhibition and Mtw1 subcomplex binding activity, which leads to defective kinetochore-microtubule attachments when the centromeric histone variant Cse4 is overexpressed. Altogether, our work provides a direct view of kinetochore assembly and reveals highly interdependent regulatory events that control its order and timing.}, }
@article {pmid40667132, year = {2025}, author = {Walter, M and Haick, AK and Massa, PA and Klouser, LM and Stensland, L and Santo, TK and Xie, H and Jerome, KR}, title = {Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667132}, issn = {2692-8205}, abstract = {Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions causes oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We report that this R2[17] virus has residual retrograde travel. We show that R2[17] can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.}, }
@article {pmid40667113, year = {2025}, author = {MacLean, F and Zemek, RM and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, NB and Talavera, IC and Warrier, L and Dubrulle, J and Schroeder, LK and Elz, A and Sowerby, D and Saito, A and Thomas, KK and Mack, M and Schiffer, JT and McClelland, RS and Jerome, KR and Chohan, BH and Ngure, K and Mugo, NR and Newell, EW and Lingappa, JR and Lund, JM}, title = {Genital herpes shedding episodes associate with alterations in the spatial organization and activation of mucosal immune cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667113}, issn = {2692-8205}, abstract = {Herpes Simplex Virus 2 (HSV-2) infection results in variable rates of local viral shedding in anogenital skin. The impact of episodic viral exposures on immune cells in adjacent mucosal tissues, including the genital tract, is unknown. However, any immune responses at this site could impact protective mucosal immunity, tissue homeostasis, and adverse health outcomes. To investigate the impact of HSV-2 on cervicovaginal tract immunity, we applied flow cytometry, immunofluorescent imaging, analysis of soluble immune factors, and spatial transcriptomics to cervicovaginal tissue and blood samples provided by a total of 232 HSV-2 seropositive and seronegative participants, with genital HSV-2 shedding evaluated at the time of biopsy. This unique dataset was used to define and spatially map immune cell subsets and localized gene expression via spatial transcriptomics. HSV-2 seropositivity alone was associated with minimal differences in cervicovaginal and circulating T cell phenotypes. However, the vaginal mucosa during active HSV-2 shedding was associated with alterations in T cell, macrophage, and dendritic cell localization and gene expression consistent with increased immune surveillance, with immune activating and suppressing signals potentially reinforcing mucosal tissue homeostasis.}, }
@article {pmid40661279, year = {2025}, author = {Bulstra, CA and Dai, X and Ngure, K and Rosenberg, MS and Wamuti, BM and Hontelez, JAC and Salomon, JA and Ortblad, KF and Bärnighausen, T}, title = {The real-world association between male circumcision and risk of HIV infection in sub-Saharan Africa: a household fixed-effects analysis of 279,351 men from 29 countries.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40661279}, abstract = {INTRODUCTION: While voluntary medical male circumcision (VMMC) reduces the individual-level risk of HIV acquisition by approximately 60% in randomised-controlled trials, little is known about the 'real-world' long-term effect of medical and traditional male circumcision on the cumulative risk of HIV infection. We estimate the association between these for the first time using a quasi-experimental study design-a household fixed-effects analysis-for sub-Saharan Africa, the global region with the largest HIV burden.
METHODS: We pooled individual-level cross-sectional data from the nationally-representative Demographic and Health Surveys and AIDS Indicator Surveys across all sub-Saharan African countries in which the surveys included data on both male circumcision and HIV status. We estimated the association between male circumcision and HIV status using modified Poisson regression models with household fixed-effects-which control for unobserved and observed confounding shared by men living in the same household-and included additional individual-level controls for demographic characteristics, socio-economic factors, and sexual behaviour.
RESULTS: We included individual data from 279,351 male participants in 48 nationally-representative surveys conducted in 29 countries between 2003-2018. The mean survey-level prevalence of male circumcision was 65.9% (median 84.5%, IQR 28.8%-68.1%) and HIV was 5.6% (median 2.5%, IQR 1.2%-10.2%). We estimated that male circumcision was significantly associated with a nearly one-fifth reduction in the cumulative risk of HIV infection (adjusted risk ratio 0.81, 95% CI 0.73-0.89).
CONCLUSIONS: Male circumcision was associated with a significant reduction in the risk of HIV infection in sub-Saharan Africa over the past two decades. Increased political and financial commitment to VMMC could likely lead to further reductions in HIV prevalence, especially when rolled out as a HIV prevention option in combination with other interventions.}, }
@article {pmid40712781, year = {2025}, author = {Espinoza-Gutarra, MR and Collins, J and Kennedy, V and Randall, J and Su, CT and Banerjee, R and Wuliji, N and Odstricil-Bobillo, S and Amonoo, HL and Wood, WA and Hamilton, B and Sung, A and Lee, CJ}, title = {Assessing Social Determinants of Health in Transplantation and CAR-T Recipients: Expert Panel Recommendations from the Survivorship Special Interest Group of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.07.017}, pmid = {40712781}, issn = {2666-6367}, abstract = {Social determinants of health (SDOH) are an increasingly recognized prognostic factor in patients undergoing hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. However, awareness among providers of their importance and appropriate evaluation of SDOH factors in transplant candidates are insufficient in standard clinical practice and in research. As part of a coordinated effort by three American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Groups, we have developed a general overview of SDOH in transplantation and cellular therapy (TCT) along with suggested best practices. We strongly encourage the assessment of SDOH pre-TCT by a trained member of the team as well as the development of a communication plan tailored to an individual patients' background. Other recommendations include development and validation of longitudinal instruments for SDOH evaluation in TCT patients, with emphasis on those that use primary sources of information, the inclusion of SDOH in outcome and mortality benchmarks established by regulatory bodies and the development of intervention strategies in the context of clinical trials.}, }
@article {pmid40706035, year = {2025}, author = {Ahmed, N and Thiruvengadam, S and Hamadani, M and Hu, ZH and Grover, NS and Shadman, M and Locke, FL and Gerson, J and Frank, MJ and Budde, LE and Wang, ML and Kim, S and Bye, M and Kharfan-Dabaja, MA and Sauter, CS and Hematti, P and Turtle, CJ and Ahmed, S and Moskop, A and Logan, BR and Nunes, A and Dalton, DM and Kloos, IM and Lee, D and Xu, H and Pasquini, MC and Herrera, AF}, title = {Real-world outcomes of brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma: a CIBMTR analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015014}, pmid = {40706035}, issn = {2473-9537}, abstract = {Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (r/r MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with r/r MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with r/r MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of non-relapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR] 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell-associated neurotoxicity syndrome (odds ratio [OR] 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR 1.90; 95% CI, 1.13-3.21). In patients with 1-2 prior therapy lines, relapse or progression was less frequent compared with those with 3 or more prior lines (HR 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with ZUMA-2, regardless of prior therapy type or number of prior therapy lines.}, }
@article {pmid40705892, year = {2025}, author = {Liu, B and Greenwood, NF and Bonzanini, JE and Motmaen, A and Meyerberg, J and Dao, T and Xiang, X and Ault, R and Sharp, J and Wang, C and Visani, GM and Vafeados, DK and Roullier, N and Nourmohammad, A and Scheinberg, DA and Garcia, KC and Baker, D}, title = {Design of high-specificity binders for peptide-MHC-I complexes.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6758}, pages = {386-391}, doi = {10.1126/science.adv0185}, pmid = {40705892}, issn = {1095-9203}, mesh = {*Histocompatibility Antigens Class I/chemistry/immunology/metabolism ; *Peptides/chemistry/immunology/metabolism ; Humans ; T-Lymphocytes/immunology ; Lymphocyte Activation ; Receptors, Chimeric Antigen/chemistry/immunology/genetics ; Protein Engineering ; Protein Binding ; }, abstract = {Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.}, }
@article {pmid40704716, year = {2025}, author = {Boloori, A and Nategh, E and Su, CT}, title = {Association of Social Vulnerability Index and Chimeric Antigen Receptor T-Cell Therapy Administration, 2018-2023.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyaf236}, pmid = {40704716}, issn = {1549-490X}, abstract = {Chimeric antigen receptor T-cell (CAR T) therapy for patients with relapsed/refractory hematologic malignancies demands numerous visits which may pose challenges for patients with lower socioeconomic status (SES). The Centers for Disease Control and Prevention publishes the Social Vulnerability Index (SVI) which summarizes area-level SES factors that predict how residents respond to stressors, including a new cancer diagnosis. We used the nationwide MarketScan commercial and Medicare insurance claims database to analyze the association between SVI and CAR T therapy completion. We performed multivariable logistic regressions (adjusting for patient-level covariates) and found that patients with hematologic malignancies residing in areas of higher SVI (lower SES) have decreased odds of CAR T therapy completion (OR 0.84 for leukemia, P = 0.02; OR 0.72 for lymphoma, P < 0.001; OR 0.70 for myeloma, P < 0.001). Therefore, strategies to mitigate CAR T disparities may be focused on patients living in areas with higher SVI.}, }
@article {pmid40661619, year = {2025}, author = {DeWitt, WS and Vora, AA and Araki, T and Galloway, JG and Alkutkar, T and Bortolatto, J and Castro, TBR and Dumm, W and Jennings-Shaffer, C and Jia, T and Mesin, L and Ozorowski, G and Pae, J and Ralph, DK and Bloom, JD and Nourmohammad, A and Song, YS and Ward, AB and Starr, TN and Matsen, FA and Victora, GD}, title = {Replaying germinal center evolution on a quantified affinity landscape.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661619}, issn = {2692-8205}, abstract = {Darwinian evolution of immunoglobulin genes within germinal centers (GC) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the mechanics of how competition between GC B cells drives increased affinity are well established, the dynamical evolutionary features of this process remain poorly characterized. We devised an experimental evolution model in which we "replay" over one hundred instances of a clonally homogenous GC reaction and follow the selective process by assigning affinities to all cells using deep mutational scanning. Our data reveal how GCs achieve predictable evolutionary outcomes through the cumulative effects of many rounds of imperfect selection, acting on a landscape shaped heavily by somatic hypermutation (SHM) targeting biases. Using time-calibrated models, we show that apparent features of GC evolution such as permissiveness to low-affinity lineages and early plateauing of affinity are best explained by survivorship biases that distort our view of how affinity progresses over time.}, }
@article {pmid40661527, year = {2025}, author = {Cao, J and Ferguson, M and Sun, J and Shen, M and Small, R and Hippe, DS and Zhao, X and Zhang, D and Watase, H and Yuan, C and Gao, P and DeMarco, JK and Nicosia, RF and Wang, Y and Li, H and Li, Z and Wang, Y and Kohler, T and Hatsukami, T and Sui, B}, title = {Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661527}, issn = {2692-8205}, abstract = {BACKGROUND: The clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging.
OBJECTIVES: The aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients.
METHODS: Carotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 μm thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallory's trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups.
RESULTS: A total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools (β=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; β=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH (β=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001).
CONCLUSIONS: The histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach.}, }
@article {pmid40704585, year = {2025}, author = {Conley, H and Oh, SY and Garrett, N and Kublin, J and Monaco, CL and Watts, S and Jha, S and Ferrari, G and Tomaras, GD and Geraghty, DE and Chan, C and Pollara, J}, title = {IgG and Fc receptor genetic variation associates with functional antibody responses in a DNA and protein candidate HIV vaccine trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000003734}, pmid = {40704585}, issn = {1944-7884}, abstract = {BACKGROUND: The HVTN108 trial evaluated the safety and immunogenicity of a DNA prime, adjuvanted protein boost HIV vaccine in the US and South Africa. The underlying factors influencing individual variation in vaccine responsiveness are unknown. Here, we defined the IgG Fc and Fc receptor (FcR) genotypes in the HVTN108 cohort to test our hypothesis that IgG and FcR genetic variation can affect vaccine-elicited functional antibody responses.
METHODS: IgG Fc and FcR alleles were determined by targeted PCR amplification and next-generation sequencing. Vaccine-elicited functional antibody responses, including binding antibody multiplex assay (BAMA), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) activity were measured utilizing standardized and qualified methods. Relationships between alleles and antibody responses were identified by linear regression controlling for treatment group and region.
RESULTS: The distribution of many polymorphisms significantly differed between the US and South Africa. Within the subset of the cohort tested for functional antibody responses (IgG, n=41; FcR, n=55), IgG genotypes such as IGHG1*12 (p=0.012), IGHG3*11 (p=0.033), IGHG2*02 (p=0.038), IGHG4*07 (p=0.076), and others were associated with ADCC antibody responses when corrected for vaccine group and regional effects. In the same way, we identified that the FCER1A rs2427827 mutation had a significant association with lower peak ADCC activity and the FCER2 rs2228137 mutation was associated with lower antibody binding to Con6 gp120 protein.
CONCLUSION: Genetic variation in both antibodies and FcRs associated with levels of HIV- vaccine-elicited functional antibodies. Significant regional differences in distribution of this variation support the need for vaccine testing in diverse populations.}, }
@article {pmid40703805, year = {2025}, author = {Campian, JL and Grossman, SA and Kask, AS and Kosydar, S and Strowd, R and Piotrowski, A and Tang, J and Chheda, MG and DiPersio, JF and Schullery, D and D'Amico, L and Desideri, S and Danda, N and Ferrando-Martinez, S and Lee, BH and Fling, SP and Ye, X}, title = {Phase I study of NT-I7, a long-acting interleukin-7, in severe treatment-related lymphopenia following standard radiation and temozolomide for high-grade glioma.}, journal = {Neuro-oncology advances}, volume = {7}, number = {1}, pages = {vdaf117}, pmid = {40703805}, issn = {2632-2498}, abstract = {BACKGROUND: High-grade gliomas (HGG) have a poor prognosis despite aggressive treatment. Severe, persistent lymphopenia occurring in HGG patients after concurrent chemoradiation is associated with worse survival. NT-I7, a long-acting interleukin-7 analog, has been shown to increase CD4 and CD8 counts in healthy, septic, and HIV-positive adults. This multi-institutional, NCI-funded dose-escalation trial is the first to evaluate NT-I7 safety and activity in HGG patients with severe treatment-related lymphopenia (TRL) and the effect of co-administered glucocorticoids.
METHODS: Eligible HGG patients had CD4 counts <300 cells/mm[3] after 5 weeks of standard chemoradiation and were receiving either ≤0.75 or ≥4 mg/day of dexamethasone. Patients received a single intramuscular dose of NT-I7 (60 or 360 µg/kg) post-chemoradiation, followed by safety evaluation and multi-parameter, longitudinal monitoring of lymphocyte populations and immunologic function.
RESULTS: NT-I7 was well tolerated in all 12 patients (median age 64; median CD4 count 161 cells/mm³) before the study closed prematurely. Absolute lymphocyte counts doubled in 83% (10/12; 95% CI: 51.6%-97.9%) of patients, and CD4 counts doubled in 42% (5/12; 95% CI: 15.2%-72.3%) of patients. Glucocorticoid use did not significantly affect CD4 or lymphocyte increases. Correlative immune profiling revealed increased Ki67 expression in CD4 (P < .005) and CD8 (P < .05) after one week, along with the expansion of CD4 and CD8 T-cell subsets and CD56 + natural killer cells.
CONCLUSIONS: NT-I7 is well tolerated and effectively increases lymphocyte and CD4 counts in severe TRL patients, regardless of glucocorticoid use, suggesting its potential to mitigate TRL and improve outcomes in HGG.}, }
@article {pmid40702172, year = {2025}, author = {Dai, Y and Aizenbud, L and Qin, K and Austin, M and Jaycox, JR and Cunningham, J and Wang, EY and Zhang, L and Fischer, S and Carroll, SM and van Aggelen, H and Kluger, Y and Herold, KC and Furchtgott, L and Kluger, HM and Ring, AM}, title = {Humoral determinants of checkpoint immunotherapy.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40702172}, issn = {1476-4687}, abstract = {Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established[1,2], the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling[3] to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the 'exoproteome'). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.}, }
@article {pmid40701614, year = {2025}, author = {Nemutlu, GS and Mercaldo, ND and Thayumanavan, E and Zhan, T and Duggan, C and Blauvelt, BM and Chhatwal, J}, title = {Forecasting global progress in breast cancer control in the context of the sustainable development goals.}, journal = {BMJ global health}, volume = {10}, number = {7}, pages = {}, doi = {10.1136/bmjgh-2025-019497}, pmid = {40701614}, issn = {2059-7908}, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/mortality/prevention & control ; *Global Health ; *Sustainable Development ; *Forecasting ; Incidence ; Developing Countries/statistics & numerical data ; Early Detection of Cancer/trends ; Mortality/trends ; *Global Burden of Disease/trends ; }, abstract = {INTRODUCTION: The United Nations Sustainable Development Goal (UN-SDG) 3.4 aims to reduce premature mortality from non-communicable diseases, including breast cancer, by one-third by 2030 relative to 2015. However, many countries, particularly those with lower income, appear off track. Although mortality rates are commonly used to gauge progress, mortality-to-incidence ratios (MIRs) may provide additional insight by accounting for varying incidence and the effectiveness of cancer control measures.
METHODS: We obtained age-standardised breast cancer incidence and mortality rates for women aged 30-69 years from 2000 to 2019, covering 199 countries stratified by World Bank income groups (low, lower middle, upper middle and high) from the Institute for Health Metrics and Evaluation Global Burden of Disease (GBD) 2019 study. Using vector autoregressive time-series analyses, we modelled and forecasted income-level and county-level mortality rates and MIRs for female breast cancer from 2020 to 2030.
RESULTS: From 2015 to 2030, breast cancer mortality is projected to increase by 22.8% and 7.8% in low-income and lower middle-income countries, while decreasing by 10% and 5.4% in upper middle-income and high-income countries. MIR is projected to decrease across all income groups, with the most significant reductions seen in lower income countries, highlighting incremental improvements in breast cancer control initiatives. Only nine countries, predominantly higher income, are expected to achieve the one-third mortality reduction target. Despite MIR improvements in lower income countries, substantial mortality reductions remain elusive.
CONCLUSION: Relying solely on mortality underestimates progress in breast cancer control. Although most countries are unlikely to meet the SDG 3.4 target, concurrent use of mortality and MIR provides a more nuanced understanding of screening, diagnosis and treatment advances. Integrating MIR trends into global health evaluations may better inform breast cancer prevention strategies.}, }
@article {pmid40699439, year = {2025}, author = {Alberts, NM and Stratton, KL and Leisenring, WM and Pizzo, A and Lamoureux, É and Alschuler, K and Flynn, J and Krull, KR and Jibb, LA and Nathan, PC and Olgin, JE and Stinson, JN and Armstrong, GT}, title = {Intolerance of uncertainty, psychological symptoms, and pain in long-term childhood cancer survivors: a report from the Childhood Cancer Survivor Study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {40699439}, issn = {1932-2267}, support = {U2CEB021881/NH/NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Intolerance of uncertainty is central to many psychological disorders and may contribute to pain. Despite the uncertainty inherent in childhood cancer survivorship, little is known about intolerance of uncertainty in this population. This study aimed to characterize intolerance of uncertainty, its risk factors, and its associations with psychological symptoms and pain in childhood cancer survivors.
METHODS: Survivors from the Childhood Cancer Survivor Study completed psychosocial measures via online survey, including the Intolerance of Uncertainty Scale-12 (score range = 12-60). Cancer and treatment variables were abstracted from medical records. Multivariable regression models with 95% confidence intervals (CI) adjusted for age and sex examined the effects of demographic, disease, treatment, pain, and psychological variables on intolerance of uncertainty.
RESULTS: Participants included 228 adult survivors of childhood cancer (mean age = 39.6 years, 50.4% female, n = 93 chronic pain). Mean level of intolerance of uncertainty among survivors was 26.2 (SD = 10.0, 95% CI 24.9 to 27.5). Intolerance of uncertainty was associated with female sex (β [95% CI]; 2.7 [0.2-5.3]), unemployment (5.2 [1.9-8.5]), neurologic (4.1 [0.5-7.7]) and cardiovascular (5.0 [2.2-7.8]) chronic health conditions, elevated anxiety (10.9 [8.1-13.7]), and perceived poor health status (4.5 [1.4-7.6]). Higher levels of intolerance of uncertainty were observed in survivors with chronic pain (LS mean = 29.2) compared to survivors without (LS mean = 23.5; p < 0.01).
CONCLUSIONS: Mean levels of intolerance of uncertainty in childhood cancer survivors are comparable to the general population and associated with psychological symptoms and chronic pain.
Intolerance of uncertainty may be a modifiable target for transdiagnostic interventions in survivorship care.}, }
@article {pmid40435412, year = {2025}, author = {Escherich, CS and Li, Z and Barnett, KR and Li, Y and Walker, M and Yoshimura, S and Yang, W and Huang, X and Yu, J and Stock, W and Paietta, E and Konopleva, MY and Kornblau, SM and Jabbour, E and Litzow, MR and Inaba, H and Pui, CH and Loh, ML and Evans, WE and Savic, D and Yang, JJ}, title = {Differentiation-dependent EBF1 activity determines CD22 transcription and leukemia sensitivity to inotuzumab ozogamicin.}, journal = {Blood}, volume = {146}, number = {4}, pages = {471-481}, doi = {10.1182/blood.2024028215}, pmid = {40435412}, issn = {1528-0020}, mesh = {*Sialic Acid Binding Ig-like Lectin 2/genetics/metabolism ; Humans ; *Inotuzumab Ozogamicin/pharmacology/therapeutic use ; *Drug Resistance, Neoplasm/genetics ; *Trans-Activators/metabolism/genetics ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/drug therapy/pathology/metabolism ; Cell Differentiation/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; *Antineoplastic Agents, Immunological/pharmacology/therapeutic use ; *Transcription, Genetic/drug effects ; Cell Line, Tumor ; }, abstract = {Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-cell acute lymphoblastic leukemia (B-ALL) cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multiomic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we showed that early leukemia differentiation arrest at the pre-pro-B stage is associated with resistance to InO. Screening of 1639 transcription factor genes identified early B-cell factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate of 7.1 × 10-4). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration <10th vs >90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 × 10-174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an ∼50-fold reduction in cell surface CD22 expression and, consequently, an ∼22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intrasubtype heterogeneity linked to EBF1 transcriptional downregulation (P = 1.1 × 10-15) and/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 × 10-11) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which, in turn, contributes to interpatient variability in InO response, even within the same subtype of B-ALL.}, }
@article {pmid40698029, year = {2025}, author = {Stankiewicz Karita, HC and Magaret, AS and Selke, S and Pascual, R and Irimia, B and Barbee, LA and Wald, A and Soge, OO}, title = {Stability of Spiked Chlamydia Trachomatis and Neisseria Gonorrhea in Urine and Swab Specimens After Prolonged Storage at Room and Freezer Temperatures Using Aptima Combo-2 Test.}, journal = {Open forum infectious diseases}, volume = {12}, number = {7}, pages = {ofaf388}, pmid = {40698029}, issn = {2328-8957}, abstract = {We evaluated whether prolonged storage at room and freezer temperatures affects detection of Chlamydia trachomatis and Neisseria gonorrhoeae (CT/GC) using Aptima Combo-2 assay for research studies. Three hundred specimens were spiked with CT/GC; half were stored at room temperature and half at -80°C. All specimens remained CT/GC positive for 36 months.}, }
@article {pmid40695269, year = {2025}, author = {Takle, M and Andrews, A and Riggle, BA and Zelleke, T and Harrar, D and Zhang, J and Zhang, B and Wilson, KJ and Beare, NAV and Taylor, TE and Seydel, KB and Ray, S and Postels, DG}, title = {Using Electroencephalography to Assess Coma Etiology in Children with Retinopathy-Negative Cerebral Malaria.}, journal = {The American journal of tropical medicine and hygiene}, volume = {}, number = {}, pages = {}, doi = {10.4269/ajtmh.25-0377}, pmid = {40695269}, issn = {1476-1645}, abstract = {Autopsy studies of children dying of cerebral malaria (CM) have revealed that those with malarial retinopathy exhibited high levels of sequestration in the cerebral vasculature, whereas children with retinopathy-negative CM exhibited lower sequestration levels and possible nonmalarial causes of death. This suggests that children dying of retinopathy-negative CM have nonmalarial coma etiologies with concomitant incidental parasitemia, which is common in high malaria transmission areas. Subsequent studies have challenged this assertion, positing that retinopathy-negative CM and retinopathy-positive CM are variants of the same disease pathophysiology or host biology, both caused by acute malaria infection. We recently determined that electroencephalography (EEG) can be used to discriminate between a malarial coma (CM) and a nonmalarial coma. To better understand the contribution of acute malaria infection in the pathophysiology of retinopathy-negative CM, we compared qualitative and quantitative EEG findings from 30-minute EEG recordings of Malawian children aged 3 months to 14 years hospitalized at Queen Elizabeth Central Hospital with retinopathy-negative CM, retinopathy-positive CM, and nonmalarial coma. Neither qualitative nor quantitative EEG interpretation methods allow for the discrimination between children with retinopathy-positive CM and those with retinopathy-negative CM. Conversely, quantitative EEG readily differentiated children with retinopathy-negative CM from those with nonmalarial coma (area under the receiving operating characteristic [AUROC] curve of 0.83). When combining qualitative and quantitative EEG interpretation methods, the ability of EEG to distinguish retinopathy-negative CM from nonmalarial EEG increases (AUROC of 0.87). The EEGs of children with retinopathy-negative CM are similar to those of children with retinopathy-positive CM and significantly different from those of children with nonmalarial coma, supporting the hypothesis that acute malarial infection is pathophysiologically important in retinopathy-negative CM.}, }
@article {pmid40694868, year = {2025}, author = {Farland, LV and Degnan, WJ and Harris, HR and Sasamoto, N and Rexrode, KM and Missmer, SA}, title = {Laparoscopically confirmed endometriosis and midlife plasma markers of inflammation, cholesterol, and adipokines among participants in the Nurses' Health Study II.}, journal = {Maturitas}, volume = {200}, number = {}, pages = {108663}, doi = {10.1016/j.maturitas.2025.108663}, pmid = {40694868}, issn = {1873-4111}, abstract = {OBJECTIVE: Endometriosis may increase the risk of cardiovascular disease, possibly through a detrimental impact on circulating biomarkers. However, there is a paucity of research on endometriosis and inflammation, lipids, and adipokines at midlife.
METHODS: We used generalized linear models to determine the association between laparoscopically confirmed endometriosis and log-transformed levels of plasma C-reactive protein (n = 3936), interleukin-6 (n = 3495), tumor necrosis factor-alpha receptor 2 (n = 2967), high-density lipoprotein cholesterol (n = 1533), low-density lipoprotein cholesterol (n = 1324), total cholesterol (n = 4898), leptin (n = 2480), and adiponectin (n = 4262) among participants with existing biomarker measurements in the Nurses' Health Study II (average age 44 years). We investigated heterogeneity by body mass index (<25 kg/m[2] vs. ≥ 25 kg/m[2]).
RESULTS: We did not observe associations between endometriosis and midlife inflammatory biomarkers (C-reactive protein % difference: -4.6, 95 % CI [-15.7,7.9]; interleukin-6: -0.4 % [-7.2,7.1]; tumor necrosis factor-alpha receptor 2: -1.3 % [-4.1,1.6]) or levels of high-density lipoprotein cholesterol (0.8 % [-3.7,5.6]), low-density lipoprotein cholesterol (-0.2 % [-5.2,5.1]), total cholesterol (1.0 % [-0.7,2.7]), or adiponectin (-4.0 [-8.8,1.0]). Women with endometriosis had higher leptin levels (9.0 % [0.5, 18.1]). Associations varied by body mass index for total cholesterol (p-value 0.05) and leptin (p-value 0.02). Among women with a body mass index ≥25 kg/m[2], those with endometriosis had a mean total cholesterol level that was 2.7 % higher (0.2,5.2) than among those without; among those with a body mass index <25 kg/m[2], those with endometriosis had a mean leptin level that was 15.7 % higher (4.6, 28.1) than among those without endometriosis.
CONCLUSIONS: Endometriosis was not associated with midlife systemic inflammation, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or adiponectin. Endometriosis was associated with higher leptin among those with a body mass index <25 kg/m[2] and higher total cholesterol among those with a body mass index ≥25 kg/m[2]. These findings suggest that endometriosis may influence cardiovascular disease risk via midlife cholesterol and leptin.}, }
@article {pmid40694438, year = {2025}, author = {Pete, D and Lampe, JW and Liu, H and Salama, NR and Wu, MC and Phipps, AI}, title = {A Cross-Sectional Study of Dietary Patterns and Helicobacter pylori Infection Among American Indian Adults in the Southwest.}, journal = {Nutrition and cancer}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/01635581.2025.2535055}, pmid = {40694438}, issn = {1532-7914}, abstract = {High sodium diets have been shown to promote stomach colonization and the induction of tissue damage by Helicobacter pylori (H. pylori), a risk factor for gastric cancer. Among American Indians in the Southwest, where the H. pylori prevalence is 60%, the association between diet and H. pylori infection has not been studied. We conducted a cross-sectional pilot study with 93 adults (51%, 18-44 years, 73% female) in the Navajo Nation to assess their diet with self-administered food questionnaires and to detect H. pylori from stool samples using droplet digital PCR. Three diet patterns were identified using Principal Component Analysis: 1) Western, 2) Soups and Mixed Dishes, and 3) Fruits and Vegetables. Participants in the highest and middle tertiles of the Soups and Mixed Dishes pattern scores had higher odds of having H. pylori (ORHighest=5.59, 95% CI, 1.50-23.70; ORMiddle=3.48, 95% CI, 1.08-12.32) than those in the lowest tertile. This positive association may be linked to the sodium content of foods in this diet pattern. Soups and Mixed Dishes may contribute to H. pylori infection and may be incorporated in nutrition education for individuals positive for H. pylori infection in the Navajo Nation.}, }
@article {pmid40694037, year = {2025}, author = {Rebolj, M and Brentnall, AR and Geppert, J and Kouppa, N and Shinkins, B and Freeman, K and Stinton, C and Randell, MJ and Johnson, S and Smith, RA and Sasieni, P and Janes, SM and Etzioni, R and Duffy, SW and Taylor-Phillips, S}, title = {LATE-STAGE OUTCOMES AS SURROGATES FOR MORTALITY IN CANCER SCREENING TRIALS: A SYSTEMATIC REVIEW AND META-ANALYSIS.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0201}, pmid = {40694037}, issn = {1538-7755}, abstract = {Late-stage cancer incidence has been proposed as a surrogate outcome for cancer-specific mortality in future screening trials. Two previous meta-analyses with 33 and 39 trials assessed trial-level surrogacy but provided inconsistent conclusions about the suitability of late-stage cancer endpoints replacing mortality. Our systematic review and meta-analysis (PROSPERO, CRD42023369320) investigated the association between the effect of cancer screening on incidence of late-stage cancer and cancer-specific mortality. From 57 trials with 61 trial arm comparisons, correlation between late-stage incidence and mortality outcomes was 0.69 (95% confidence interval (CI): 0.47-0.84) for all cancers combined. Specifically, correlations were: 0.58 (0.27-0.93) for bowel (N=11 trials), 0.79 (0.49-0.94) for breast (N=13), and 0.91 (0.84-0.96) for lung cancer (N=14). Trial point estimates of the screening effect on mortality were within each trial's 95% CI late-stage incidence estimates in 56/61 (92%) trial-arm comparisons, and in 16/19 (84%) trial arm comparisons where the entire 95% CI for screening effect on late-stage incidence was below 1. Evidence suggests potential for late-stage cancer incidence as a key outcome in screening trials, but further research is needed to clarify when to measure late-stage outcomes, extrapolation for cancer types without trials, and the conditions when late-stage cancer does not accurately predict mortality.}, }
@article {pmid40692216, year = {2025}, author = {Koo, J and Cooper, R and Edwards, SL and Lane, A and Loveless, SK and Strecker, L and Lake, KE and Myers, KC and Towe, C and Patti, J and Walkup, LL and Wikenheiser-Brokamp, KA and MacMillan, ML and Lacher, P and Griffin, T and Tekman, M and Cisneros, GS and Wu, K and Zinter, MS and Urrego, FA and Baker, KS and Abts, MF and Ballard, S and Freedman, JL and Caraballo, A and Young, LR and Josephson, MB and Allen, JL and Camburn, DM and Doherty, EE and Azamian, MS and Arredondo, M and Silva-Carmona, M and Lehmann, LE and Wong, W and Gaffin, JM and McAlpine, W and Li, M and Goldfarb, SB and Woods, JC and Davies, SM}, title = {High Prevalence of Abnormal Baseline Lung Function in Pediatric and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Report from the TRANSPIRE Study.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e31916}, doi = {10.1002/pbc.31916}, pmid = {40692216}, issn = {1545-5017}, support = {R01HL157392/HB/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Pulmonary complications are a major cause of morbidity and mortality in pediatric and young adult hematopoietic stem cell transplant (HSCT) recipients. The impact of preexisting lung dysfunction on posttransplant outcomes remains understudied.
METHODS: In a multi-institutional prospective cohort of 444 patients (≤24 years) undergoing allogeneic HSCT at eight centers, baseline lung function was categorized as normal or abnormal using clinical history, imaging, pulmonary function tests (PFTs), and pulmonologist review. Spirometry and diffusion capacity were assessed at baseline, Day 100, 1 year, and 2 years post-HSCT.
RESULTS: Baseline pulmonary dysfunction was present in 224 patients (50.4%), including impaired spirometry (46.4%), low diffusion capacity (33.8%), and imaging abnormalities (e.g., nodules 19%, interstitial changes 7.9%). These patients had significantly lower median z-scores for forced expiratory volume in 1 s (FEV1) (-2.3 vs. -0.5), forced vital capacity (FVC) (-2.0 vs. -0.3), and diffusion capacity of the lung for carbon monoxide (-2.4 vs. -0.7; all p < 0.001). Lung function impairments persisted through 2 years post-HSCT. FEV1 and FVC remained significantly lower at all time points; FEV1/FVC ratios were similar. Overall survival was lower in the abnormal group (88.4 vs. 95.9%). Seven respiratory-related deaths occurred, including acute respiratory distress syndrome (n = 3), respiratory failure (n = 2), diffuse alveolar hemorrhage (n = 1), and fibrotic lung disease (n = 1).
CONCLUSIONS: Pretransplant pulmonary dysfunction is common and predicts sustained posttransplant impairment and lower survival. Comprehensive baseline assessment may aid in risk stratification and guide early interventions to improve long-term respiratory outcomes in pediatric and young adult HSCT patients.}, }
@article {pmid40691366, year = {2025}, author = {Smit, RAJ and Wade, KH and Hui, Q and Arias, JD and Yin, X and Christiansen, MR and Yengo, L and Preuss, MH and Nakabuye, M and Rocheleau, G and Graham, SE and Buchanan, VL and Chittoor, G and Graff, M and Guindo-Martínez, M and Lu, Y and Marouli, E and Sakaue, S and Spracklen, CN and Vedantam, S and Wilson, EP and Chen, SH and Ferreira, T and Ji, Y and Karaderi, T and Lüll, K and Machado, M and Malden, DE and Medina-Gomez, C and Moore, A and Rüeger, S and Akiyama, M and Allison, MA and Alvarez, M and Andersen, MK and Appadurai, V and Arbeeva, L and Bartell, E and Bhaskar, S and Bielak, LF and Bis, JC and Bollepalli, S and Bork-Jensen, J and Bradfield, JP and Bradford, Y and Brandl, C and Braund, PS and Brody, JA and Broeckel, U and Burgdorf, KS and Cade, BE and Cai, Q and Camarda, S and Campbell, A and Cañadas-Garre, M and Chai, JF and Chesi, A and Choi, SH and Christofidou, P and Couture, C and Cuellar-Partida, G and Danning, R and Degenhardt, F and Delgado, GE and Delitala, A and Demirkan, A and Deng, X and Dietl, A and Dimitriou, M and Dimitrov, L and Dorajoo, R and Eichelmann, F and Eliasen, AU and Engmann, JE and Erdos, MR and Fairhurst-Hunter, Z and Farmaki, AE and Faul, JD and Fernandez-Lopez, JC and Forer, L and Frank, M and Freitag-Wolf, S and Fritsche, LG and Fuchsberger, C and Galesloot, TE and Gao, Y and Geller, F and Giannakopoulou, O and Giulianini, F and Gjesing, AP and Goel, A and Gordon, SD and Gorski, M and Grove, J and Guo, X and Gustafsson, S and Haessler, J and Hansen, TF and Havulinna, AS and Haworth, SJ and Heard-Costa, N and Hemerich, D and Highland, HM and Hindy, G and Ho, YL and Hofer, E and Holliday, E and Horn, K and Hornsby, WE and Hottenga, JJ and Huang, H and Huang, J and Huerta-Chagoya, A and Huo, S and Hwang, MY and Hwu, CM and Iha, H and Ikeda, DD and Isono, M and Jackson, AU and Jansen, IE and Jiang, Y and Johansson, I and Jonsson, A and Jørgensen, T and Kalafati, IP and Kanai, M and Kanoni, S and Kårhus, LL and Kasturiratne, A and Katsuya, T and Kawaguchi, T and Kember, RL and Kentistou, KA and Kim, D and Kim, HN and Kim, YJ and Kleber, ME and Knol, MJ and Kurbasic, A and Lauzon, M and Le, P and Lea, R and Lee, JY and Lee, WJ and Leonard, HL and Li, H and Li, SA and Li, X and Li, X and Liang, J and Lin, H and Lin, K and Liu, J and Liu, X and Lo, KS and Long, J and Lores-Motta, L and Luan, J and Lyssenko, V and Lyytikäinen, LP and Mahajan, A and Malik, MZ and Mamakou, V and Mangino, M and Manichaikul, A and Marten, J and Mattheisen, M and McDaid, AF and Mei, Q and Meiselbach, H and Melendez, TL and Milaneschi, Y and Miller, JE and Millwood, IY and Mishra, PP and Mitchell, RE and Møllehave, LT and Mononen, N and Mucha, S and Munz, M and Mykkänen, J and Nakatochi, M and Nardone, GG and Nelson, CP and Nethander, M and Nho, CW and Nielsen, AA and Nolte, IM and Nongmaithem, SS and Noordam, R and Ntalla, I and Nutile, T and Pandit, A and Pauper, M and Petersen, ERB and Petersen, LV and Piluso, F and Polašek, O and Poveda, A and Pyarajan, S and Raffield, LM and Rakugi, H and Ramirez, J and Rasheed, A and Raven, D and Rayner, NW and Riveros, C and Rohde, R and Ruggiero, D and Ruotsalainen, SE and Ryan, KA and Sabater-Lleal, M and Santin, A and Saxena, R and Scholz, M and Shen, B and Shi, J and Shin, JH and Sidore, C and Sidorenko, J and Sim, X and Slieker, RC and Smith, AV and Smith, JA and Smyth, LJ and Southam, L and Steinthorsdottir, V and Sun, L and Takeuchi, F and Taylor, KD and Tayo, BO and Tcheandjieu, C and Terzikhan, N and Tesolin, P and Teumer, A and Theusch, E and Thompson, DJ and Thorleifsson, G and Timmers, PRHJ and Trompet, S and Turman, C and Vaccargiu, S and van der Laan, SW and van der Most, PJ and van Klinken, JB and van Setten, J and Verma, SS and Verweij, N and Veturi, Y and Wang, CA and Wang, C and Wang, JS and Wang, L and Wang, YX and Wang, Z and Warren, HR and Bin Wei, W and Wen, W and Wheeler, WA and Wickremasinghe, AR and Wielscher, M and Winsvold, BS and Wong, A and Wuttke, M and Xia, R and Yamamoto, K and Yang, J and Yao, J and Young, H and Yousri, NA and Yu, L and Zeng, L and Zhang, W and Zhang, X and Zhao, JH and Zhao, W and Zhou, W and Zimmermann, ME and Zoledziewska, M and 't Hart, LM and Adair, LS and Adams, HHH and Aguilar-Salinas, CA and Al-Mulla, F and Arnett, DK and Asselbergs, FW and Åsvold, BO and Attia, J and Banas, B and Bandinelli, S and Beilin, LJ and Bennett, DA and Bergler, T and Bharadwaj, D and Biino, G and Boerwinkle, E and Böger, CA and Borja, JB and Bouchard, C and Bowden, DW and Brandslund, I and Brumpton, B and Buring, JE and Caulfield, MJ and Chambers, JC and Chandak, GR and Chanock, SJ and Chaturvedi, N and Ida Chen, YD and Chen, Z and Cheng, CY and Cho, YS and Christensen, K and Christophersen, IE and Ciullo, M and Cole, JW and Collins, FS and Concas, MP and Cooper, RS and Cruz, M and Cucca, F and Cutler, MJ and Damrauer, SM and Dantoft, TM and de Borst, GJ and de Geus, EJC and de Groot, LCPGM and De Jager, PL and de Kleijn, DPV and de Silva, HJ and Dedoussis, GV and den Hollander, AI and Du, S and Easton, DF and Eckardt, KU and Elders, PJM and Eliassen, AH and Ellinor, PT and Elmståhl, S and Erdmann, J and Evans, MK and Fatkin, D and Feenstra, B and Feitosa, MF and Ferrucci, L and Florez, JC and Ford, I and Fornage, M and Franke, A and Franks, PW and Freedman, BI and Gieger, C and Girotto, G and Golightly, YM and Gonzalez-Villalpando, C and Gordon-Larsen, P and Grallert, H and Grant, SFA and Grarup, N and Griffiths, L and Gudnason, V and Haiman, C and Hakonarson, H and Hansen, T and Hartman, CA and Hattersley, AT and Hayward, C and Heid, IM and Heng, CK and Hengstenberg, C and Herzig, KH and Hewitt, AW and Hishigaki, H and Hougaard, DM and Hoyng, CB and Huang, PL and Huang, W and Huang, WY and Huffman, JE and Hunt, SC and Hutri, N and Hveem, K and Hyppönen, E and Iacono, WG and Ichihara, S and Ikram, MA and Isasi, CR and Jarvelin, MR and Jin, ZB and Jöckel, KH and Jonas, JB and Joshi, PK and Jousilahti, P and Jukema, JW and Kähönen, M and Kamatani, Y and Kang, KD and Kaprio, J and Kardia, SLR and Karpe, F and Kato, N and Kavousi, M and Kee, F and Kessler, T and Khera, AV and Khor, CC and Kiemeney, LALM and Kim, BJ and Kim, EK and Kim, HL and Kirchhof, P and Kivimaki, M and Koh, WP and Koistinen, HA and Kokkinos, A and Kooner, JS and Kooperberg, C and Kovacs, P and Kraaijeveld, A and Kraft, P and Krauss, RM and Kumari, M and Kutalik, Z and Laakso, M and Lange, LA and Langenberg, C and Launer, LJ and Lee, H and Lee, NR and Lehtimäki, T and Lemaitre, RN and Li, H and Li, L and Lieb, W and Lin, X and Lind, L and Linneberg, A and Liu, CT and Liu, J and Loeffler, M and London, B and Lu, F and Lubitz, SA and Mackey, DA and Magnusson, PKE and Manson, JE and Marcus, GM and Marques Vidal, P and Martin, NG and März, W and Matsuda, F and McCarthy, MI and McGarrah, RW and McGue, M and McKnight, AJ and Medland, SE and Mellström, D and Metspalu, A and Mitchell, BD and Mitchell, P and Mook-Kanamori, DO and Mori, TA and Morris, AD and Mucci, LA and Munroe, PB and Nalls, MA and Nazarian, S and Nelson, AE and Neville, MJ and Newton-Cheh, C and Nielsen, CS and Niinikoski, H and Nikus, K and Nöthen, MM and Ogunniyi, A and Ohlsson, C and Oldehinkel, AJ and Orozco, L and Pahkala, K and Pajukanta, P and Palmer, CNA and Parra, EJ and Pattaro, C and Pedersen, O and Pennell, CE and Penninx, BWJH and Perusse, L and Peters, A and Peyser, PA and Porteous, DJ and Posthuma, D and Power, C and Pramstaller, PP and Province, MA and Psaty, BM and Qi, Q and Qu, J and Rader, DJ and Raitakari, OT and Rallidis, LS and Rao, DC and Redline, S and Reilly, DF and Reiner, AP and Rhee, SY and Ridker, PM and Rienstra, M and Ripatti, S and Ritchie, MD and Rivadeneira, F and Roden, DM and Rosendaal, FR and Rotter, JI and Rudan, I and Rutters, F and Ryu, S and Sabanayagam, C and Salako, B and Saleheen, D and Salomaa, V and Samani, NJ and Sanghera, DK and Sattar, N and Schmidt, B and Schmidt, H and Schmidt, R and Schulze, MB and Schunkert, H and Scott, LJ and Scott, RJ and Sever, P and Sheu, WHH and Shoemaker, MB and Shu, XO and Simonsick, EM and Sims, M and Singleton, AB and Sinner, MF and Smith, JG and Snieder, H and Spector, TD and Spedicati, B and Stampfer, MJ and Stark, KJ and Strachan, DP and Tabara, Y and Tai, ES and Tang, H and Tardif, JC and Thanaraj, TA and Tönjes, A and Tuomi, T and Tuomilehto, J and Tusié-Luna, MT and van Dam, RM and van der Harst, P and Van der Velde, N and van Duijn, CM and van Schoor, NM and Vitart, V and Vohl, MC and Völker, U and Vollenweider, P and Völzke, H and Vrieze, S and Wacher-Rodarte, NH and Walker, M and Wander, GS and Wareham, NJ and Watanabe, RM and Watkins, H and Weir, DR and Werge, TM and Widen, E and Willemsen, G and Willett, WC and Wilson, JF and Wilson, PWF and Wong, TY and Woo, JT and Wright, AF and Xu, H and Yajnik, CS and Yang, J and Yokota, M and Yuan, JM and Zeggini, E and Zemel, BS and Zheng, W and Zhu, X and Zillikens, MC and Zonderman, AB and Zwart, JA and , and , and , and , and , and , and , and Abecasis, GR and Assimes, TL and Auton, A and Boehnke, M and Chasman, DI and Esko, T and Stefansson, K and Lettre, G and Lindgren, CM and Ng, MCY and O'Donnell, CJ and Thorsteinsdottir, U and Visscher, PM and Walters, RG and Winkler, TW and Wood, AR and Deloukas, P and Frayling, TM and Justice, AE and Kilpeläinen, TO and Locke, AE and Mohlke, KL and North, KE and Okada, Y and Willer, CJ and Young, KL and Fatumo, S and McCaffery, JM and Timpson, NJ and Hirschhorn, JN and Sun, YV and Berndt, SI and Loos, RJF}, title = {Polygenic prediction of body mass index and obesity through the life course and across ancestries.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40691366}, issn = {1546-170X}, abstract = {Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.}, }
@article {pmid40690761, year = {2025}, author = {Banerjee, R and Mohan, M and Rejeski, K and Puliafito, BR and Cirstea, DD and Kaur, G and Midha, S and McCaughan, GJ and Kumar, NM and Mehra, N and Bagal, B and Raje, NS}, title = {IVIG prophylaxis should be initiated following bispecific antibody therapy in multiple myeloma regardless of IgG levels.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016490}, pmid = {40690761}, issn = {2473-9537}, abstract = {Bispecific antibodies (bsAbs) such as teclistamab, elranatamab, linvoseltamab, and talquetamab have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG), may lower these risks. In this Viewpoint, we contrast primary IgRT prophylaxis (initiation regardless of IgG levels) with preemptive IgRT treatment (initiation only once IgG levels fall below a certain threshold) in this setting. We make evidence-based arguments for primary prophylaxis as a safer and simpler approach compared to preemptive IgG-guided IgRT. We also discuss strategies to improve the cost-effectiveness of IVIG and SCIG across the world. Given the overwhelmingly favorable benefit-risk profile of IgRT coupled with the limitations inherent to IgG measurements in MM, withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM receiving bsAb therapy.}, }
@article {pmid40689664, year = {2025}, author = {Ding, S and Tauzin, A and Pinto-Santini, D and Dasgupta, S and Yang, D and Tolbert, WD and Chandravanshi, M and Benlarbi, M and Verly, M and Lama, JR and Huryn, DM and Smith, AB and Pazgier, M and Finzi, A and Duerr, A}, title = {CD4-mimetics sensitize HIV-infected cells to ADCC mediated by plasma from persons with early-stage HIV-1 infection.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0085825}, doi = {10.1128/jvi.00858-25}, pmid = {40689664}, issn = {1098-5514}, abstract = {UNLABELLED: The viral reservoir in long-lived memory CD4+ cells, established in the early stages of HIV infection, represents the main obstacle to an HIV cure. Some strategies being developed to target the reservoir rely on rendering HIV-1 envelope glycoproteins (Env) visible to the immune system. Small molecule CD4-mimetics (CD4mcs) expose vulnerable Env epitopes, which can be targeted by non-neutralizing antibodies (nnAbs) that are abundant in the plasma of people living with HIV (PLWH) and can mediate antibody-dependent cellular cytotoxicity (ADCC). Administration of CD4mcs in combination with plasma from PLWH or nnAbs efficiently reduces the size of the HIV-1 reservoir and postpones viral rebound upon antiretroviral therapy (ART) interruption in humanized mice. However, it remains unclear when these nnAbs are elicited after HIV infection. In this study, we collected longitudinal plasma samples before acquisition, at diagnosis, and at multiple time points up to 33 weeks after the estimated date of detectable infection (EDDI) and before ART treatment initiation. We found that plasma samples collected as early as 3 to 10 weeks after EDDI neutralized viral particles and mediated ADCC in the presence of the CJF-III-288 CD4mc. Recognition of HIV-1-infected cells and ADCC progressively increased over time, reaching a plateau by 19-25 weeks after EDDI. ADCC activity increased concomitantly with the elicitation of anti-gp120 and anti-gp41 CD4-induced (CD4i) Abs and improved over time with the appearance of anti-coreceptor binding site antibodies. Our results show that CD4i nnAbs, able to eliminate HIV-1-infected cells in the presence of CD4mc, are elicited within a few weeks after HIV acquisition.
IMPORTANCE: A viral reservoir is established at the early stages of HIV-1 infection. This reservoir persists during antiretroviral therapy (ART) treatment, and viral rebound is observed after ART interruption. New strategies are needed to reduce the size of the viral reservoir and prevent virus rebound. Several families of non-neutralizing antibodies, which are abundant in plasma from people living with HIV-1, neutralize viral particles and mediate the elimination of HIV-1-infected cells through antibody-dependent cellular cytotoxicity (ADCC) when combined with CD4-mimetic compounds. The presence of non-neutralizing antibodies in plasma during early-stage HIV-1 infection would support the use of CD4-mimetic compounds as an early intervention to decrease the size of the latent HIV-1 reservoir by eliminating infected cells.}, }
@article {pmid40685311, year = {2025}, author = {Mehra, N and Antonarakis, ES and Park, SH and Goh, JC and McDermott, R and Sala Gonzalez, N and Fong, PC and Greil, R and De Santis, M and Yanez, PE and Huang, YH and Begbie, SD and Rey, F and Kramer, G and Suzuki, H and Saretsky, TL and Ghate, SR and Cui, Y and Hosius, C and Yu, EY}, title = {Patient-reported Outcomes in KEYLYNK-010: Pembrolizumab Plus Olaparib Versus Abiraterone or Enzalutamide for Participants with Biomarker-unselected, Previously Treated Metastatic Castration-resistant Prostate Cancer.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.04.018}, pmid = {40685311}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: Pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival versus a next-generation hormonal agent (NHA) in participants with biomarker-unselected, pretreated metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 KEYLYNK-010 trial. We present prespecified patient-reported outcomes (PROs) from KEYLYNK-010.
METHODS: Participants were randomly assigned 2:1 to receive pembrolizumab plus olaparib or an NHA (abiraterone acetate or enzalutamide). PROs were evaluated using the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate Cancer (FACT-P), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires. The PRO endpoints included time to pain progression (TTPP) as per BPI-SF and the least squares mean (LSM) change from baseline to week 15 in FACT-P total, BPI-SF, and EQ-5D visual analog scale (VAS) scores.
KEY FINDINGS AND LIMITATIONS: The PRO analysis population included 774 participants (pembrolizumab plus olaparib, n = 520; NHA, n = 254). The median follow-up was 18.7 (range, 6.1-31.7) mo. No meaningful differences were observed in TTPP for pembrolizumab plus olaparib versus NHA (median: 13.5 vs 12.0 mo; hazard ratio 0.95; 95% confidence interval 0.72-1.26). From baseline to week 15, no meaningful LSM differences were observed between the treatment groups in FACT-P total, BPI-SF, and EQ-5D VAS scores. Limitations include no formal hypothesis testing.
No meaningful differences were observed in health-related quality of life (HRQoL) or disease-related symptom scores for pembrolizumab plus olaparib versus NHA in participants with biomarker-unselected, pretreated mCRPC. These findings suggest that pembrolizumab plus olaparib did not negatively impact HRQoL in participants with pretreated mCRPC.
CLINICAL TRIAL REGISTRY: NCT03834519.}, }
@article {pmid40685016, year = {2025}, author = {Leu, J and Narra, LR and Gooley, T and Cross, N and Vuong, W and Khan, H and Kang, J and Yang, JT and Grassberger, C and Gillespie, EF}, title = {Evaluating risk factors for skeletal-related events among bone metastases from solid tumors.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {111048}, doi = {10.1016/j.radonc.2025.111048}, pmid = {40685016}, issn = {1879-0887}, abstract = {BACKGROUND AND PURPOSE: Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment.
MATERIALS AND METHODS: This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility.
RESULTS: Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE.
CONCLUSION: Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.}, }
@article {pmid40681809, year = {2025}, author = {Goodsell, KE and Chauhan, SSB and Pillarisetty, VG and Sham, JG}, title = {ASO Visual Abstract: Somatostatin Analogues for Preventing Postoperative Pancreatic Fistula: Past Evidence Reveals New Opportunities.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1245/s10434-025-17828-2}, pmid = {40681809}, issn = {1534-4681}, }
@article {pmid40631121, year = {2025}, author = {Kenaston, MW and Cherkashchenko, L and Skawinski, CLS and Fishburn, AT and Peddamallu, V and Florio, CJ and Robertson, AE and Bhattacharya, T and Young, JM and Malik, HS and Shah, PS}, title = {Yellow Fever Virus Interactomes Reveal Common and Divergent Strategies of Replication and Evolution for Mosquito-borne Flaviviruses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40631121}, issn = {2692-8205}, support = {R01 AI170857/AI/NIAID NIH HHS/United States ; R21 AI168716/AI/NIAID NIH HHS/United States ; S10 OD026702/OD/NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Pathogenic mosquito-borne flaviviruses infect mosquito and human hosts, relying on host protein interactions to replicate, evade immunity, and mediate pathogenesis. Prior proteomic studies mapped such interactions for some flaviviruses, but yellow fever virus (YFV)-a pathogen of resurgent concern-remains understudied. Here, we map YFV interactomes in human and mosquito cells to identify interactions common among divergent flaviviruses or unique to YFV. Functional assays reveal a previously unrecognized YFV restriction factor: RBBP6 inhibits YFV genome replication by interacting with the viral polymerase NS5. We enhance the identification of dual-host interactions using structural modeling and holistic network integration. Extending our holistic approach to other flavivirus interactomes, we distinguish conserved mechanisms of host targeting from those unique to YFV. Contrary to expectations that conserved viral proteins lead to conserved protein interactions, we find that Capsid, a divergent structural protein, shares more host interactions than NS5, a conserved enzyme. Integrating proteomics with complementary analyses defines new principles of host-targeting strategies across flavivirus and host evolution, offering a versatile resource for navigating the complex landscape of flavivirus biology.}, }
@article {pmid38328033, year = {2025}, author = {Arimura, Y and Konishi, HA and Funabiki, H}, title = {MagIC-Cryo-EM: Structural determination on magnetic beads for scarce macromolecules in heterogeneous samples.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38328033}, issn = {2692-8205}, support = {R35 GM132111/GM/NIGMS NIH HHS/United States ; }, abstract = {Cryo-EM single-particle analyses typically require target macromolecule concentration at 0.05~5.0 mg/ml, which is often difficult to achieve. Here, we devise Magnetic Isolation and Concentration (MagIC)-cryo-EM, a technique enabling direct structural analysis of targets captured on magnetic beads, thereby reducing the targets' concentration requirement to < 0.0005 mg/ml. Adapting MagIC-cryo-EM to a Chromatin Immunoprecipitation protocol, we characterized structural variations of the linker histone H1.8-associated nucleosomes that were isolated from interphase and metaphase chromosomes in Xenopus egg extract. Combining Duplicated Selection To Exclude Rubbish particles (DuSTER), a particle curation method that excludes low signal-to-noise ratio particles, we also resolved the 3D cryo-EM structures of nucleoplasmin NPM2 co-isolated with the linker histone H1.8 and revealed distinct open and closed structural variants. Our study demonstrates the utility of MagIC-cryo-EM for structural analysis of scarce macromolecules in heterogeneous samples and provides structural insights into the cell cycle-regulation of H1.8 association to nucleosomes.}, }
@article {pmid40680922, year = {2025}, author = {Lauro, FD and Probert, WJM and Pickles, M and Cori, A and Hinch, R and Ferretti, L and Panovska-Griffiths, J and Abeler-Dörner, L and Dunbar, R and Bock, P and Donnell, DJ and Ayles, H and Fidler, S and Hayes, R and Fraser, C and , }, title = {Large connected components in sexual networks and their role in HIV transmission in Sub-Saharan Africa: A model-based analysis of HPTN 071(PopART) data.}, journal = {Journal of theoretical biology}, volume = {}, number = {}, pages = {112218}, doi = {10.1016/j.jtbi.2025.112218}, pmid = {40680922}, issn = {1095-8541}, abstract = {The HIV epidemic in sub-Saharan Africa is historically characterised by high levels of prevalence and incidence. With the global effort to reach UNAIDS 95-95-95 targets, the scaling-up of HIV treatment, and focused preventive interventions, incidence has been declining over the past decade, albeit non-consistently across different sex and age groups. Two questions remain to be addressed to help tailor setting-specific interventions and allocate resources optimally. Firstly, are there unidentified demographic groups that are sources of transmission? Secondly, what are the patterns of decline in incidence across different groups? Model-based assessment is a valuable tool for the design of focused interventions and to answer these questions. PopART-IBM, an individual-based model calibrated to (anonymised) age-and-sex stratified data, was developed in the context of the HPTN-071 (PopART) trial, and it offers a unique opportunity to explore such questions in the context of high-burden HIV communities in Zambia and South Africa. The outputs of the model include the full HIV transmission and partnership networks. In this work, we explore these and show that the sexual partnership network exhibits a large connected component, usually comprising over 40 % of the population, in each of the studied communities. An analysis of the large connected component reveals that it is formed by young people (20-40 years old) and is centered around the most sexually active individuals of the community. At the same time, many individuals in the large connected component only have one partner, highlighting the complex dynamics of risk correlations in a population. Inspecting the transmission network reveals that, on average, more than 80% of transmissions occur among individuals belonging to the large connected component. These findings indicate that populations consisting of young and highly sexually active individuals should be given high priority when designing or deploying interventions.}, }
@article {pmid40680268, year = {2025}, author = {DeFilipp, Z and Choe, HK and Efebera, YA and Saad, A and Farhan, S and Lekakis, LJ and Yared, JA and Schiller, GJ and Mapara, MY and Assal, A and Gooley, TA and Bui, JD and Lee, DD and Lane, H and Chen, YB}, title = {---RGI-2001 for the Prophylaxis of Acute Graft-Versus-Host Disease Following Allogeneic HCT.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025029584}, pmid = {40680268}, issn = {1528-0020}, abstract = {RGI-2001, a liposomal glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T cells and stimulate cytokine-dependent proliferation of regulatory T-cells (Tregs). This open-label, single-arm, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies. RGI-2001 was infused at a dose of 100 ug/kg for six weekly doses starting on Day 0 of HCT. The primary endpoint was grades II-IV acute GVHD by Day 100 after HCT. Forty-nine participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, with the most common being decreased appetite, leukopenia, thrombocytopenia and stomatitis. The estimated probability of grades II-IV and III-IV acute GVHD were 24.9% and 4.1%, respectively. Compared to controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including Day-180 grades II-IV acute GVHD-free survival (70.8% vs 50.7%, adjusted hazard ratio 0.45, 95% CI 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunological changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as NCT04014790.}, }
@article {pmid40451158, year = {2025}, author = {Scadden, AW and Kakar, A and Litkowski, EM and Meyer, MC and Armstrong, ND and Buyske, S and Cai, Y and Cheng, I and Darst, BF and Fornage, M and Graff, M and Guo, B and Haiman, CA and Highland, HM and Kooperberg, C and Le Marchand, L and North, K and Peters, U and Rich, SS and Rotter, JI and Srinivasasainagendra, V and Tiwari, HK and Waldrop, S and Young, K and Raghavan, S and Lange, EM and Lange, LA and Irvin, MR and Stanislawski, MA}, title = {Type 2 Diabetes Polygenic Risk Score Interactions with Lifestyle Risk Factors in Black Americans.}, journal = {Lifestyle genomics}, volume = {18}, number = {1}, pages = {90-97}, pmid = {40451158}, issn = {2504-3188}, support = {N01 HC095168/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 HG004802/HG/NHGRI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; R01 HL086694/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01 CA098758/CA/NCI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; K01 HL157658/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; R01 HL136666/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL087641/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; U01 CA136792/CA/NCI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/epidemiology ; *Black or African American/genetics ; Female ; Male ; Risk Factors ; *Life Style ; Middle Aged ; Genetic Predisposition to Disease ; Body Mass Index ; Adult ; *Multifactorial Inheritance/genetics ; Cohort Studies ; Aged ; Logistic Models ; White People/genetics ; Genetic Risk Score ; White ; }, abstract = {INTRODUCTION: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.
METHODS: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.
RESULTS: The results are generally consistent with prior work in White populations. The PRS showed a significant interaction with body mass index, with a greater effect on T2D risk in individuals who were leaner (pinteraction = 0.038).
CONCLUSION: These results contribute to understanding the relationship between genetics and other T2D risk factors in Black Americans who have a high burden of T2D, potentially informing targeted prevention strategies.}, }
@article {pmid40679980, year = {2025}, author = {McCrady, A and Friedman, S and Wang, L and Shaw, D and Tawil, R and Statland, J and Tapscott, S and Blemker, S}, title = {3D finite element models reveal regional fatty infiltration modulates tibialis anterior force generating capacity in FSHD.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0319881}, doi = {10.1371/journal.pone.0319881}, pmid = {40679980}, issn = {1932-6203}, mesh = {Humans ; *Muscular Dystrophy, Facioscapulohumeral/physiopathology/pathology/diagnostic imaging ; *Muscle, Skeletal/physiopathology/pathology/diagnostic imaging ; Finite Element Analysis ; Muscle Strength/physiology ; Male ; Magnetic Resonance Imaging ; *Adipose Tissue/pathology/physiopathology/diagnostic imaging ; Middle Aged ; Adult ; Female ; Imaging, Three-Dimensional ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder characterized by muscle damage, fibro-fatty infiltration, and ultimately weakness. The tibialis anterior (TA), very often involved relatively early in FSHD, is a primary dorsiflexor and important for ambulation. Recent work using magnetic resonance imaging to quantify fat infiltration in the TA volume observed a steep decline in force generation after fat reached ~20% in volume. Additional imaging studies have identified regional fat infiltration patterns that may contribute to the non-linear relationship between fat volume and muscle strength due to the distribution of fat within the muscle structure. The goals of this study were to 1) develop a pipeline for creating subject-specific models of the TA that include fat infiltration patterns measured from MRI and predict force generation, 2) compare models created using this pipeline with clinical measures of muscle strength, and 3) use the models to investigate the impact of regional fat distribution on muscle force generation. Twelve subject-specific models were created, and the model-predicted forces strongly correlate to clinical measures of strength in the same subjects (manual muscle testing (MMT): r = 0.75, and quantitative muscle testing (QMT): r = 0.54). The models showed fat amount accounts for 48% and muscle volume accounts for 74% of the variation in force. To investigate the impact of fat distribution, we developed eight pseudo maps to systematically vary fat location and amount in all subject-specific geometries. The models revealed that fat location modulates force generation, with the middle region involvement having the greatest impact in reducing force. This work highlights the need to characterize and understand the impact of intra-muscular fat distributions in neuromuscular diseases.}, }
@article {pmid40679371, year = {2025}, author = {Gilad, M and Partridge, SC and Iima, M and Md, RR and Freiman, M}, title = {Radiomics-based Machine Learning Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Using Physiologically Decomposed Diffusion-weighted MRI.}, journal = {Radiology. Imaging cancer}, volume = {7}, number = {4}, pages = {e240312}, doi = {10.1148/rycan.240312}, pmid = {40679371}, issn = {2638-616X}, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging/drug therapy/pathology ; Female ; *Neoadjuvant Therapy ; *Diffusion Magnetic Resonance Imaging/methods ; *Machine Learning ; Retrospective Studies ; Middle Aged ; Adult ; Breast/diagnostic imaging ; Treatment Outcome ; Chemotherapy, Adjuvant ; Predictive Value of Tests ; Radiomics ; }, abstract = {Purpose To evaluate the performance of a machine learning model developed using radiomics data derived from physiologically decomposed diffusion-weighted MRI data for predicting pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer compared with baseline and benchmark models. Materials and Methods This retrospective study included data from the Breast Multiparametric MRI for prediction of neoadjuvant chemotherapy Response (BMMR2) challenge dataset, comprising longitudinal multiparametric breast MRI studies (diffusion-weighted imaging [DWI] and dynamic contrast-enhanced MRI) from participants enrolled in the I-SPY 2/ACRIN 6698 trial (ClinicalTrials.gov: NCT01042379). Piecewise linear physiologic decomposition was applied to DWI data (PD DWI) to isolate pseudo-diffusion, pure-diffusion, and pseudo-diffusion fraction components for radiomics feature extraction. These features were used to develop a boosted decision tree model to predict pCR following neoadjuvant chemotherapy. Model performance was compared with performance of baseline models, including data on tumor size and mean apparent diffusion coefficient, and the BMMR2 challenge benchmark model using area under the receiver operating characteristic curve, F1 score, and positive and negative predictive values. Model calibration was assessed via the Brier score, and a decision curve analysis was performed to estimate the potential reduction in unnecessary interventions when using the proposed model. Results The study included multiparametric MRI scans from 190 female participants (mean age ± SD, 48.4 years ± 10.5). PD DWI achieved the highest area under the receiver operating characteristic curve (0.89, 95% CI: 0.81, 0.96) among all evaluated models, demonstrating statistically significant improvements over baseline approaches (all P < .04). Decision curve analysis showed that the PD DWI model provided a greater net benefit compared with the BMMR2 challenge benchmark model (0.17, 95% CI: 0.13, 0.21 vs 0.09, 95% CI: 0.05, 0.13; P < .001). Conclusion A machine learning model using radiomics data derived from PD DWI achieved higher performance than baseline and benchmark models in predicting pCR following neoadjuvant chemotherapy for breast cancer. Keywords: Image Postprocessing, MR-Diffusion Weighted Imaging, Breast, Tumor Response, Experimental Investigations ClinicalTrials.gov: NCT01042379 © RSNA, 2025.}, }
@article {pmid40676597, year = {2025}, author = {Rajabli, F and Benchek, P and Tosto, G and Kushch, N and Sha, J and Bazemore, K and Zhu, C and Lee, WP and Haut, J and Hamilton-Nelson, KL and Wheeler, NR and Zhao, Y and Farrell, JJ and Grunin, MA and Leung, YY and Kuksa, PP and Li, D and da Fonseca, EL and Mez, JB and Palmer, EL and Pillai, J and Sherva, RM and Song, YE and Zhang, X and Ikeuchi, T and Iqbal, T and Pathak, O and Valladares, O and Reyes-Dumeyer, D and Kuzma, AB and Abner, E and Adams, LD and Adams, PM and Aguirre, A and Albert, MS and Albin, RL and Allen, M and Alvarez, L and Apostolova, LG and Arnold, SE and Asthana, S and Atwood, CS and Auerbach, S and Ayres, G and Baldwin, CT and Barber, RC and Barnes, LL and Barral, S and Beach, TG and Becker, JT and Beecham, GW and Beekly, D and Benitez, BA and Bennett, D and Bertelson, J and Bird, TD and Blacker, D and Boeve, BF and Bowen, JD and Boxer, A and Brewer, J and Burke, JR and Burns, JM and Buxbaum, JD and Cairns, NJ and Cantwell, LB and Cao, C and Carlson, CS and Carlsson, CM and Carney, RM and Carrasquillo, MM and Chasse, S and Chesselet, MF and Chin, NA and Chui, HC and Chung, J and Craft, S and Crane, PK and Cribbs, DH and Crocco, EA and Cruchaga, C and Cuccaro, ML and Cullum, M and Darby, E and Davis, B and De Jager, PL and DeCarli, C and DeToledo, J and Dick, M and Dickson, DW and Dombroski, BA and Doody, RS and Duara, R and Ertekin-Taner, N and Evans, DA and Faber, KM and Fairchild, TJ and Fallon, KB and Fardo, DW and Farlow, MR and Fernandez-Hernandez, V and Ferris, S and Friedland, RP and Foroud, TM and Frosch, MP and Fulton-Howard, B and Galasko, DR and Gamboa, A and Gearing, M and Geschwind, DH and Ghetti, B and Gilbert, JR and Go, RCP and Goate, AM and Grabowski, TJ and Graff-Radford, NR and Green, RC and Growdon, JH and Hakonarson, H and Hall, J and Hamilton, RL and Harari, O and Hardy, J and Harrell, LE and Head, E and Henderson, VW and Hernandez, M and Hohman, T and Honig, LS and Huebinger, RM and Huentelman, MJ and Hulette, CM and Hyman, BT and Hynan, LS and Ibanez, L and Jarvik, GP and Jayadev, S and Jin, LW and Johnson, K and Johnson, L and Kamboh, MI and Karydas, AM and Katz, MJ and Kauwe, JS and Kaye, JA and Keene, CD and Khaleeq, A and Kikuchi, M and Kim, R and Knebl, J and Kowall, NW and Kramer, JH and Kukull, WA and LaFerla, FM and Lah, JJ and Larson, EB and Lerner, A and Leverenz, JB and Levey, AI and Lieberman, AP and Lipton, RB and Logue, M and Lopez, OL and Lunetta, KL and Lyketsos, CG and Mains, D and Margaret, FE and Marson, DC and Martin, ER and Martiniuk, F and Mash, DC and Masliah, E and Massman, P and Masurkar, A and McCormick, WC and McCurry, SM and McDavid, AN and McDonough, S and McKee, AC and Mesulam, M and Miller, BL and Miller, CA and Miller, JW and Montine, TJ and Monuki, ES and Morris, JC and Mukherjee, S and Myers, AJ and Nguyen, T and Obisesan, T and O'Bryant, S and Olichney, JM and Ory, M and Palmer, R and Parisi, JE and Paulson, HL and Pavlik, V and Paydarfar, D and Perez, V and Peskind, E and Petersen, RC and Petrovitch, H and Pierce, A and Polk, M and Poon, WW and Potter, H and Qu, L and Quiceno, M and Quinn, JF and Raj, A and Raskind, M and Reiman, EM and Reisberg, B and Reisch, JS and Ringman, JM and Roberson, ED and Rodriguear, M and Rogaeva, E and Rosen, HJ and Rosenberg, RN and Royall, DR and Sabbagh, M and Sadovnick, AD and Sager, MA and Sano, M and Saykin, AJ and Schneider, JA and Schneider, LS and Seeley, WW and Slifer, SH and Small, S and Smith, AG and Smith, JP and Sonnen, JA and Spina, S and George-Hyslop, PS and Starks, TD and Stern, RA and Stevens, AB and Strittmatter, SM and Sultzer, D and Swerdlow, RH and Tanzi, RE and Tilson, JL and Trojanowski, JQ and Troncoso, JC and Tsolaki, M and Tsuang, DW and Van Deerlin, VM and van Eldik, LJ and Vance, JM and Vardarajan, BN and Vassar, R and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Whitehead, PL and Wijsman, EM and Wilhelmsen, KC and Williams, B and Williamson, J and Wilms, H and Wingo, TS and Wisniewski, T and Woltjer, RL and Woon, M and Wright, CB and Wu, CK and Younkin, SG and Yu, CE and Yu, L and Zhu, X and Kunkle, BW and Bush, WS and Miyashita, A and Byrd, GS and Wang, LS and Farrer, LA and Haines, JL and Mayeux, R and Pericak-Vance, MA and Schellenberg, GD and Jun, GR and Reitz, C and Naj, AC and , }, title = {Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {210}, pmid = {40676597}, issn = {1474-760X}, support = {U01 AG032984/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; *Alzheimer Disease/genetics/ethnology ; Black or African American/genetics ; *Genetic Loci ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Hispanic or Latino/genetics ; Polymorphism, Single Nucleotide ; White/genetics ; }, abstract = {BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.
RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14).
CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.}, }
@article {pmid40675830, year = {2025}, author = {Moon, HH and Aragon-Ching, JB and Thompson, A and Abraham, A and Vlahiotis, A and Ike, C and Benjumea, D and Shao, A and Sun, H and Kearney, M and Gharibian, N and Hanson, S and Li, B and Kirker, M and Grivas, P}, title = {Early real-world utilization of avelumab switch maintenance among patients with advanced urothelial carcinoma without progression following treatment with first-line platinum-based chemotherapy.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.05.014}, pmid = {40675830}, issn = {1873-2496}, abstract = {BACKGROUND: A standard treatment option for patients with locally advanced/metastatic urothelial carcinoma (la/mUC) is first-line platinum-based chemotherapy (1L PBC) followed by avelumab 1L switch maintenance (1LM) in patients without progression. This study aimed to evaluate the real-world treatment patterns and outcomes in patients with la/mUC in the US treated with 1L PBC and characterize the early adoption of avelumab 1LM following FDA approval in June 2020.
METHODS: This retrospective cohort study identified adults diagnosed with la/mUC between January 2017 and September 2021 using electronic health records from the Flatiron Health database. Patients were grouped based on real-world response to 1L PBC: complete or partial response (rwCR/PR) or stable disease (rwSD). Baseline characteristics and treatment patterns were described. Clinical outcomes, including real-world overall survival (rwOS) and progression-free survival (rwPFS), were analyzed using the Kaplan-Meier method.
RESULTS: Of 1,703 identified patients with la/mUC treated with 1L PBC, 1,245 (73%) had response data available during the study period, with 998 (80%) having a best response of rwCR/PR (60%) or rwSD (20%). Demographic and clinical characteristics were similar between patients with rwCR/PR and rwSD. Patients with rwCR/PR had longer median rwOS and rwPFS from 1L PBC initiation vs patients with rwSD. Of patients evaluated after FDA approval of avelumab 1LM on June 30, 2020, 435 discontinued 1L PBC. Of these patients, 339 had response data, and 138 of those without progression were considered avelumab 1LM eligible. Of these, 97 (70%) initiated avelumab 1LM within 180 days following last administration of 1L PBC, with 40 patients receiving second-line (2L) treatment, most commonly enfortumab vedotin (60%).
CONCLUSION: In the post-FDA approval period, uptake of avelumab 1LM was high (70%) in patients with rwSD or rwCR/PR following 1L PBC, and 41% of these patients received 2L treatment, most commonly with enfortumab vedotin.}, }
@article {pmid40675169, year = {2025}, author = {Weinstein, E and Paredes, R and Gardner, A and Almas, M and Baniecki, ML and Guan, S and Tudone, E and Antonucci, S and Gregg, K and Garcia-Vidal, C and Camacho-Ortiz, A and Wisemandle, W and Terra, SG and Liu, S and Aberg, JA and Rana, MM and Corey, L and Ford, ES and Hammond, J and Rusnak, J}, title = {Extended nirmatrelvir-ritonavir treatment durations for immunocompromised patients with COVID-19 (EPIC-IC): a placebo-controlled, randomised, double-blind, phase 2 trial.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00221-X}, pmid = {40675169}, issn = {1474-4457}, abstract = {BACKGROUND: Nirmatrelvir-ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease. There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir-ritonavir with 10-day and 15-day regimens.
METHODS: This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigned and dosed participants with sustained nasopharyngeal SARS-CoV-2 RNA concentrations below the lower limit of quantification (2·0 log10 copies per mL) from days 15 to 44. Secondary endpoints included the incidence of viral rebound after the end of treatment up to day 44. Safety, a secondary endpoint, was assessed in all randomly assigned participants who received at least one dose of nirmatrelvir-ritonavir. This trial was registered with ClinicalTrials.gov (NCT05438602) and is completed.
FINDINGS: Among 156 participants (84 female, 72 male) randomly assigned from Aug 3, 2022 to July 17, 2023, 150 comprised the analysis population. The primary endpoint was reached in 32 (61·5%, 95% CI 48·3-74·8) of 52 participants in the 5-day treatment group, 34 (70·8%, 58·0-83·7) of 48 participants in the 10-day treatment group, and 33 (66·0%, 52·9-79·1) of 50 participants in the 15-day treatment group. Viral rebound occurred in 17·3% (95% CI 8·2-30·3) of participants in the 5-day group, 2·1% (0·1-11·1) in the 10-day group, and 2·0% (0·1-10·6) in the 15-day group. Adverse events occurred in 28 (52·8%) of 53, 34 (66·7%) of 51, and 31 (60·8%) of 51 participants across the 5-day, 10-day, and 15-day groups, respectively. Two COVID-19-related hospitalisations were reported, both in the 5-day treatment group.
INTERPRETATION: No difference was observed between the three treatment durations in the primary endpoint. Extending nirmatrelvir-ritonavir treatment beyond 5 days resulted in a nominal improvement in the frequency of viral rebound and was generally well tolerated.
FUNDING: Pfizer.}, }
@article {pmid40675159, year = {2025}, author = {Yang, X and Zhao, F and Ren, T and Chen, C and Byrne, KT and Danilov, AV and Sears, RC and Nelson, PS and Coussens, LM and Mills, GB and Xia, Z}, title = {OmicsTweezer: A distribution-independent cell deconvolution model for multi-omics Data.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {100950}, doi = {10.1016/j.xgen.2025.100950}, pmid = {40675159}, issn = {2666-979X}, abstract = {Cell deconvolution estimates cell type proportions from bulk omics data, enabling insights into tissue microenvironments and disease. However, practical applications are often hindered by batch effects between bulk data and referenced single-cell data, a challenge that is frequently overlooked. To address this discrepancy, we developed OmicsTweezer, a distribution-independent cell deconvolution model. By integrating optimal transport with deep learning, OmicsTweezer aligns simulated and real data in a shared latent space, effectively mitigating data shifts and inter-omics distribution differences. OmicsTweezer is versatile, capable of deconvolving bulk RNA-seq, bulk proteomics, and spatial transcriptomics. Extensive evaluations on simulated and real-world datasets demonstrate its robustness and accuracy. Furthermore, applications in prostate and colon cancer showcase OmicsTweezer's ability to identify biologically meaningful cell types. As a unified deconvolution framework for multi-omics data, OmicsTweezer offers an efficient and powerful tool for studying disease microenvironments.}, }
@article {pmid40674120, year = {2025}, author = {Hadland, B}, title = {Unusual suspects: a surprise cast in making blood stem cells.}, journal = {Blood}, volume = {146}, number = {3}, pages = {265-266}, doi = {10.1182/blood.2025029369}, pmid = {40674120}, issn = {1528-0020}, }
@article {pmid40674082, year = {2025}, author = {Rini, BI and Best, AF and Bowman, MD and Mishkin, GE and Denicoff, AM and Rubinstein, LV and Harris, L and Geiger, AM and Mark, NM and Pergam, SA and Warner, JL and Khorana, AA and Gnjatic, S and Yen, TWF and Liles, DK and Bestvina, CM and Shah, NJ and Norrell, JT and Hershman, DL and Holter-Chakrabarty, JL and Poklepovic, AS and Chanock, SJ and Sankaran, H and Korde, LA}, title = {Risk Factors for COVID-19-Related Hospitalization and Death in Patients With Cancer: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS).}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2025.2010}, pmid = {40674082}, issn = {2374-2445}, abstract = {IMPORTANCE: Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes.
OBJECTIVE: To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection.
The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025.
MAIN OUTCOMES AND MEASURES: The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models).
RESULTS: Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days.
CONCLUSIONS AND RELEVANCE: The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.}, }
@article {pmid40672105, year = {2025}, author = {Nakasone, ES and Coveler, AL}, title = {Targeting metabolism in pancreatic ductal adenocarcinoma: challenges and insights from the AVENGER 500 trial.}, journal = {Journal of gastrointestinal oncology}, volume = {16}, number = {3}, pages = {1351-1355}, pmid = {40672105}, issn = {2078-6891}, }
@article {pmid40671547, year = {2025}, author = {Heffner, JL and Giustini, N and Anderson, N and Go, T and Scout, NFN and Hippe, DS and Triplette, M}, title = {Implementation of sexual orientation and gender identity data collection in a cancer care setting.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {69}, pages = {139-146}, doi = {10.1093/jncimonographs/lgaf004}, pmid = {40671547}, issn = {1745-6614}, support = {/NH/NIH HHS/United States ; #P30CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Gender Identity ; Female ; Male ; *Sexual Behavior/statistics & numerical data ; *Neoplasms/therapy/epidemiology/psychology ; *Sexual and Gender Minorities/statistics & numerical data ; *Data Collection/methods ; Cancer Care Facilities ; United States ; Pilot Projects ; Adult ; Middle Aged ; }, abstract = {Cancer research focusing on sexual and gender minority populations is limited by lack of sexual orientation and gender identity data in medical records and cancer registries. We implemented multimethod sexual orientation and gender identity data collection in 2 pilot clinics at a National Cancer Institute-Designated Comprehensive Cancer Center, with first-line collection by telephone intake schedulers and second-line via physical form in clinics. Changes in data completion were compared with 2 control clinics, and staff shared intervention experiences. In pilot clinics, completion rates statistically significantly increased for gender identity (from 55.6% to 65.1%), sex assigned at birth (from 58.4% to 63.2%), sexual orientation (from 45.1% to 53.7%), and all 3 (from 37.8% to 44.7%) when compared with control clinics (P < .05). Staff reported a mix of patient reactions to sexual orientation and gender identity data collection. Sexual orientation and gender identity data collection can be enhanced in the cancer care setting with multimethod approaches.}, }
@article {pmid40671098, year = {2025}, author = {Zhou, HJ and Ge, X and Li, JJ}, title = {ClipperQTL: ultrafast and powerful eGene identification method.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {207}, pmid = {40671098}, issn = {1474-760X}, support = {DGE-1829071//National Science Foundation/ ; DBI-1846216//National Science Foundation/ ; T32HL139450/HL/NHLBI NIH HHS/United States ; R35GM140888/GM/NIGMS NIH HHS/United States ; R01GM120507/GM/NIGMS NIH HHS/United States ; WiSTEM2D Award//Johnson and Johnson/ ; Sloan Research Fellowship//Alfred P. Sloan Foundation/ ; UCLA David Geffen School of Medicine W.M. Keck Foundation Junior Faculty Award//W. M. Keck Foundation/ ; }, mesh = {*Quantitative Trait Loci ; *Software ; Humans ; }, abstract = {A central task in expression quantitative trait locus analysis is to identify cis-eGenes, i.e., genes whose expression levels are regulated by at least one local genetic variant. Existing cis-eGene identification methods are either computationally expensive, requiring thousands of permutations per gene (FastQTL), or statistically underpowered (eigenMT and TreeQTL). We propose ClipperQTL, which requires only one permutation for data sets with large sample sizes (>450; ClipperQTL works on smaller data sets too). We show that ClipperQTL performs as well as FastQTL and runs up to 500 times faster. The R package ClipperQTL is available at https://github.com/heatherjzhou/ClipperQTL .}, }
@article {pmid40670774, year = {2025}, author = {Rejeski, K and Hill, JA and Dahiya, S and Jain, MD}, title = {Noncanonical and mortality-defining toxicities of CAR T cell therapy.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40670774}, issn = {1546-170X}, abstract = {Chimeric antigen receptor (CAR) T cell therapy is associated with a unique spectrum of toxicities that drive morbidity, mortality and patient quality of life. Previous efforts yielded consensus grading systems for the prototypical immunotoxicities-namely, cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These grading systems set the stage for severity-based and standardized treatment protocols that have contributed to a reduction in the acute toxicity burden of CAR T cell therapy and have enabled outpatient administration. However, understanding of CAR T cell therapy has since grown to encompass new targets, new diseases and broader patient populations-including long-term survivors. As side effects are better defined and novel toxicities emerge, there is a need to understand their mechanisms and standardize reporting to improve clinical management. Here we review the current state of knowledge for mortality-defining and rare toxicities of CAR T cell therapies, beyond CRS and ICANS. We discuss mechanisms, including on-target injury, cytokine-associated inflammation and dysregulated recovery, and how these mechanisms affect the timing and management of toxicities. Finally, we define key unmet needs and delineate future priorities and research directions.}, }
@article {pmid40670422, year = {2025}, author = {Blemker, SS and Riem, L and DuCharme, O and Pinette, M and Costanzo, KE and Weatherley, E and Statland, J and Tapscott, SJ and Wang, LH and Shaw, DWW and Song, X and Leung, D and Friedman, SD}, title = {Multi-scale machine learning model predicts muscle and functional disease progression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {25339}, pmid = {40670422}, issn = {2045-2322}, mesh = {Humans ; *Machine Learning ; Disease Progression ; *Muscular Dystrophy, Facioscapulohumeral/physiopathology/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; *Muscle, Skeletal/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Adult ; Middle Aged ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a genetic neuromuscular disorder characterized by progressive muscle degeneration with substantial variability in severity and progression patterns. FSHD is a highly heterogeneous disease; however, current clinical metrics used for tracking disease progression lack sensitivity for personalized assessment, which greatly limits the design and execution of clinical trials. This study introduces a multi-scale machine learning framework leveraging whole-body magnetic resonance imaging (MRI) and clinical data to predict regional, muscle, joint, and functional progression in FSHD. The goal this work is to create a 'digital twin' of individual FSHD patients that can be leveraged in clinical trials. Using a combined dataset of over 100 patients from seven studies, MRI-derived metrics-including fat fraction, lean muscle volume, and fat spatial heterogeneity at baseline-were integrated with clinical and functional measures. A three-stage random forest model was developed to predict annualized changes in muscle composition and a functional outcome (timed up-and-go (TUG)). All model stages revealed strong predictive performance in separate holdout datasets. After training, the models predicted fat fraction change with a root mean square error (RMSE) of 2.16% and lean volume change with a RMSE of 8.1 ml in a holdout testing dataset. Feature analysis revealed that metrics of fat heterogeneity within muscle predicts muscle-level progression. The stage 3 model, which combined functional muscle groups, predicted change in TUG with a RMSE of 0.6 s in the holdout testing dataset. This study demonstrates the machine learning models incorporating individual muscle and performance data can effectively predict MRI disease progression and functional performance of complex tasks, addressing the heterogeneity and nonlinearity inherent in FSHD. Further studies incorporating larger longitudinal cohorts, as well as comprehensive clinical and functional measures, will allow for expanding and refining this model. As many neuromuscular diseases are characterized by variability and heterogeneity similar to FSHD, such approaches have broad applicability.}, }
@article {pmid40668104, year = {2025}, author = {Elias-Warren, A and Bennett, JC and Iwu, CD and Starita, LM and Stone, J and Capodanno, B and Prentice, R and Han, PD and Acker, Z and Grindstaff, SB and Reinhart, D and Logue, JK and Wolf, CR and Boeckh, M and Kong, K and Xie, H and Kim, G and Greninger, AL and Perofsky, AC and Viboud, C and Uyeki, TM and Englund, JA and Roychoudhury, P and Chu, HY}, title = {Epidemiology of Human Metapneumovirus Infection in a Community Setting, Seattle, Washington, USA.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {Supplement_1}, pages = {S78-S92}, pmid = {40668104}, issn = {1537-6613}, mesh = {Humans ; *Paramyxoviridae Infections/epidemiology/virology ; *Metapneumovirus/genetics/isolation & purification ; Washington/epidemiology ; Child, Preschool ; Female ; Infant ; Male ; Child ; Adolescent ; Adult ; Middle Aged ; Young Adult ; Infant, Newborn ; Aged ; Risk Factors ; Whole Genome Sequencing ; }, abstract = {BACKGROUND: The clinical and genomic epidemiology of human metapneumovirus (hMPV) infections in community settings is not well understood.
METHODS: From 2018 to 2022, individuals with respiratory symptoms were recruited and enrolled from the greater Seattle, Washington community in the United States. Residual clinical specimens from individuals presenting with respiratory symptoms were additionally collected. Specimens were tested for hMPV by reverse-transcription polymerase chain reaction, with whole genome sequencing performed on a subset (209/1002).
RESULTS: hMPV positivity was higher among clinical specimens (835/21 539 [3.9%]) compared to community specimens (167/28 348 [0.6%]). Children aged 0-4 years had the highest percent positivity across both clinical and community settings (497/10 213 [4.9%] and 28/1640 [1.7%], respectively). In multivariate analysis, a household income of ≤US$100 000 (adjusted odds ratio [aOR], 1.72 [95% confidence interval {CI}, 1.07-2.85]), and recent international travel (aOR, 6.51 [95% CI, 3.11-12.22]) were associated with hMPV positivity. A subset of 209 of 1002 samples (21%) was sequenced; the distribution of subtypes A2b, A2c, B1, and B2 were similar across both community and clinical settings, with an increase in the proportion of subtype B1 after the start of the pandemic.
CONCLUSIONS: Risk factors of testing positive for hMPV in a community setting included lower household income and recent international travel. Co-circulation of hMPV subtypes was observed across community and clinical settings.}, }
@article {pmid40665819, year = {2025}, author = {Corello, H and Pang, S and Bustillos, H and Velez, JW}, title = {Clinical considerations for pharmacists regarding the use of radiopharmaceuticals in oncology.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251359187}, doi = {10.1177/10781552251359187}, pmid = {40665819}, issn = {1477-092X}, abstract = {BackgroundRadiopharmaceutical therapy encompasses the targeted delivery of radioactive atoms to sites of malignancy within the body and represent a rapidly growing area of drug development in oncology. In comparison to cytotoxic chemotherapy, radiopharmaceutical therapy has the potential for fewer adverse effects and is able to produce a strong anti-cancer response in a wide range of malignancies.ObjectiveThis article reviews radiopharmaceutical therapy mechanisms and discusses four well-established agents that are used in clinical practice, their place in therapy, safety, utilization of concomitant therapies, and contact precautions for each agent.SourcesInformation presented in this article is sourced from the available literature on radiopharmaceutical development, oncology clinical practice guidelines, clinical trial results, and package insert data.SummaryRadiopharmaceuticals possess significant differences in drug mechanism and design from that of traditional cytotoxic chemotherapy agents. The basic functional and structural variances in combination with isotope selection drive the clinical efficacy of radiopharmaceutical therapy and inform pharmacists of the important considerations of each therapy's distribution, off-target effects, clearance, and toxicities.ConclusionThe drug and safety information presented in this article pertaining to select radiopharmaceuticals is pertinent to an oncology pharmacist's role in patient care as radioactive therapies continue to expand the complexity of the oncology treatment landscape.}, }
@article {pmid40665795, year = {2025}, author = {Muchadeyi, MT and Hao, S and Hernandez-Villafuerte, K and Khan, SA and Becker, N and Krilaviciute, A and Seibold, P and Gulati, R and Albers, P and Schlander, M and Clements, M}, title = {Cost effectiveness analysis of prostate cancer screening strategies in Germany: A microsimulation study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.35513}, pmid = {40665795}, issn = {1097-0215}, abstract = {Prostate cancer (PCa) represents a significant public health challenge in Germany, with increasing incidence and economic impact. This study assessed the cost-effectiveness of 10 screening strategies: prostate-specific antigen-based risk-adaptive screening (PSA-RAS), with or without magnetic resonance imaging (MRI), in men starting at age 45 or 50 and stopping at 60 or 70, digital rectal examination (DRE) for ages 45-75 years, and no screening. Using a well calibrated microsimulation model (Swedish Prostata) from a statutory health insurance perspective, lifetime outcomes were evaluated, including cancer incidence, mortality, overdiagnosis, biopsies, life-years, and quality-adjusted life-years (QALYs) discounted annually at 3%. Cost and utility inputs were derived from the German diagnostic-related group schedule, fee-for-service catalogues, literature, and expert opinion. DRE-only was the least cost-effective, yielding high biopsy and overdiagnosis rates with minimal QALY gains. PSA-RAS reduced overdiagnosis and biopsy rates, with PSA-RAS (50-60 years) without MRI emerging as the most cost-efficient strategy, saving approximately €1.2 million per 100,000 men compared with no screening. Extending the PSA-RAS to 70 years improved its effectiveness in terms of QALYs. PSA-RAS (50-70) with MRI could become cost-effective at an increasing willingness to pay threshold or decreasing MRI cost. This study suggests the potential of PSA-RAS to improve PCa screening in Germany. Incorporating MRI, reducing MRI cost within the screening setting, and extending screening to 70 to align with EU recommendations could improve the cost-effectiveness of PSA-RAS with MRI. Future research should explore the integration of MRI with ancillary tests, such as 4K-score or risk calculators, to reduce MRI use and associated costs.}, }
@article {pmid40162240, year = {2025}, author = {Paredes, MI and Liang, C and Suen, SC and Holloway, IW and Garrigues, JM and Green, NM and Bedford, T and Müller, NF and Osmundson, J}, title = {Viral introductions and return to baseline sexual behaviors maintain low-level mpox incidence in Los Angeles County, USA, 2023-2024.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40162240}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CK000357/CK/NCEZID CDC HHS/United States ; }, abstract = {In 2022, mpox clade IIb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the accumulation of immunity within queer sexual networks, mpox continues to persist at low incidence in North America without extinction, raising concerns of future outbreaks. We combined phylodynamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023-2024. Our Bayesian phylodynamic analysis revealed a time-varying pattern of viral importations into the county that seeded a skewed distribution of mpox outbreak clusters that display a "stuttering chains" dynamic. Our phylodynamics-informed microsimulation model demonstrated that the persistent number of mpox cases in LAC can be explained by a combination of waves of viral introductions, a median Rt significantly below one, and a return to near-baseline sexual behaviors that were altered during the 2022 epidemic. Finally, our counterfactual scenario modeling showed that public health interventions that either promote increased isolation of symptomatic, infectious individuals or enact behavior-modifying campaigns during the periods with the highest viral importation intensity are both actionable and effective at curbing mpox cases. Our work highlights the heterogeneous factors that maintain present-day mpox dynamics in a large, urban US county and describes how to leverage these results to design timely and community-centered public health interventions.}, }
@article {pmid40665521, year = {2025}, author = {Watt, GP and Reiner, AS and Shu, X and Malone, KE and Knight, JA and John, EM and Chow, EJ and Lynch, CF and Mellemkjær, L and Woods, M and Liang, X and Tran, AP and Oh, JH and Derkach, A and Bernstein, JL}, title = {Polygenic risk of coronary artery disease for long-term survivors of breast cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf189}, pmid = {40665521}, issn = {1460-2105}, abstract = {AIM: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer.
METHODS: The study included 1,307 women with breast cancer first diagnosed at age <55 years who participated in the WECARE Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modelled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment.
RESULTS: There were 65 incident CAD diagnoses reported at a median of 16 years after breast cancer diagnosis. Participants with CAD-PRS≥median had a 2.48-times increased risk of CAD (95%CI = 1.44-4.29) relative to participants with CAD-PRS
CONCLUSIONS: A genome-wide CAD-PRS was associated with non-fatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.}, }
@article {pmid40665019, year = {2025}, author = {Miller, NJ and Kwan, SW and Leary, JB and Hippe, DS and McCamy, W and Veatch, JR and Hall, ET and Monsky, WL and Bhatia, S}, title = {Concurrent treatment with transarterial immunoembolization of hepatic metastases and systemic immune checkpoint inhibitors to overcome immune evasion in patients with metastatic uveal melanoma.}, journal = {Cancer immunology, immunotherapy : CII}, volume = {74}, number = {8}, pages = {270}, pmid = {40665019}, issn = {1432-0851}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/therapy/immunology/pathology/mortality ; Middle Aged ; Male ; Female ; *Uveal Neoplasms/pathology/immunology/therapy/mortality ; *Liver Neoplasms/secondary/therapy/immunology ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Retrospective Studies ; Uveal Melanoma ; Aged ; Adult ; *Tumor Escape/drug effects ; Combined Modality Therapy ; Aged, 80 and over ; Immunotherapy/methods ; *Chemoembolization, Therapeutic/methods ; }, abstract = {BACKGROUND: Metastatic uveal melanoma (mUM) is an uncommon melanoma subtype, poorly immunogenic with low objective response rates (ORR) to immune checkpoint inhibitors (ICI). Liver-directed therapies (LDT) are commonly used given the strong predilection for hepatic metastases. Transarterial immunoembolization (TAIE) with granulocyte-macrophage colony stimulating factor (GM-CSF) can potentially synergize with concurrent systemic ICI to overcome immune evasion.
METHODS: This single-center, retrospective study includes mUM patients with liver-predominant metastases who received TAIE, with/without concurrent systemic ICI (≤ 3 months before/during TAIE). Endpoints included ORR, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).
RESULTS: Between 2016 and 2023, 18 mUM patients (median age 64 years) received TAIE (median 4 procedures/patient). Fourteen patients (78%) received concurrent ICI. ORR was 17% (3/18), all in patients receiving ICI, with partial responses lasting 4.2, 35 + and 46 months. Disease control rate (stable disease or better) was 56% (10/18). Median time to next systemic therapy or death was 19.5 months (range 1.6- 46). Median PFS and OS from first TAIE treatment were 4.9 months (range 0.7-46) and 35 months (range 1.7- 46). Immune-related AEs (IRAE) during concurrent therapy occurred in seven of 10 patients receiving anti-CTLA-4/PD-1 combination, including hepatitis (n = 5; grade 2 in 1, grade 3 in 4). Four of seven patients resumed anti-PD-1 monotherapy without recurrent IRAE.
CONCLUSIONS: Concurrent LDT with GM-CSF TAIE and ICI, including anti-CTLA-4/PD-1 combination, is feasible, safe, and can lead to sustained clinical benefit in a subset of mUM patients. OS with this combination compares favorably to published outcomes for systemic therapy or LDT alone.}, }
@article {pmid40664658, year = {2025}, author = {Thiele, K and Urbschat, C and Riquelme, JIA and Ahrendt, LS and Wöhrle, R and Schepanski, S and Eckert, JJ and Becht, E and Qi, M and Alawi, M and Becker, M and Gagliani, N and Mittrücker, HW and Diemert, A and Arck, PC}, title = {Pregnancy-acquired memory CD4[+] regulatory T cells improve pregnancy outcome in mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6522}, pmid = {40664658}, issn = {2041-1723}, support = {TH 2126/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; Scholarship from the IRTG of the CRC1192//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; AR232/26-2, AR232/27-2, AR232/29-2//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; iPRIME Scholarship//Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; iPRIME Scholarship//Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; 01GL2404A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, mesh = {Female ; Pregnancy ; Animals ; *T-Lymphocytes, Regulatory/immunology ; *Immunologic Memory/immunology ; Mice ; *Pregnancy Outcome ; Th17 Cells/immunology ; Mice, Inbred C57BL ; Receptors, CXCR4/metabolism/immunology ; }, abstract = {Subsequent pregnancies are generally less prone to obstetric complications. A successful pregnancy outcome requires pivotal immunological adaptation to ensure immune tolerance towards the foetus. Thus, the lower risk for pregnancy complication during subsequent pregnancies may be attributable to immune memory mounted during first pregnancies. Here we identify higher frequencies of fetal-antigen-specific CD4[+] regulatory T (Treg) cells both postpartum and in subsequent pregnancies in mice which are partly originating from trans-differentiated Th17 cells. Our functional experiments demonstrate that these CD4[+] Treg cells have memory functions (CD4[+] mTreg) and account for an improved fetal development and pregnancy outcome, also during adverse conditions, such as gestational sound stress. Using a high-throughput single-cell quantification method, we identify candidate markers for the detection of CD4[+] mTreg cells, which include CXCR4 and CD274. Our findings thus contribute to the improved understanding of pregnancy-induced immune memory and foster the identification of immune targets aiming to reduce the risk for immune-mediated pregnancy complications.}, }
@article {pmid39651125, year = {2025}, author = {Sung, K and Johnson, MM and Dumm, W and Simon, N and Haddox, H and Fukuyama, J and Matsen, FA}, title = {Thrifty wide-context models of B cell receptor somatic hypermutation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39651125}, issn = {2692-8205}, abstract = {Somatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, for understanding the selective forces guiding affinity maturation, and for understanding the underlying biochemical process. High throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this paper we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM, however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop "thrifty" models of SHM of various sizes; these can have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model, and other modern model elaborations worsen performance. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model - on out-of-frame sequence data and on synonymous mutations - produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.}, }
@article {pmid40664448, year = {2025}, author = {Miller, NJ and Baik, C and Neal, JW and Sun, F and Santana-Davila, R and Lee, S and Eaton, KD and Martins, RG and Rodriguez, C and Wakelee, H and Padda, SK and Sotillo, E and Konnick, EQ and Camai, A and Pisarenko, T and Nair, VS and Mackall, C and Houghton, AM and Chiou, SH and Tseng, D}, title = {Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {7}, pages = {}, doi = {10.1136/jitc-2025-011907}, pmid = {40664448}, issn = {2051-1426}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/pathology/mortality ; *Lung Neoplasms/drug therapy/immunology/pathology/mortality ; Female ; *Aspartic Acid Endopeptidases/immunology/metabolism ; Male ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Middle Aged ; Aged ; *T-Lymphocytes/immunology ; *Immunotherapy/methods ; Aged, 80 and over ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.
METHODS: Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.
RESULTS: Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).
CONCLUSIONS: Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.}, }
@article {pmid40663785, year = {2025}, author = {Brooks, TR and Zabor, EC and Bedelu, Y and Yang, X and Karimi, YH and Nedved, AN and Wang, Y and Dave, NK and Landsburg, DJ and Baron, K and Hu, B and Trotier, D and Pophali, PA and Miller, J and Grover, NS and Reinert, C and Major, A and Schwarz, T and Patel, K and Salafian, K and Ayers, EC and Sundaram, S and Brody, JD and McKenna, M and Tiger, YKR and Sears-Smith, M and Ghosh, N and Peterson, C and Khan, C and Bliven, SP and Narkhede, M and Gibson, A and Kline, J and Munoz, J and Garza Morales, R and Ho, C and Smith, SD and Niu, A and Hernandez-Ilizaliturri, FJ and Chinyengetere, F and Dave, SS and Abdel-Razeq, N and Alhaj Moustafa, M and Caimi, P and Hill, BT}, title = {Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025029117}, pmid = {40663785}, issn = {1528-0020}, abstract = {Epcoritamab and glofitamab are CD20-directed bispecific antibodies approved in the US for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between January 1, 2023 and October 15, 2024 were collected from 21 US institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (mPFS) was 2.6 months (95% confidence interval [CI] 2.0 to 3.8 months), and median overall survival (mOS) was 7.8 months (95% CI 6.2 to 11.0 months). The 6-month PFS was 36% (95% CI 30% to 44%) and the 6-month OS was 60% (95% CI 54% to 67%). Both trial ineligibility and undetectable CD20 pre-bispecific portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after bispecifics with a median time to progression of 3.7 months. This analysis including R/R DLBCL patients shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 was associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL and underscore the importance of target antigen expression.}, }
@article {pmid40662973, year = {2025}, author = {Oviedo, F and Kazerouni, AS and Liznerski, P and Xu, Y and Hirano, M and Vandermeulen, RA and Kloft, M and Blum, E and Alessio, AM and Li, CI and Weeks, WB and Dodhia, R and Lavista Ferres, JM and Rahbar, H and Partridge, SC}, title = {Cancer Detection in Breast MRI Screening via Explainable AI Anomaly Detection.}, journal = {Radiology}, volume = {316}, number = {1}, pages = {e241629}, doi = {10.1148/radiol.241629}, pmid = {40662973}, issn = {1527-1315}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; Middle Aged ; *Artificial Intelligence ; Breast/diagnostic imaging ; Adult ; Aged ; *Image Interpretation, Computer-Assisted/methods ; Early Detection of Cancer/methods ; Sensitivity and Specificity ; }, abstract = {Background Artificial intelligence (AI) models hold potential to increase the accuracy and efficiency of breast MRI screening; however, existing models have not been rigorously evaluated in populations with low cancer prevalence and lack interpretability, both of which are essential for clinical adoption. Purpose To develop an explainable AI model for cancer detection at breast MRI that is effective in both high- and low-cancer-prevalence settings. Materials and Methods This retrospective study included 9738 breast MRI examinations from a single institution (2005-2022), with external testing in a publicly available multicenter dataset (221 examinations). In total, 9567 consecutive examinations were used to develop an explainable fully convolutional data description (FCDD) anomaly detection model to detect malignancies on contrast-enhanced MRI scans. Performance was evaluated in three cohorts: grouped cross-validation (for both balanced [20.0% malignant] and imbalanced [1.85% malignant] detection tasks), an internal independent test set (171 examinations), and an external dataset. Explainability was assessed through pixelwise comparisons with reference-standard malignancy annotations. Statistical significance was assessed using the Wilcoxon signed rank test. Results FCDD outperformed the benchmark binary cross-entropy (BCE) model in cross-validation for both balanced (mean area under the receiver operating characteristic curve [AUC] = 0.84 ± 0.01 [SD] vs 0.81 ± 0.01; P < .001) and imbalanced (mean AUC = 0.72 ± 0.03 vs 0.69 ± 0.03; P < .001) detection tasks. At a fixed 97% sensitivity in the imbalanced setting, mean specificity across folds was 13% for FCDD and 9% for BCE (P = .02). In the internal test set, FCDD outperformed BCE for balanced (mean AUC = 0.81 ± 0.02 vs 0.72 ± 0.02; P < .001) and imbalanced (mean AUC = 0.78 ± 0.05 vs 0.76 ± 0.01; P < .02) detection tasks. For model explainability, FCDD demonstrated better spatial agreement with reference-standard annotations than BCE (internal test set: mean pixelwise AUC = 0.92 ± 0.10 vs 0.81 ± 0.13; P < .001). External testing confirmed that FCDD performed well, and better than BCE, in the balanced detection task (AUC = 0.86 ± 0.01 vs 0.79 ± 0.01; P < .001). Conclusion The developed explainable AI model for cancer detection at breast MRI accurately depicted tumor location and outperformed commonly used models in both high- and low-cancer-prevalence scenarios. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Bae and Ham in this issue.}, }
@article {pmid40661112, year = {2025}, author = {Read, C and Bhatia, S and Totonchy, M}, title = {Programmed cell death 1 blockade in the setting of severe ocular sarcoidosis: Cancer immunotherapy in a patient with autoimmunity.}, journal = {JAAD case reports}, volume = {62}, number = {}, pages = {43-45}, pmid = {40661112}, issn = {2352-5126}, }
@article {pmid40660865, year = {2025}, author = {Hope, A and Mundis, M and Sonke, JJ and Kang, J and Korreman, S and Napolitano, B and Elguindi, S and Joiner, MC and Burmeister, J and Dominello, MM}, title = {Three discipline collaborative radiation therapy (3DCRT) special debate: AI structure segmentation is better than clinician contouring for both OARs and targets.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {7}, pages = {e70183}, doi = {10.1002/acm2.70183}, pmid = {40660865}, issn = {1526-9914}, }
@article {pmid40659309, year = {2025}, author = {Ehret, F and Ebner, DK and Kutuk, T and Shakeri, A and Shrestha, S and Skalina, KA and Fekrmandi, F and Lo, SS and Gore, JL and Kotecha, R and Lee, P and Slotman, BJ and Fürweger, C and Muacevic, A and Siva, S and Reddy, K}, title = {Stereotactic Body Radiotherapy for the Treatment of Adrenal Metastases - A Case-Based Radiosurgery Society Practice Guide and Review.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2025.06.011}, pmid = {40659309}, issn = {1879-8519}, abstract = {PURPOSE: Adrenal metastases are frequently diagnosed in patients with common solid tumors. Surgical adrenalectomy has historically been used for their management. However, stereotactic body radiotherapy (SBRT) has emerged as a safe and effective alternative. Careful treatment planning is essential, considering multiple factors such as tumor size and location, motion management, dose and fractionation, and proximity to adjacent organs at risk. This case-based practice guide and review provides an overview of SBRT for the management of adrenal tumors, with a particular focus on adrenal metastases.
METHODS AND MATERIALS: Three clinical scenarios were selected to illustrate the use of SBRT in managing adrenal tumors. These include a small right-sided metastasis treated with single-fraction, fiducial-based SBRT, a large left-sided metastasis treated with fractionated SBRT under magnetic resonance imaging guidance, and a case of bilateral metastases, which emphasizes the potential risk of adrenal insufficiency. We also address the limited evidence available regarding the management of primary adrenal gland tumors with SBRT.
RESULTS: SBRT is an effective treatment modality for most adrenal tumors, demonstrating a favorable safety profile. Thoughtful treatment planning and an understanding of potential pitfalls, limitations, and risks are essential to ensure the appropriate use of SBRT.
CONCLUSIONS: This case-based guide and review provides a comprehensive overview of SBRT for treating adrenal tumors, specifically metastases. We present and discuss clinical cases and relevant literature, highlighting key considerations specific to adrenal SBRT.}, }
@article {pmid40658949, year = {2025}, author = {Tsai, CS and Szewczyk, W and Drerup, M and Liao, J and Vasbinder, A and Greenlee, H and Heffner, JL and Yung, R and Reding, KW}, title = {A Personalized, Texting-Based Conversational Agent to Address Sleep Disturbance in Individuals Who Have Survived Breast Cancer: Protocol for a Pilot Waitlist Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e62712}, doi = {10.2196/62712}, pmid = {40658949}, issn = {1929-0748}, mesh = {Humans ; *Text Messaging ; *Breast Neoplasms/complications/psychology ; Female ; Pilot Projects ; *Cancer Survivors/psychology ; Quality of Life ; *Cognitive Behavioral Therapy/methods ; Adult ; *Sleep Initiation and Maintenance Disorders/therapy/etiology ; *Sleep Wake Disorders/therapy/etiology ; Randomized Controlled Trials as Topic ; Middle Aged ; }, abstract = {BACKGROUND: Sleep disturbance is one of the most common health concerns reported by individuals who have survived breast cancer (BC) and is associated with poor quality of life (QoL) and greater mortality after treatment. Cognitive behavioral therapy for insomnia (CBTi) has shown efficacy for improving sleep and QoL for this population. Considered the gold standard for insomnia treatment, CBTi can be delivered remotely, including via digital intervention. Despite the potential for wider dissemination of CBTi via digital means, these modalities have unique challenges, including technology barriers and poor adherence. We developed a conversational agent (CA) to deliver CBTi via a SMS text messaging intervention, supported by mobile-ready web content. Named "Cecebot," this CA delivers sleep education, implements sleep compression, provides just-in-time interventions for sleep-disrupting behaviors, and includes enhanced support for physical activity (PA) beyond what is typically included in CBTi. This represents a novel modality for a CBTi and PA intervention among individuals who have survived BC.
OBJECTIVE: We aim to examine the safety and acceptability of the Cecebot intervention, developed by an academic partnership between Dr Reding's research team and Moby Inc, for individuals who have survived BC and experience symptoms of insomnia, and to explore its efficacy.
METHODS: This trial will recruit 60 individuals who have survived BC and are experiencing moderate to severe sleep disturbance. Participants will be assigned to the Cecebot intervention or waitlist control group at a 1:1 ratio. The treatment group will receive the Cecebot intervention during weeks 1-6 of the study, while the waitlist control condition will receive the Cecebot intervention during weeks 6-12. The Cecebot intervention uses SMS text messaging technology paired with a Fitbit. Participants will be assessed at baseline, week 6, and week 12. Measurements will include feasibility and acceptability and will explore the effect of the Cecebot intervention. Feasibility will be assessed through recruitment, enrollment, and retention rates. Acceptability will be evaluated using a satisfaction survey and open-ended responses. Quantitative analysis, such as t test, Fisher exact tests, and generalized linear models, will be used to assess feasibility, baseline group differences, and the outcomes of the intervention.
RESULTS: Recruitment of participants began in Fall 2024. The completion of data collection is anticipated to be by Fall 2025.
CONCLUSIONS: The study results will give insight into the potential for an SMS text messaging-based CA to improve sleep in individuals who have survived BC and experience sleep disturbances.
TRIAL REGISTRATION: ClinicalTrials.gov NCT06392789; https://clinicaltrials.gov/study/NCT06392789.
DERR1-10.2196/62712.}, }
@article {pmid37333272, year = {2025}, author = {Ishida, T and Mercoli, J and Heck, AM and Phelps, I and Varnum-Finney, B and Dozono, S and Nourigat-McKay, C and Kraskouskas, K and Wellington, R and Waltner, O and Jackson, DL and Delaney, C and Rafii, S and Bernstein, ID and Aldinger, KA and , and Trapnell, C and Zhao, HG and Hadland, B}, title = {Differentiation latency, cell division symmetry, and dormancy signatures define fetal liver HSCs at single cell resolution.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37333272}, issn = {2692-8205}, support = {K08 HL140143/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; RC2 DK114777/DK/NIDDK NIH HHS/United States ; }, abstract = {Decoding the gene regulatory mechanisms and signaling interactions that orchestrate the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. Here, to explore intrinsic and extrinsic regulation of FL-HSC self-renewal at the single cell level, we engineered a culture platform designed to recapitulate the FL endothelial niche, which supports the ex vivo amplification of serially engraftable HSCs. Leveraging this platform in combination with single cell index flow cytometry, live imaging, serial transplantation assays, and single cell RNA-sequencing, we uncovered previously unrecognized heterogeneity within immunophenotypically defined FL-HSCs. Specifically, we demonstrated that differentiation latency, symmetric cell divisions, and transcriptional signatures of biosynthetic dormancy and lipid metabolism are distinguishing properties of rare FL-HSCs capable of serial, long-term multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and extrinsic signals combinatorially facilitate the symmetric self-renewal and expansion of nascent HSCs in the FL niche while delaying their active participation in hematopoiesis. Additionally, our study provides a valuable resource for future investigations into the intrinsic and niche-derived signaling pathways that govern FL-HSC self-renewal.}, }
@article {pmid40658837, year = {2025}, author = {McGrosky, A and Luke, A and Arab, L and Bedu-Addo, K and Bonomi, AG and Bovet, P and Brage, S and Buchowski, MS and Butte, N and Camps, SG and Casper, R and Cummings, DK and Krupa Das, S and Deb, S and Dugas, LR and Ekelund, U and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and Hambly, C and Joosen, A and Katzmarzyk, PT and Kempen, KP and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Medin, AC and Neuhouser, ML and Pietilainen, KH and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, L and Reynolds, RM and Rimm, EB and Roberts, S and Rosinger, AY and Samuels, MH and Sinha, S and Snodgrass, JJ and Stice, E and Uauy, R and Urlacher, SS and Verbunt, JA and Wolfe, B and Wood, B and Zhang, X and Murphy-Alford, AJ and Loechl, CJ and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Yamada, Y and Speakman, JR and Pontzer, H and , }, title = {Energy expenditure and obesity across the economic spectrum.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {29}, pages = {e2420902122}, doi = {10.1073/pnas.2420902122}, pmid = {40658837}, issn = {1091-6490}, support = {BCS-1824466//National Science Foundation (NSF)/ ; CAS 153E11KYSB20190045//Chinese Academy of Sciences (CAS)/ ; }, mesh = {Humans ; *Obesity/epidemiology/metabolism/economics ; *Energy Metabolism/physiology ; Body Mass Index ; Adult ; Male ; Female ; Middle Aged ; Energy Intake ; Life Style ; }, abstract = {Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.}, }
@article {pmid40658414, year = {2025}, author = {Kanaya, AM and Anderson, GL}, title = {MOSAAIC to Capture Key Measures of Aging Across the Lifespan.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamainternmed.2025.2908}, pmid = {40658414}, issn = {2168-6114}, }
@article {pmid40656602, year = {2025}, author = {Shadman, M and Brown, JR and Williams, R and Mohseninejad, L and Yang, K and Rakonczai, P and Lamanna, N and Xu, S and Cleary Cohen, A and O'Brien, SM and Tedeschi, A and Tam, CS}, title = {Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).}, journal = {Therapeutic advances in medical oncology}, volume = {17}, number = {}, pages = {17588359251340554}, pmid = {40656602}, issn = {1758-8340}, abstract = {BACKGROUND: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).
OBJECTIVE: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.
DESIGN: An unanchored matching-adjusted indirect comparison (MAIC) was performed.
METHODS: Individual patient-level data from ALPINE (zanubrutinib) were reweighted using prognostic/effect-modifying variables to match aggregate data from ASCEND (acalabrutinib). MAIC outcomes included investigator-assessed progression-free survival (PFS-INV), overall survival (OS), and complete response (CR).
RESULTS: Post-matching, PFS-INV was improved significantly for zanubrutinib versus acalabrutinib (hazard ratio (HR) = 0.68 (95% confidence interval (CI): 0.46-0.99); p = 0.0448) and OS showed a trend toward improvement for zanubrutinib (HR = 0.60; 95% CI: 0.35-1.02, p = 0.0575). CR was significantly higher for zanubrutinib versus acalabrutinib (odds ratio = 2.90 (95% CI: 1.13-7.43); p = 0.0270).
CONCLUSION: Zanubrutinib was associated with a significant PFS-INV and CR advantage over acalabrutinib, with a trend toward improvement in OS.}, }
@article {pmid40656459, year = {2025}, author = {Zhang, T and Ameen, S and Ghosh, S and Kim, K and Pandey, M and Cheung, BCH and Thanh, M and Patteson, AE and Wu, M and Schwarz, JM}, title = {Enhanced extracellular matrix remodeling due to embedded spheroid fluidization.}, journal = {New journal of physics}, volume = {27}, number = {7}, pages = {073301}, pmid = {40656459}, issn = {1367-2630}, abstract = {Embedding a collective of tumor cells, i.e. a tumor spheroid, in a fibrous environment, such as a collagen network, provides an essential in vitro platform to investigate the biophysical mechanisms of tumor invasion. To predict new mechanisms, we develop a three-dimensional computational model of an embedded spheroid using a vertex model, with cells represented as deformable polyhedrons, mechanically coupled to a fiber network via active linker springs. As the linker springs actively contract, the fiber network remodels. As we tune the rheology of the spheroid and the fiber network stiffness, we find that both factors affect the remodeling of the fiber network with fluid-like spheroids densifying and radially realigning the fiber network more on average than solid-like spheroids but only for a range of intermediate fiber network stiffnesses. Our predictions are supported by experimental studies comparing non-tumorigenic MCF10A spheroids and malignant MDA-MB-231 spheroids embedded in collagen networks. The spheroid rheology-dependent effects are the result of cellular motility generating spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network. This emergent feedback occurs only at intermediate fiber network stiffness since at low fiber network stiffness, the mechanical response of the coupled system is dominated by the spheroid and for high fiber network stiffness, the mechanical response is dominated by the fiber network. We are therefore able to quantify the regime of optimal spheroid-fiber network mechanical reciprocity. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.}, }
@article {pmid40655537, year = {2025}, author = {Krawczuk, P and Fox, ZR and Petkov, V and Negoita, S and Doherty, J and Stroup, A and Schwartz, S and Penberthy, L and Hsu, E and Gounley, J and Hanson, HA}, title = {Large-scale deep learning for metastasis detection in pathology reports.}, journal = {JAMIA open}, volume = {8}, number = {4}, pages = {ooaf070}, pmid = {40655537}, issn = {2574-2531}, abstract = {OBJECTIVES: No existing algorithm can reliably identify metastasis from pathology reports across multiple cancer types and the entire US population. In this study, we develop a deep learning model that automatically detects patients with metastatic cancer by using pathology reports from many laboratories and of multiple cancer types.
MATERIALS AND METHODS: We use 60 471 unstructured pathology reports from 4 Surveillance, Epidemiology, and End Results (SEER) registries. The reports were coded into 1 of 3 labels: metastasis negative, metastases positive, or metastasis undetermined. We utilize a task-specific deep neural network trained from scratch and compare its performance with a widely used large language model (LLM).
RESULTS: Our deep learning architecture trained on task-specific data outperforms a general-purpose LLM, with a recall of 0.894 compared to 0.824. We quantified model uncertainty and used it to defer reports for human review. We found that retaining 72.9% of reports increased recall from 0.894 to 0.969.
DISCUSSION: A smaller deep learning architecture trained on task-specific data outperforms a general LLM. Equally critical to model performance is the incorporation of uncertainty quantification, achieved here through an abstention mechanism.
CONCLUSIONS: This study's finding demonstrate the feasibility of developing algorithms to automatically identify metastatic cancer cases from unstructured pathology reports.}, }
@article {pmid40650496, year = {2025}, author = {Smith, D and Fleming, T and Gianella, S and Halloran, E and Hillier, S and Longini, I and Smeaton, L and DeGruttola, V}, title = {Salvaging information from paused or stopped clinical studies.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745251353429}, doi = {10.1177/17407745251353429}, pmid = {40650496}, issn = {1740-7753}, }
@article {pmid40646132, year = {2025}, author = {Apperley, JF and Milojkovic, D and Cross, NCP and Hjorth-Hansen, H and Hochhaus, A and Kantarjian, H and Lipton, JH and Malhotra, H and Niederwieser, D and Radich, J and Rousselot, P and Saussele, S and Schiffer, CA and Silver, R and Soverini, S and Stenke, L and Turkina, A and Casado, LF and Castagnetti, F and Cervantes, F and Clark, RE and Cortes, J and Deininger, M and Hughes, TP and Janssen, J and Jiang, Q and Kim, DW and Larson, RA and Mahon, FX and Mauro, M and Mayer, J and Nicolini, FE and Pane, F and Rea, D and Richter, J and Rosti, G and Saglio, G and Hehlmann, R}, title = {2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {40646132}, issn = {1476-5551}, abstract = {In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.}, }
@article {pmid39713402, year = {2025}, author = {Ellison, ST and Hayman, I and Derr, K and Derr, P and Frebert, S and Itkin, Z and Shen, M and Jones, A and Olson, W and Corey, L and Wald, A and Johnston, C and Fong, Y and Ferrer, M and Zhu, J}, title = {Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713402}, issn = {2692-8205}, support = {R01 AI143773/AI/NIAID NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; U18 TR003208/TR/NCATS NIH HHS/United States ; }, abstract = {Herpes simplex virus (HSV) infection has worldwide public health concerns and lifelong medical impacts. The standard therapy, acyclovir, has limited efficacy in preventing HSV subclinical virus shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. HSV manifests in the skin and mucosal epithelium. Here, we found acyclovir significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. To recapitulate in vivo tissue architecture, we 3D bioprinted human skin equivalents (HSE) in a 96-well plate format amenable for antiviral screening and preclinical testing. We screened a library of 738 compounds with broad targets and mechanisms of action and identified potent antivirals, including 23 known or experimental HSV treatments, validating the translational relevance of our assay. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways displayed similar potency across cell types and donor sources in 2D and 3D models. Our 3D bioprinted platform allowed for integrating patient-derived cells and incorporating genetic variability early in drug development. The reduced potency in keratinocytes helps explain the limited benefit acyclovir and its congeners play in reducing sexual transmission. These data indicate that the 3D bioprinted HSE assay platform provides a more physiologically relevant approach to identifying potential antivirals for HSV.}, }
@article {pmid39574839, year = {2025}, author = {Chang, YH and Bresnahan, ST and Head, ST and Harrison, T and Yu, Y and Huff, CD and Pasaniuc, B and Lindström, S and Bhattacharya, A}, title = {Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574839}, support = {R01 CA194393/CA/NCI NIH HHS/United States ; R21 CA293419/CA/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; }, abstract = {Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify mediators for genetic risk of cancer. Traditional methods often are insufficient as they rely on total gene expression measures and overlook alternative splicing, which generates different transcript-isoforms with potentially distinct effects. Here, we integrate multi-tissue isoform expression data from the Genotype Tissue-Expression Project with GWAS summary statistics (all N > 20,000 cases) to identify isoform- and gene-level associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Directly modeling isoforms using transcriptome-wide association studies (isoTWAS) significantly improves discovery of genetic associations compared to gene-level approaches, identifying 164% more significant associations (6,163 vs. 2,336) with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes. isoTWAS tags transcriptomic associations at 52% more independent GWAS loci across the six cancers. Isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression. We highlight several isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the importance of modeling isoforms to maximize discovery of genetic risk mechanisms for cancers.}, }
@article {pmid39071291, year = {2025}, author = {Frank, S and Persse, T and Coleman, I and Bankhead, A and Li, D and De-Sarkar, N and Wilson, D and Rudoy, D and Vashisth, M and Galipeau, P and Yang, M and Hanratty, B and Dumpit, R and Morrissey, C and Corey, E and Montgomery, RB and Haffner, MC and Pritchard, CC and Vasioukhin, V and Ha, G and Nelson, PS}, title = {Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071291}, issn = {2692-8205}, support = {F32 CA243286/CA/NCI NIH HHS/United States ; R21 CA277368/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, abstract = {Genomic loss of the transcriptional kinase CDK12 occurs in ~6% of metastatic castration-resistant prostate cancers (mCRPC) and correlates with poor patient outcomes. Prior studies demonstrate that acute CDK12 loss confers a homologous recombination (HR) deficiency (HRd) phenotype via premature intronic polyadenylation (IPA) of key HR pathway genes, including ATM. However, mCRPC patients have not demonstrated benefit from therapies that exploit HRd such as inhibitors of polyADP ribose polymerase (PARP). Based on this discordance, we sought to test the hypothesis that an HRd phenotype is primarily a consequence of acute CDK12 loss and the effect is greatly diminished in prostate cancers adapted to CDK12 loss. Analyses of whole genome sequences (WGS) and RNA sequences (RNAseq) of human mCRPCs determined that tumors with biallelic CDK12 alterations (CDK12 [BAL]) lack genomic scar signatures indicative of HRd, despite carrying bi-allelic loss and the appearance of the hallmark tandem-duplicator phenotype (TDP). Experiments confirmed that acute CDK12 inhibition resulted in aberrant polyadenylation and downregulation of long genes (including BRCA1 and BRCA2) but such effects were modest or absent in tumors adapted to chronic CDK12 [BAL] . One key exception was ATM, which did retain transcript shortening and reduced protein expression in the adapted CDK12 [BAL] models. However, CDK12 [BAL] cells demonstrated intact HR as measured by RAD51 foci formation following irradiation. CDK12 [BAL] cells showed a vulnerability to targeting of CDK13 by sgRNA or CDK12/13 inhibitors and in vivo treatment of prostate cancer xenograft lines showed that tumors with CDK12 [BAL] responded to the CDK12/13 inhibitor SR4835, while CDK12-intact lines did not. Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.}, }
@article {pmid39005367, year = {2025}, author = {Gao, Y and Feder, AF}, title = {Detecting branching rate heterogeneity with tree balance statistics in lineage tracing trees.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005367}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; }, abstract = {Understanding variation in cellular growth rates among cells in tumors is crucial for predicting cancer progression and interpreting tumor-derived genetic data. Advances in lineage tracing technologies enable the reconstruction of high-resolution, single-cell phylogenies of cancer cell populations, but methods to detect cellular growth rate differences on these phylogenies remain limited. Tree balance statistics offer a way forward, but it is unknown if and how these statistics are distorted when applied to phylogenetic reconstructions built from lineage tracing data, and if these distortions limit the utility of tree balance statistics to distinguish between evolutionary scenarios characterized by variable or homogeneous cellular growth rates. Here, we examined two tree balance statistics, J 1 and the Sackin index, and benchmarked their performance in distinguishing lineage tracing trees derived from populations with and without variable cellular growth rates. We found that when tumor population sizes and lineage tracing editing rates are approximately known and in favorable ranges, J 1 detects departures from homogenous growth rates just as well on lineage tracing trees as on true genealogical trees, while the Sackin index loses most of its power even under the most favorable conditions. We applied our J 1 -based test to data derived from cancer lineage tracing experiments and found widespread signals of growth rate heterogeneity in murine autochthonous lung cancers, and lung and PDAC xenograft experiments in mice. Our results demonstrate the potential and challenges of tree balance statistics in analyzing growth dynamics in lineage tracing data.}, }
@article {pmid40645851, year = {2025}, author = {Huang, J and Shadman, M}, title = {First-line Therapy: Time-Limited Venetoclax Doublet Therapy.}, journal = {Hematology/oncology clinics of North America}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.hoc.2025.05.007}, pmid = {40645851}, issn = {1558-1977}, abstract = {Studies examining venetoclax in combination with anti-CD20 monoclonal antibodies and covalent Bruton tyrosine kinase inhibitors (BTKi) demonstrated a progression-free survival and in some cases overall survival benefit over chemoimmunotherapy. It is currently unclear what is the most optimal combination partner for a B-cell leukemia/lymphoma 2 inhibitor (BCL2i). We are eagerly awaiting results from studies to determine the most effective BCL2i and BTKi combination for the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma given the development of second-generation drugs.}, }
@article {pmid40645186, year = {2025}, author = {Chiou, SH and Tseng, D}, title = {Blood TCRs go to town with early NPC detection.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2025.06.016}, pmid = {40645186}, issn = {1878-3686}, abstract = {In this issue of Cancer Cell, Zhang et al. report an innovative approach utilizing patients' blood T cell receptor (TCR) sequences for the early detection of nasopharyngeal cancer. This study highlights the potential of harnessing highly public TCRs in the peripheral blood as biomarkers for virally associated malignancies.}, }
@article {pmid40644338, year = {2025}, author = {Koric, A and Chang, CE and Lee, YA and Wei, M and Lee, C and Wang, J and Hashibe, M}, title = {Incident depression after breast cancer among older Asian, Native Hawaiian, and Pacific Islander women.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkaf066}, pmid = {40644338}, issn = {2515-5091}, abstract = {INTRODUCTION: Longitudinal studies focusing on the mental health of older (≥66 years) Asian, Native Hawaiian, and Pacific Islander (ANHPI) women diagnosed with breast cancer are limited. We evaluated incident depression after breast cancer among specific groups of older ANHPI compared with older non-Hispanic White (NHW) women. Predictors of depression and the risk of death following early onset of depression after breast cancer were also evaluated.
METHODS: A cohort of 26,776 older ANHPI women in the US diagnosed with breast cancer between 2000-2017 was identified from the SEER-Medicare linked claims. There were 6,694 older ANHPI and 20,082 older NHW women diagnosed with breast cancer. Adjusted hazard ratios (HRs) were assessed using Cox proportional hazards model with 99% confidence intervals (CI) to evaluate incident depression and death among older ANHPI compared with age-matched NHW counterparts.
RESULTS: Compared with older NHW women with breast cancer, older Japanese (HR = 0.43, 99%CI 0.31, 0.66), Chinese (HR = 0.46, 99%CI 0.31, 0.67), Filipino (HR = 0.43, 99%CI 0.30, 0.60), and Asian Indian/Pakistani women (HR = 0.49, 99%CI 0.28, 0.84) had a lower risk of depression overall and within 5 years of follow-up; lower risk persisted for Japanese and Chinese women >5 years. ANHPI breast cancer patients with early onset of depression had a higher risk of death (HR = 1.46, 99%CI 1.30, 1.65) compared to those without depression.
CONCLUSION: Compared with older NHW women, older ANHPI women had a lower incidence of depression, although disentangling the stigma surrounding depression by race and ethnicity remains challenging.}, }
@article {pmid40641655, year = {2025}, author = {Chakraborty, H and Sun, Q and Bhupathiraju, SN and Schenk, JM and Mishchuk, DO and Bain, JR and He, X and Sun, J and Harnly, J and Simmons, W and Raftery, D and Liang, L and Newman, JW and Fiehn, O and Clish, CB and Lampe, JW and Bennett, BJ and Navarro, SL and Wang, Y and Zheng, C and Mossavar-Rahmani, Y and McCullough, ML and Huang, Y and Shojaie, A and Zhu, W and Djukovic, D and Sacks, F and Williams, J and Steinberg, FM and Adams, SH and Hu, FB and Neuhouser, ML and Slupsky, CM and Maruvada, P}, title = {The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition.}, journal = {Current developments in nutrition}, volume = {9}, number = {5}, pages = {107435}, pmid = {40641655}, issn = {2475-2991}, abstract = {UNLABELLED: Diet is a complex exposure that affects health across the lifespan. Objective biomarkers that can reliably reflect intake of nutrients, foods, and dietary patterns with sufficient accuracy are an important tool for assessing associations of diet with health outcomes. Advances in metabolomics, coupled with feeding trials and high-dimensional bioinformatics analyses, pave the way for discovering compounds that can serve as sensitive and specific biomarkers of dietary exposures. The Dietary Biomarkers Development Consortium (DBDC) is leading the first major effort to improve dietary assessment through the discovery and validation of biomarkers for foods commonly consumed in the United States diet. To achieve this goal, a 3-phase approach will be implemented to identify, evaluate, and validate food biomarkers. In phase 1, 3 controlled feeding trial designs will be implemented by administering test foods in prespecified amounts to healthy participants, followed by metabolomic profiling of blood and urine specimens collected during the feeding trials to identify candidate compounds. Data from these studies will characterize the pharmacokinetic parameters of candidate biomarkers associated with specific foods. In phase 2, the ability of candidate biomarkers to identify individuals eating the biomarker-associated foods will be evaluated using controlled feeding studies of various dietary patterns. In phase 3, the validity of candidate biomarkers to predict recent and habitual consumption of specific test foods will be evaluated in independent observational settings. Data generated during all study phases will be archived in a publicly accessible database as a resource for the research community. The DBDC aims to significantly expand the list of validated biomarkers of intake for foods consumed in the United States diet, which can help advance understanding of how diet influences human health. This manuscript discusses the DBDC's organizational infrastructure, study design, laboratory methods, and strategies for dietary biomarker discovery and validation.
TRIAL REGISTRATION NUMBER: This trial was registered at Phase 1 Seattle Dietary Biomarkers Development Center (P1-SDBDC) as NCT05580653, at Fruit and Vegetable Biomarker Discovery (UCD-DBDC) as NCT05621863, and at Dietary Biomarkers Intervention Core as NCT05616585.}, }
@article {pmid40640959, year = {2025}, author = {Cai, Y and Johnson, M and Haessler, J and Molstad, AJ and Hwang, SJ and Joehanes, R and Murabito, JM and Tahir, UA and Franceschini, N and Gerszten, RE and Sun, W and Levy, D and Raffield, LM and Kooperberg, C and Hsu, L and Reiner, AP}, title = {Protein quantitative trait locus analysis in African American and non-Hispanic White individuals.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {200}, pmid = {40640959}, issn = {1474-760X}, support = {R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; K08 HL161445-01A1/GF/NIH HHS/United States ; HHSN268201600034I, HL133870/GF/NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; }, abstract = {BACKGROUND: Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry.
RESULTS: We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women's Health Initiative and Framingham Heart Study. For replication of candidate pQTLs, we use data from 534 self-identified AA adults from the Jackson Heart Study and protein genome-wide association analysis statistics from the UK Biobank Pharma Proteomics Project, including 54,219 participants, of whom 931 are of African ancestry. In total, we identify and validate 5103 pQTLs (4496 or 88% cis- and 602 or 12% trans-pQTLs) for 983 proteins. Among these, 195 are previously unreported, with most (166 or 85%) identified in our AA sample, many of which were essentially monomorphic in European reference populations. Several of these newly identified African ancestry-specific pQTLs have been reported in ClinVar; our results suggest impact on circulating protein levels, potentially bolstering evidence for clinical significance. We identify a "cis pQTL hotspot" within the leukocyte receptor gene cluster on human chromosome 19q13.4. We also provide examples where a particular cis-pQTL, identified through conditional analysis, offers biological insights into an overlapping GWAS signal for disease susceptibility.
CONCLUSIONS: The identification of previously undescribed African ancestry-specific pQTLs contributes to understanding protein genetic regulation and highlights the significance of proteomic analysis in diverse populations.}, }
@article {pmid40639916, year = {2025}, author = {Zheng, C and Casjens, SR and Davidson, AR and Amundsen, SK and Smith, GR}, title = {Lambdoid phages with abundant Chi recombination hotspots reflect diverse viral strategies for recombination-dependent growth.}, journal = {Genome research}, volume = {}, number = {}, pages = {}, doi = {10.1101/gr.280248.124}, pmid = {40639916}, issn = {1549-5469}, abstract = {Many phages encode recombination-mediating enzymes, but characterization of their roles in phage lifecycles is limited, and their impact on phage replication is controversial. To address these issues, we have searched for phages whose growth is impacted by the major recombination-promoting helicase-nuclease of Escherichia coli, the RecBCD enzyme. Although no phages inhibited by RecBCD are identified, growth of a newly isolated phage, named LLS, is enhanced by RecBCD. LLS's genome sequence reveals it is related to bacteriophage λ but encodes no recombination-promoting (Rec) proteins or associated RecBCD inhibitor. However, it contains an unexpectedly high number of Chi sites, activators of RecBCD-dependent recombination. Through analysis of 325 genomes of phages related to λ (lambdoid phages), we have found 71 other phage genomes that encode no Rec proteins but mostly possess large numbers of Chi sites. Conversely, phages encoding Rec proteins and a RecBCD inhibitor (collectively a Rec module) mostly lack Chi sites. Lambdoid phages of both diverse enteric bacteria and a pseudomonad have these properties. For this study, we thoroughly analyze the Rec modules of 246 lambdoid phage genomes. These analyses reveal a remarkable heterogeneity of Rec module protein types, both in sequence and in function, and allow us to identify phages that do not contain Rec modules. We conclude that phages lacking their own recombination systems have compensated by becoming enriched in Chi sites, enabling them to use the host's RecBCD to fulfill the requirement for recombination to efficiently replicate. This study highlights the importance of recombination for phage survival and the diversity of strategies to achieve it.}, }
@article {pmid40639796, year = {2025}, author = {Parnes, M and Gonzalez, E and Tran, N and Stein, MA and Mendoza, J and Tandon, P}, title = {Adherence to 24-Hour Movement Guidelines and Behavioral Health in Children With Attention Deficit Hyperactivity Disorder in the United States.}, journal = {Journal of physical activity & health}, volume = {}, number = {}, pages = {1-10}, doi = {10.1123/jpah.2024-0497}, pmid = {40639796}, issn = {1543-5474}, abstract = {BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a 24-hour disorder that both impacts, and, is impacted by, daily activity and sleep. Children with ADHD are less likely to meet recommended 24-hour movement guidelines (ie, on average 60 min of moderate to vigorous physical activity and several hours of light activity per day, less than 2 h of screen time, and 9-11 h of sleep). The current study examined associations between meeting 24-hour movement guidelines with ADHD symptoms, sleep problems, and media use.
METHODS: Accelerometer data measured physical activity and sleep among a sample of 93 children with ADHD (mean age = 8.10, SDage = 1.37, 58.9% male). Parent-report measures assessed ADHD symptoms, sleep difficulties, and media use. Multivariate analysis of covariance analyses explored associations between meeting 24-hour movement guidelines and outcomes. Latent class analysis (LCA) identified unique combinations of 24-hour movement guideline adherence. Associations were examined between classes and outcomes.
RESULTS: Overall, 41.5% of children met physical activity guidelines, 23.4% met sedentary behavior guidelines, and 45.7% met sleep guidelines. Multivariate analysis of covariance analyses found that meeting more guidelines was associated with less sleep difficulties and problematic media use. LCA revealed 2 classes: Hypoactive children who were unlikely to meet activity guidelines and Work Hard, Play Hard children who were likely to meet activity and sleep guidelines. Children in the Work Hard, Play Hard class had less bedtime resistance compared with the Hypoactive class.
CONCLUSION: Findings have implications for clinicians and caregivers supporting children with ADHD to take a holistic approach to improve health behaviors throughout the whole day.}, }
@article {pmid40637727, year = {2025}, author = {Dima, D and Logue, JM and Waqar, SHB and Peres, LC and Colin-Leitzinger, CM and De Avila, G and Smith, EC and Skelson, L and Matte, KL and Blue, B and Hovanky, VN and Gaballa, M and Pasvolsky, O and Oswald, LB and Fortuna, GGM and Wagner, CB and DeJarnette, S and Dillard, C and Perna, F and Mikkilineni, L and Hosoya, H and Freeman, CL and Shain, KH and Baz, RC and Grajales-Cruz, A and Puglianini, OC and Alsina, M and Locke, FL and Shune, LO and Sborov, DW and Patel, KK and Sidana, S and Hansen, DK}, title = {Cytopenias and infections following ciltacabtagene autoleucel in heavily-pretreated relapsed or refractory multiple myeloma.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.287783}, pmid = {40637727}, issn = {1592-8721}, abstract = {Ciltacabtagene autoleucel (cilta-cel) was FDA-approved in February 2022 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On CARTITUDE-1 trial, grade ≥3 cytopenias and infections were common. Herein, we sought to characterize cytopenias and infections after cilta-cel infusion in the standard-of-care setting. This multicenter retrospective study included 105 patients who received cilta-cel; 91 reached day-90 and 49 reached day-180 follow-up. Grade ≥3 cytopenia was present among 52% of patients on day-30, and 24% of patients on day-90. Based on the newer immune effector cell-associated hematotoxicity (ICAHT) grading for neutropenia severity, 11 patients (10%) experienced grade ≥3 early ICAHT in the first 30 days, while only 3 (3.3%) experienced grade ≥3 late ICAHT after day-30. On univariate analysis, any grade thrombocytopenia at apheresis was associated with grade ≥3 cytopenia at both days 30 and 90. Granulocyte colony-stimulating factor was administered to 65%, transfusion support to 38%, thrombopoietin agonists to 10%, intravenous immunoglobulin to 52%, and CD34+ stem cell boosts to 9.5% of patients. Infections occurred in 49% of patients and were severe in 32%. Earlier infections in the first 30 days were equally bacterial (42%) and viral (42%). Later infections between days 31-100 and after day 100 were mostly viral (59% and 60%), with only 32% and 12% being grade ≥3 at each time period. On univariate analysis, worse ECOG performance status at lymphodepletion, higher maximum grade of CRS, delayed neurotoxicity, steroid and anakinra use, and lower IgA levels at day 90 were associated with severe infections.}, }
@article {pmid40635049, year = {2025}, author = {Rosenthal, EA and Wei, WQ and Luo, Y and Namjou-Khales, B and Schaid, DJ and Esplin, ED and Lape, M and Kottyan, L and Pacheco, JA and Weng, C and Gordon, AS and Kullo, IJ and Crosslin, DR and Grady, WM and Hsu, L and Peters, U and Jarvik, GP}, title = {Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer.}, journal = {Human genomics}, volume = {19}, number = {1}, pages = {77}, doi = {10.1186/s40246-025-00791-0}, pmid = {40635049}, issn = {1479-7364}, support = {U01HG008657, U01HG008685, U01HG008672, U01HG008666, U01HG006379, U01HG008679 , U01HG008680 , U01HG008684 , U01HG008673 , U01HG008701 , U01HG008676 , U01HG008664 , U54MD007593/HG/NHGRI NIH HHS/United States ; }, abstract = {BACKGROUND: Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors may also underlie multiple phenotypes, including behavioral traits. In order to understand the biology of CRC risk better, it is important to understand the shared polygenic genetic architecture contributing to CRC risk and other phenotypes, including CRC associated risk factors.
METHODS: We investigated potential shared genetics by performing a Phenome-wide association study (PheWAS) with a multi-ancestry CRC polygenic risk score (PRS). The discovery cohort (N = 426,464) consisted of ancestrally diverse participants from the United Kingdom Biobank. The replication cohort (N = 87,271) consisted of ancestrally diverse participants from the electronic Medical Records and Genomics Network phase 3. We used a mixed-effects model to adjust for the presence of related individuals. To preserve power, we limited the number of tests by restricting analysis to ancestor phecodes derived from the electronic health record (EHR) that were not likely to be a result of CRC or its treatment.
RESULTS: We discovered and replicated associations between the CRC PRS and breast cancer, prostate cancer, obesity, smoking and alcohol use (discovery p < 1.1e-4; replication p < 0.0019). The association between CRC risk and prostate cancer may be a novel finding, whereas the association with breast cancer has been previously observed using orthogonal methods. The association between CRC risk and behavioral risk factors corroborate previous studies, also using orthogonal methods, and may reveal potential prevention or treatment strategies.
CONCLUSIONS: As these results corroborate findings from other studies using orthogonal methods, we demonstrate that a CRC PRS can be used as a proxy for genetic risk for CRC when investigating shared genetics between CRC and other phenotypes. Further study of the relationship between PRS from multiple traits with EHR data may reveal additional shared genetic factors. Ultimately, understanding these underlying genetic correlations may identify prevention and treatment strategies for CRC.}, }
@article {pmid40634609, year = {2025}, author = {Tortorici, MA and Choi, A and Gibson, CA and Lee, J and Brown, JT and Stewart, C and Joshi, A and Harari, S and Willoughby, I and Treichel, C and Leaf, EM and Bloom, JD and King, NP and Tait-Burkard, C and Whittaker, GR and Veesler, D}, title = {Loss of FCoV-23 spike domain 0 enhances fusogenicity and entry kinetics.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40634609}, issn = {1476-4687}, abstract = {The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat[1,2]. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis. Here we report cryogenic electron microscopy structures of two FCoV-23 spike isoforms that correspond to the in-host loss of domain 0 observed in clinical samples. The loss of domain 0 markedly enhances the fusogenicity and kinetics of entry into cells and possibly enables biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N orthologues as receptors and reveal the molecular determinants of receptor species tropism, including a glycan that modulates human receptor engagement. We define antigenic relationships among alphacoronaviruses that infect humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody that inhibits FCoV-23 entry. Our results pave the way for the development of vaccines and therapeutics that target this highly pathogenic virus.}, }
@article {pmid40633624, year = {2025}, author = {Chari, ST and Wu, B and Lopez, C and Lustigova, E and Chen, Q and Van Den Eeden, SK and Leimpeter, AD and Fisher, W and Wood, A and Alexander, AS and Valenta, J and Vege, SS and Carlson, EE and Rabe, KG and Hart, PA and Qian, L and Zhao, YQ and Yosuf, N and Matrisian, L and Kenner, B and Rinaudo, JA and Maitra, A and Feng, Z}, title = {RISK OF PANCREATIC CANCER IN GLYCEMICALLY DEFINED NEW-ONSET DIABETES: A PROSPECTIVE COHORT STUDY.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2025.06.025}, pmid = {40633624}, issn = {1528-0012}, abstract = {BACKGROUND: Increased 3-year incidence of pancreatic cancer following new-onset diabetes (NOD) observed in retrospective studies needs prospec4ive validation. It is unknown if incidence varies by race/ethnicity.
METHODS: In a prospective, observational study using active real-time surveillance of electronic health records we identified 18,838 adults >50 years of age with NOD defined by glycemic criteria (GNOD). In this interim analysis, we report 3-year Kaplan-Meier estimates of proportion diagnosed with pancreatic cancer following GNOD (absolute incidence (95% Confidence Intervals)) and associated Standardized Incidence Ratio (SIR) by race/ethnicity; overall 3-year incidence of pancreatic cancer adjusting for racial distribution of incident diabetes in the United States; and interval between GNOD and pancreatic cancer diagnosis.
RESULTS: During median follow-up of 2.3 years, 82 pancreatic cancers have been diagnosed (60% male, mean age 71±8 years). The 3-year estimates for proportion diagnosed with pancreatic cancer (95% CI) and associated SIR (95% CI) by race/ethnicity were: non-Hispanic Whites (n=6,518) 0.84% (CI: 0.60, 1.07) (SIR 6.4 (CI: 4.8, 8.4)); Hispanics (n=5,984) 0.40% (0.20, 0.60) (SIR 4.2 (2.6, 6.3)); African Americans (n=2,192) 0.37% (0.07, 0.67) (SIR 2.4 (1.0, 5.0), and Asian/Pacific Islander (n=3,360) 0.22% (.06, 0.39) (SIR 3.0 (1.4, 6.0). Overall, race-adjusted 3-year pancreatic cancer incidence was 0.62%. On average GNOD occurred 8 months prior to clinical diagnosis; 0-4 months in 30.5%, 4-12 months in 31.3%, 12-24 months in 19.5%, and 24-36 months in 18.7%.
CONCLUSIONS: Glycemically defined new-onset diabetes, identifiable in real-time using active surveillance of electronic health records, is associated with a high 3-year incidence of pancreatic cancer with marked racial/ethnic differences. Longer term risk needs further study.}, }
@article {pmid40633141, year = {2025}, author = {Ramachandran, D and Wang, X and Laisk, T and Zheng, Y and Ingold, N and Canson, DM and Kho, PF and Naumann, BJ and Chapman, CJ and Bousset, K and Krause, AV and Schürmann, P and Wieland, B and Hanel, P and Hülse, F and Häfner, N and Runnebaum, I and Dubrowinskaja, N and Turmanov, N and Yugay, T and Yessimsiitova, ZB and Amant, F and Annibali, D and Beckmann, MW and Bodelon, C and Buchanan, DD and Chen, C and Clarke, MA and Cook, LS and De Vivo, I and De Wispelaere, W and Du, M and Easton, DF and Emons, J and Fasching, PA and Friedenreich, CM and Gallagher, G and Giles, GG and Goode, EL and Harris, HR and Hunter, DJ and Kolin, DL and Kraft, P and Lacey, JV and Lambrechts, D and Lu, L and Mutter, GL and Naduparambil, J and O'Connell, K and Patel, AV and Pharoah, PDP and Rebbeck, TR and Ricceri, F and Risch, HA and Ruebner, M and Sacerdote, C and Scott, RJ and Setiawan, VW and Shu, XO and Southey, MC and Tham, E and Tomlinson, I and Turman, C and Wentzensen, N and Xu, W and Yu, H and Zheng, W and Spurdle, AB and Yarden, Y and , and Mägi, R and Hillemanns, P and Glubb, DM and Dörk, T and O'Mara, TA}, title = {GWAS meta-analysis identifies five susceptibility loci for endometrial cancer.}, journal = {EBioMedicine}, volume = {118}, number = {}, pages = {105830}, doi = {10.1016/j.ebiom.2025.105830}, pmid = {40633141}, issn = {2352-3964}, abstract = {BACKGROUND: Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.
METHODS: Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.
FINDINGS: GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.
INTERPRETATION: Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.
FUNDING: This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.}, }
@article {pmid40632975, year = {2025}, author = {Anbil, S and Seewald, NJ and Chiorean, EG and Hussein, M and Kasi, PM and Laux, DE and Schwartz, GK and Shapiro, GI and Lin, KK and Craib, M and Maloney, L and McLachlan, K and Tukachinsky, H and Schrock, AB and Wang, S and Sokol, ES and Decker, B and Nathanson, KL and Domchek, SM and Reiss, KA}, title = {LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500090}, doi = {10.1200/PO-25-00090}, pmid = {40632975}, issn = {2473-4284}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Neoplasms/drug therapy/genetics ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Aged ; Adult ; *Indoles/therapeutic use ; *Recombinational DNA Repair/genetics ; Germ-Line Mutation ; }, abstract = {PURPOSE: To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity.
PATIENTS AND METHODS: This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, and RAD51D (cohort A) or BARD1, BRIP1, FANCA, NBN, and RAD51B (cohort B). The primary end point was overall response rate (ORR) in cohort A. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. A scar-based homologous recombination deficiency signature (HRDsig) and platinum sensitivity status were explored post hoc.
RESULTS: Fifty-one patients in cohort A and 12 in cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI, 10 to 30). A significantly higher ORR was observed with HRDsig+ tumors compared with HRDsig- tumors (32%; 95% CI, 15 to 54 v 0%; 95% CI, 0 to 14; P < .01). In the entire study population, DCR was 65% (95% CI, 53 to 76), median PFS (mPFS) 5.5 months (95% CI, 3.68 to 7.82), and median OS 12.1 months (95% CI, 10.6 to inferred). PFS and hazard of death from any cause was significantly better for platinum-sensitive tumors (mPFS: 7.8 months v 3.5 months; P = .02; hazard ratio, 0.11 [95% CI, 0.02 to 0.55]). Tumor histology was not independently predictive of outcome. Tumors with PVs in cohort A genes were more likely to be HRDsig+ than tumors with PVs in cohort B genes. Analysis of a large commercial database showed that in noncanonical tumors with BRCA PVs, 30.2% were HRDsig+.
CONCLUSION: Rucaparib has activity in HRDsig+ solid tumors with PVs in homologous recombination repair genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.}, }
@article {pmid40632513, year = {2025}, author = {Raychaudhuri, R and Lin, DW and Montgomery, RB}, title = {Complexity of Prostate Cancer-Reply.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.7193}, pmid = {40632513}, issn = {1538-3598}, }
@article {pmid40632085, year = {2025}, author = {Han, C and Zhang, Z and Crosse, EI and Sajedi, S and Lu, B and Wang, X and Karma, S and Kostich, M and Rajendran, SH and Udy, DB and Chen, S and Arnuk, A and Lawal, AE and Koenig, KR and McKenna, M and Reville, PK and Abbas, HA and Abdel-Wahab, O and Miura, P and Bradley, RK and Wang, E}, title = {An isoform-specific RUNX1C-BTG2 axis governs AML quiescence and chemoresistance.}, journal = {Blood cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2643-3230.BCD-24-0327}, pmid = {40632085}, issn = {2643-3249}, abstract = {Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet its role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in AML patients before therapy and at relapse post-chemotherapy, identifying and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long isoform RUNX1C through its alternative distal promoter. The N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted ribosomal RNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of ribosomal RNA's increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineate an isoform-specific transcriptional circuit that governs chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.}, }
@article {pmid40629516, year = {2025}, author = {Razzo, BM and Midha, S and Portuguese, AJ and Grajales-Cruz, AF and De Menezes Silva Corraes, A and Costello, P and Liu, Y and Sperling, AS and Nadeem, O and Dima, D and Banerjee, R and Cowan, AJ and Afrough, A and Anderson, LD and Lieberman-Cribbin, A and Kaur, G and Goyal, A and Atrash, S and Ferreri, CJ and Voorhees, PM and Pasvolsky, O and Lee, HC and Patel, KK and Julian, KL and Forsberg, PA and Herr, MM and Chhabra, S and Parrondo, RD and Lin, Y and Chen, A and Susanibar-Adaniya, SP and Khouri, J and Raza, S and Anwer, F and Vazquez-Martinez, M and Castaneda Puglianini, O and Sborov, DW and Davis, JA and Rossi, A and Shune, L and Bhurtel, J and Hwang, WT and Hansen, DK and Sidana, S and Garfall, AL and Richard, S}, title = {Real-World Experience with Teclistamab for Relapsed/ Refractory Multiple Myeloma from the U.S. Myeloma Immunotherapy Consortium.}, journal = {Blood cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2643-3230.BCD-24-0354}, pmid = {40629516}, issn = {2643-3249}, abstract = {Teclistamab is an anti-CD3xBCMA bispecific antibody approved for use in relapsed/refractory multiple myeloma (MM). We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the U.S. MM Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3) with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR (VGPR) or better in 45%. With 10.1 months median follow-up, estimated median progression-free survival (PFS) was 5.8 months, and 12-month overall survival was 61%. Independent predictors of
METHODS: Bacteremia episodes were considered "persistent" if there was a lack of clearance on day four while receiving ≥ 48 hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, "recalcitrant" bacteremia). A matched comparison group of non-recalcitrant bacteremia patients was chosen in a 2:1 control:case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline.
FINDINGS: A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the ICU upon admission relative to controls. E. faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between E. faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation.
DISCUSSION: Enterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index vs. persistent isolates revealed that E. faecium may be genetically pre-adapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. This data lays groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.}, }
@article {pmid40628699, year = {2025}, author = {Li, Z and Yang, W and Wu, G and Chang, TC and Cheng, Z and Devidas, M and Shago, M and Carroll, AJ and Heerema, NA and Gastier-Foster, JM and Wood, BL and Sanclemente, L and Raetz, EA and Hunger, SP and Loh, ML and Feingold, E and Rosser, TC and Allen, EG and Sherman, SL and Rabin, KR and Lupo, PJ and Yang, JJ}, title = {Inferring chromosome segregation error stage and crossover in trisomic disorders with application to Down syndrome.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6316}, pmid = {40628699}, issn = {2041-1723}, mesh = {Humans ; *Down Syndrome/genetics ; *Chromosome Segregation/genetics ; *Crossing Over, Genetic ; Meiosis/genetics ; *Nondisjunction, Genetic/genetics ; Female ; Markov Chains ; *Trisomy/genetics ; Male ; Child ; }, abstract = {Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. In 152 Down syndrome (DS) cases, MeiHMM achieved an accuracy of 96.1% in classifying NDJ errors, with a sensitivity of 91.6% in crossover identification, compared to proband-parents trio analysis. 17% of Meiosis II errors were misclassified as Meiosis I, mainly due to small proximal crossover events. Applying MeiHMM to 509 children with DS-associated childhood leukemia, we demonstrate that NDJ error is associated with the age of disease onset, somatic genomic abnormalities, and prognosis. Thus, MeiHMM is an effective method for trisomic NDJ error classification and crossover identification that can be applied broadly to study the etiology of congenital aneuploidy conditions.}, }
@article {pmid40628395, year = {2025}, author = {Farrell-Sherman, A and de la Force, N and Prator, CA and Valieris, R and Azam, W and Da Silva, I and Deeks, SG and Thanh, C and Bosch, RJ and Henrich, TJ and Cohn, LB}, title = {Antiviral Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf367}, pmid = {40628395}, issn = {1537-6613}, abstract = {The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16++ monocytes with increased antiviral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.}, }
@article {pmid40627547, year = {2025}, author = {Paatela, EM and St Amant, FG and Hamm, DC and Bennett, SR and Gujral, TS and van der Maarel, SM and Tapscott, SJ}, title = {A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf114}, pmid = {40627547}, issn = {1460-2083}, support = {P50AR065139/NH/NIH HHS/United States ; R01AR066248/NH/NIH HHS/United States ; }, abstract = {The DUX4 transcription factor is briefly expressed in the early embryo and is epigenetically repressed in somatic tissues. Loss of epigenetic repression can result in the aberrant expression of DUX4 in skeletal muscle and can cause facioscapulohumeral dystrophy (FSHD). Multiple factors have been identified as necessary to maintain epigenetic silencing of DUX4 in skeletal muscle, but whether specific sequences at the DUX4 locus are sufficient for initiating epigenetic silencing has not been known. We cloned fragments of the D4Z4 macrosatellite repeat, the DNA region that encompasses the DUX4 retrogene, adjacent to a reporter driven by a constitutive promoter and identified a single fragment sufficient to epigenetically repress reporter gene expression. Previously identified repressors of DUX4 expression-SETDB1, ATF7IP, SIN3A/B, and LRIF1-were necessary for silencing activity and p38 inhibitors enhanced suppression. These findings identify a key regulatory sequence for D4Z4 epigenetic repression and establish a model system for mechanistic and discovery studies.}, }
@article {pmid40627379, year = {2025}, author = {Chatterjee, S and Rückert, T and Martin, I and Michaeli, E and Buescher, J and Apostolova, P and Erny, D and Lalioti, ME and Biavasco, F and Hartmann, A and Runge, S and Braun, LM and Talvard-Balland, N and Adams, RC and Schmitt-Graeff, A and Cook, J and Wenger, V and Athanassopoulos, D and Hasavci, D and Vallejo-Janeta, AP and Blank, T and Schaible, P and Vinnakota, JM and Zähringer, A and Ganal-Vonarburg, SC and Melchinger, W and Pfeifer, D and Köhler, N and Rosshart, SP and Michonneau, D and Socié, G and Andrieux, G and Cabezas-Wallscheid, N and Boerries, M and Prinz, M and Zeiser, R}, title = {Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {9}, pages = {}, doi = {10.1084/jem.20242180}, pmid = {40627379}, issn = {1540-9538}, support = {2021/A2-Fol//University of Freiburg/ ; 2021/B3-Fol//University of Freiburg/ ; 450392965//Deutsche Forschungsgemeinschaft/ ; 259373024//Deutsche Forschungsgemeinschaft/ ; 441891347//Deutsche Forschungsgemeinschaft/ ; 256073931//Deutsche Forschungsgemeinschaft/ ; 431984000//Deutsche Forschungsgemeinschaft/ ; 491676693//Deutsche Forschungsgemeinschaft/ ; 471011418//Deutsche Forschungsgemeinschaft/ ; 493802833//Deutsche Forschungsgemeinschaft/ ; 872/4-1//Deutsche Forschungsgemeinschaft/ ; ZE 872/7-1//Deutsche Forschungsgemeinschaft/ ; ZE 872/8-1//Deutsche Forschungsgemeinschaft/ ; RO 6247/1-1//Deutsche Forschungsgemeinschaft/ ; 446316360//Deutsche Forschungsgemeinschaft/ ; 256073931//Deutsche Forschungsgemeinschaft/ ; 491676693//Deutsche Forschungsgemeinschaft/ ; 101094168/ERC_/European Research Council/International ; 70114655//Deutsche Krebshilfe/ ; 70116490//Deutsche Krebshilfe/ ; DJCLS 09R/2022//Jose-Carreras Leukemia Foundation/ ; 7030-23//Leukemia and Lymphoma Society/ ; 390939984//Germany's Excellence Strategy/ ; 560868983//Germany's Excellence Strategy/ ; 10.001.317/SNSF_/Swiss National Science Foundation/Switzerland ; //European Hematology Association/ ; 24C246//Novartis Foundation for Biomedical Research/ ; 2015_A147//Else Kröner-Fresenius-Stiftung/ ; //Albert-Ludwigs-University of Freiburg/ ; 01ZZ2322A//German Federal Ministry of Education and Research/ ; 01ZZ2015//German Federal Ministry of Education and Research/ ; 101119855//Deutschen Konsortium für Translationale Krebsforschung/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; Microglia/metabolism/drug effects ; *Graft vs Host Disease/microbiology/metabolism/pathology/etiology ; Mice ; Toll-Like Receptor 4/metabolism ; Mice, Inbred C57BL ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Anti-Bacterial Agents/pharmacology ; Male ; p38 Mitogen-Activated Protein Kinases/metabolism ; Acute Disease ; *Central Nervous System/pathology ; T-Lymphocytes/immunology ; Female ; Specific Pathogen-Free Organisms ; }, abstract = {Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.}, }
@article {pmid40624354, year = {2025}, author = {Baele, G and Ji, X and Hassler, GW and McCrone, JT and Shao, Y and Zhang, Z and Holbrook, AJ and Lemey, P and Drummond, AJ and Rambaut, A and Suchard, MA}, title = {BEAST X for Bayesian phylogenetic, phylogeographic and phylodynamic inference.}, journal = {Nature methods}, volume = {}, number = {}, pages = {}, pmid = {40624354}, issn = {1548-7105}, abstract = {Here we present the open-source and cross-platform BEAST X software that combines molecular phylogenetic reconstruction with complex trait evolution, divergence-time dating and coalescent demographics in an efficient statistical inference engine. BEAST X significantly advances the flexibility and scalability of evolutionary models supported. Novel clock and substitution models leverage a large variety of evolutionary processes; discrete, continuous and mixed traits with missingness and measurement errors; and fast, gradient-informed integration techniques that rapidly traverse high-dimensional parameter spaces.}, }
@article {pmid40624264, year = {2025}, author = {Templin, T and Fort, S and Padmanabham, P and Seshadri, P and Rimal, R and Oliva, J and Hassmiller Lich, K and Sylvia, S and Sinnott-Armstrong, N}, title = {Framework for bias evaluation in large language models in healthcare settings.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {414}, pmid = {40624264}, issn = {2398-6352}, support = {2026498//National Science Foundation/ ; N/A//Public Health Sciences Klorfine Pilot Award/ ; N/A//Public Health Sciences Klorfine Pilot Award/ ; K01AI159233/AI/NIAID NIH HHS/United States ; }, abstract = {A critical gap in the adoption of large language models for AI-assisted clinical decisions is the lack of a standardized audit framework to evaluate models for accuracy and bias. Our framework introduces a five-step framework that guides practitioners through stakeholder engagement, model calibration to specific patient populations, and rigorous testing through clinically relevant scenarios. We provide open-access tools for stakeholder engagement and an example of an audit. As the regulation of models becomes more critical, we believe adoption of an audit framework that tests model outputs, rather than regulating specific hyperparameters or inputs, will encourage the responsible use of AI in clinical settings.}, }
@article {pmid40623313, year = {2025}, author = {Aragaki, AK and Manson, JE and LeBlanc, ES and Chlebowski, RT and Tinker, LF and Allison, MA and Haring, B and Odegaard, AO and Wassertheil-Smoller, S and Saquib, N and Masaki, K and Harris, HR and Jager, LR and Bea, JW and Wactawski-Wende, J and Anderson, GL}, title = {Development and Validation of Body Mass Index-Specific Waist Circumference Thresholds in Postmenopausal Women : A Prospective Cohort Study.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/ANNALS-24-00713}, pmid = {40623313}, issn = {1539-3704}, abstract = {BACKGROUND: A 2020 consensus statement proposed body mass index (BMI)-specific waist circumference (WC) thresholds to improve patient care.
OBJECTIVE: To determine whether stratifying BMI categories by BMI-specific WC thresholds improves mortality risk prediction.
DESIGN: Prospective cohort study.
SETTING: Women's Health Initiative multicenter, population-based U.S. study, with enrollment from 1993 to 1998 and follow-up through 2021.
PARTICIPANTS: 139 213 postmenopausal women aged 50 to 79 years were included in a development cohort (n = 67 774) and 2 external validation cohorts. Validation Cohort 1 had high prevalence of overweight or obesity (n = 48 335), and Validation Cohort 2 included diverse, geographically separate centers (n = 23 104).
MEASUREMENTS: Height, weight, and WC measured at enrollment. BMI categories were normal weight (18.5 to <25 kg/m[2]), overweight (25 to <30 kg/m[2]), obesity-1 (30 to <35 kg/m[2]), obesity-2 (35 to <40 kg/m[2]), and obesity-3 (≥40 kg/m[2]), with further stratification by prespecified WC thresholds (≥80, ≥90, ≥105, ≥115, and ≥115 cm, respectively). Mortality was ascertained annually and was supplemented with serial National Death Index queries. Ten- and 20-year mortality prediction models that included BMI categories were compared to models with BMI categories stratified by WC thresholds using c-statistics and continuous net reclassification improvement (NRI).
RESULTS: Over a median of 24 years of follow-up, 69 297 participants died. Multivariable-adjusted mortality risk was consistently greater for BMI categories with large WC than those with normal WC. Compared with women with normal weight and normal WC, women with normal or overweight BMI but large WC (hazard ratios [HRs], 1.17 [95% CI, 1.12 to 1.21] and 1.19 [CI, 1.15 to 1.24], respectively) had risk similar to those with obesity-1 but normal WC (HR, 1.12 [CI, 1.08 to 1.16]). Mortality associated with obesity-1 and large WC (HR, 1.45 [CI, 1.35 to 1.55]) was similar to that with obesity-3 and normal WC (HR, 1.40 [CI, 1.28 to 1.54]). Models with BMI-specific WC thresholds improved discrimination and risk stratification at 10 years for Validation Cohort 1; c-statistics improved by 0.7% (CI, 0.3% to 1.0%) to 61.3% (CI, 60.2% to 62.5%), and continuous NRI was 20.4% (CI, 17.3% to 23.6%). Results were mixed for Validation Cohort 2; risk stratification improved (continuous NRI, 12.3% [CI, 8.5% to 16.0%]), but not discrimination. Results were similar at 20 years.
LIMITATION: The study did not include men or younger women.
CONCLUSION: Further stratifying BMI categories by WC thresholds modestly improved mortality risk stratification, with larger WC predicting greater mortality, although the degree of improvement varied by cohort. Discrimination did not improve consistently.
PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.}, }
@article {pmid40623281, year = {2025}, author = {Montano-Campos, JF and Hahn, E and Haupt, E and Radich, J and Bansal, A}, title = {Using Early Biomarker Change and Treatment Adherence to Predict Risk of Relapse Among Patients With Chronic Myeloid Leukemia Who Are in Remission.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500003}, pmid = {40623281}, issn = {2473-4276}, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/pathology/genetics/diagnosis ; Male ; Female ; Middle Aged ; *Biomarkers, Tumor ; Adult ; Aged ; *Neoplasm Recurrence, Local/epidemiology ; *Fusion Proteins, bcr-abl/genetics ; Remission Induction ; Prognosis ; *Treatment Adherence and Compliance ; Risk Assessment ; }, abstract = {PURPOSE: There is little guidance for decision making in chronic myeloid leukemia (CML) after patients achieve molecular remission. Our study addresses this gap by developing a risk prediction model for molecular relapse using early longitudinal factors, such as BCR::ABL1 biomarker-level changes and treatment adherence.
METHODS: We analyzed electronic health record data of patients with CML diagnosed between 2007 and 2019 from an integrated health system. We used a time-to-event modeling framework using a Cox proportional hazards approach where we evaluated time from molecular remission to molecular relapse. The main predictors were early changes in BCR::ABL1 levels from treatment initiation to the first follow-up measurement (typically around 3 months) and treatment adherence in the first 6 months, categorized as perfect (≥0.98) or less-than-perfect (<0.98). Model performance was assessed through five-fold cross-validation combined with 100 Monte Carlo bootstrapping iterations to ensure robustness and minimize bias.
RESULTS: Patients with early improvement in BCR::ABL1 levels had a 70% lower risk relapse (hazard ratio [HR], 0.30 [95% CI, 0.15 to 0.59]) compared with those without early molecular response. Perfect adherence during this critical early phase of treatment was associated with a 56% lower relapse risk (HR, 0.44 [95% CI, 0.22 to 0.85]). Predictive accuracy was high at 6 months (AUC, 0.90; 95% CI, 0.87 to 0.95) and 1-year postremission (AUC, 0.78; 95% CI, 0.74 to 0.81). Relapse risk was significantly higher among Black, Asian, and Hispanic patients compared with non-Hispanic White patients.
CONCLUSION: Early biomarker trends and adherence after treatment initiation are critical for accurately predicting relapse among patients who achieve molecular remission. The proposed model addresses a gap in guidance after molecular remission and has the potential to enable personalized monitoring and optimize surveillance strategies, offering transformative potential for CML care.}, }
@article {pmid40623109, year = {2025}, author = {Jochim, B and Topalidou, I and Lehrbach, N}, title = {Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.}, journal = {PLoS genetics}, volume = {21}, number = {7}, pages = {e1011780}, doi = {10.1371/journal.pgen.1011780}, pmid = {40623109}, issn = {1553-7404}, abstract = {The Nrf/NFE2L family of transcription factors regulates redox balance, xenobiotic detoxification, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is primarily responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. Nrf2/NFE2L2 is mainly involved in activating oxidative stress responses and promoting xenobiotic detoxification. Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively, and share an identical DNA binding domain. Thus, the extent to which SKN-1A/Nrf1 and SKN-1C/Nrf2 functions are distinct or overlapping has been unclear. Regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term 'sequence editing'. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We confirm that activation of proteasome subunit genes is strictly dependent on sequence editing. In addition, we find that sequence edited SKN-1A can also activate genes linked to redox homeostasis and xenobiotic detoxification that are also regulated by SKN-1C, but the extent of these genes' activation is antagonized by sequence editing. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that both isoforms promote optimal oxidative stress resistance, acting as effectors for distinct signaling pathways. These findings suggest that sequence editing governs SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.}, }
@article {pmid40623049, year = {2025}, author = {Perales, MA and Awan, FT and Boumendil, A and Patel, J and Castagna, L and Angelucci, E and Finel, H and Kulagin, AD and Glass, B and Corradini, P and Herrera, AF and Blaise, D and Kharfan-Dabaja, MA and Halahleh, K and Ahmed, S and Martinez, C and Giebel, S and Montoto, S and Jones, RJ and Ahmed, N and Lynch, RC and de Lima, MJ and Shadman, M and Sauter, CS and Ahn, KW and Hamadani, M and Bazarbachi, A and Sureda, A}, title = {Outcomes of Allogeneic HCT in Hodgkin Lymphoma in the Era of Checkpoint Inhibitors: A Joint CIBMTR and EBMT Analysis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027197}, pmid = {40623049}, issn = {1528-0020}, abstract = {Checkpoint inhibitors (CPI) have shown remarkable efficacy in patients with Hodgkin lymphoma (HL) and are now used routinely for this disease. While allogeneic hematopoietic cell transplantation (alloHCT) remains a curative option for HL, there are concerns that prior CPI may exacerbate post alloHCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a CIBMTR/EBMT study to examine the impact of prior CPI in alloHCT outcomes. We included 2186 adult patients > 18 years who received a first alloHCT using a matched related, unrelated or haploidentical donor from 2008-2023. Twenty-seven percent of patients received prior CPI. GVHD prophylaxis was post-transplant cyclophosphamide in 55.8% patients in the CPI cohort and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In the multivariate analysis, prior CPI exposure did not affect overall survival or non-relapse mortality but resulted in improved progression-free survival (non-CPI vs. CPI HR 0.81, 0.67-0.98, p=0.03) and lower incidence of relapse (HR 0.58, 0.45-0.76, p<0001). While grade II-IV (HR1.26, 1.04-1.53; p=0.02) and III-IV (HR1.41, 1.04-1.92; p=0.03) acute GVHD were increased differences in chronic GVHD were not significant. Use of post-transplant cyclophosphamide based GVHD prophylaxis resulted in improved OS, lower grade II-IV acute GVHD and chronic GVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of checkpoint inhibitors.}, }
@article {pmid40623045, year = {2025}, author = {Dhodapkar, MV and Paiva, B}, title = {Immune Alterations in Myeloma Evolution and Outcomes: Quo Vadis?.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024026227}, pmid = {40623045}, issn = {1528-0020}, abstract = {The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the elderly. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in-situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells and increases the risk of infections in MM patients. Immune profiles in blood or marrow exhibit considerable heterogeneity and have been linked to outcomes following immune therapies including T cell redirection. Understanding how underlying systemic immune changes impact in-vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in-vivo, are needed to optimize immune approaches and improve outcomes in MM.}, }
@article {pmid40622392, year = {2025}, author = {Naidoo, N and Bell-Brown, A and Kimura, A and Akinsoto, N and Fang, V and Peck, A and Wood, J and Issaka, RB}, title = {Fecal Immunochemical Test (FIT) Completion by Instruction Type: A Randomized Clinical Trial Comparing QR-Code linked Video to Pictorial Instructions.}, journal = {The American journal of gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.14309/ajg.0000000000003637}, pmid = {40622392}, issn = {1572-0241}, abstract = {BACKGROUND AND AIMS: Low-literacy, pictorial instructions improve fecal immunochemical test (FIT) completion and might enhance colorectal cancer (CRC) screening. The aim of this study was to compare FIT completion among English- and Spanish-speaking patients in an organized CRC screening program based on the type of instructions received (quick response (QR)-code linked to a video vs. pictorial instructions).
METHODS: In this randomized controlled quality improvement study, English- and Spanish-speaking patients eligible for mailed outreach through an organized CRC screening program were randomized 1:1 to receive a FIT kit with either a QR-code linked video or pictorial instructions in their preferred language. Patient demographics (gender, age, race, ethnicity, and insurance type) and clinical outcomes (FIT completion and time to completion) were abstracted from electronic health records.
RESULTS: 13,471 English-speaking patients and 508 Spanish-speaking patients were included. Overall, 31.9% of patients who received mailed outreach completed CRC screening by FIT. However, FIT completion was higher among patients who received QR-code instructions vs. pictorial instructions (33.5% vs 30.4%, absolute difference 3.1%, 95% CI 1.5% - 4.6%). These findings were similar among English- and Spanish-speaking patients. The median time to FIT completion was two days longer (24 days, 95% CI 23-25) for patients who received QR-code instructions versus pictorial instructions, however there was no difference in time to FIT completion by language group.
CONCLUSION: Providing QR-code based education offers a promising format for delivering low literacy instructions, which might be a practical strategy to improve FIT completion for CRC screening.}, }
@article {pmid40622009, year = {2025}, author = {Chen, W and Majovski, J and Bhatia, S and Chan, A and Grivas, P and Lee, S and Shah, S and Thompson, JA and Tykodi, SS and Veatch, JR and Schapira, L and Hall, ET}, title = {A mixed-method analysis of oncologist-patient communications about immune checkpoint inhibitors (COACH).}, journal = {The oncologist}, volume = {30}, number = {7}, pages = {}, pmid = {40622009}, issn = {1549-490X}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Female ; *Oncologists/psychology ; Male ; *Physician-Patient Relations ; Middle Aged ; *Communication ; *Neoplasms/drug therapy/immunology ; Aged ; Adult ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Despite significant attention in the media and oncology community about improved outcomes associated with immune checkpoint inhibitors (ICIs), there remains a gap in our understanding of how oncologists describe ICIs to their patients. Communication around ICIs represents a challenge as some patients have durable, remarkable benefits while others experience severe toxicities. We investigated oncologist-patient communication practices by performing a mixed-methods study of in-clinic discussions about ICIs.
MATERIALS AND METHODS: This was a mixed-method study in which in-clinic conversations between oncologists and their patients with advanced cancers about ICIs as potential treatments were audio-recorded. Patients were asked to complete a post-discussion survey. Qualitative data was derived from a general inductive thematic approach while descriptive statistics were used to analyze the survey responses.
RESULTS: We recorded and analyzed 13 in-clinic conversations involving 8 oncologists and 13 patients. Twelve patients completed the post-discussion surveys. The conversations involved sophisticated discussions of immune function, cancer and ICI mechanisms, and trade-offs between anticancer benefits and toxicities. Oncologists incorporated metaphors and probabilistic information in their explanations. In the post-discussion surveys, patients indicated a preference for detailed information about ICIs and reported that they received the right depth of information in these discussions.
CONCLUSIONS: During in-clinic discussions of ICI therapy, oncologists provided detailed information about immunology and cancer, often aided by metaphors. Probabilities were commonly used to describe the likelihood of toxicities and benefits. The amount of information provided by the oncologists aligned with the patients' preference for detailed information about their cancer treatments.}, }
@article {pmid40620045, year = {2025}, author = {Kauffman, ZJ and Koesser, K and Helzer, KT and Sharifi, MN and Heninger, E and Li, C and Juang, DS and Jarrard, DF and Zhao, SG and Haffner, MC and Beebe, DJ and Lang, JM and Sperger, JM}, title = {Lossless Altered Histone Modification Analysis System (LAHMAS).}, journal = {Lab on a chip}, volume = {}, number = {}, pages = {}, doi = {10.1039/d5lc00060b}, pmid = {40620045}, issn = {1473-0189}, abstract = {Miniaturized biological assays using microfluidics have the potential to enhance assay sensitivity, reduce reagent consumption, and increase throughput. However, challenges to miniaturization include increased platform complexity and increased surface to volume ratios leading to risk of evaporation and analyte loss through surface binding. Exclusive Liquid Repellency (ELR) enables open microfluidic systems that minimize these challenges through an oil phase that protects small aqueous volumes from temperature fluctuation and evaporation while eliminating surface fouling that leads to sample loss. Here we report a novel microfluidic platform leveraging ELR and Exclusion-based Sample Preparation (ESP) for the miniaturization of CUT&Tag, a complex multistep biological assay. The resultant Lossless Altered Histone Modification Analysis System (LAHMAS) employs a PDMS-silane treated glass surface immersed in silicone oil to facilitate lossless liquid handling and prevent sample evaporation. The device design, compatible with standard laboratory equipment, allows effective processing of cell inputs as low as 100 cells with higher specificity than macroscale CUT&Tag facilitating accurate chromatin profiling of low input and rare cell samples.}, }
@article {pmid40619101, year = {2025}, author = {Jimenez Jimenez, AM and Spellman, SR and Politikos, I and McCurdy, SR and Devine, SM and Malki, MMA and Bolon, YT and Lee, SJ and Dehn, J and Pidala, J and Maiers, M and Askar, M and Malmberg, C and Auletta, JJ and Stefanski, H and Broglie, L and Qayed, M and Horwitz, M and Wilder, JS and Gooptu, M and Mehta, RS and Fernandez-Viña, M and Shaw, BE and Shaffer, BC}, title = {Allogeneic Hematopoietic Cell Donor Selection: Contemporary Guidelines from the NMDP/CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.07.004}, pmid = {40619101}, issn = {2666-6367}, abstract = {Allogeneic hematopoietic cell transplantation (HCT) remains a curative therapy for many patients with hematologic malignancies, bone marrow failure syndromes, inborn errors of immunity and metabolic disorders. Current donor selection strategies typically prioritize the selection of an HLA-matched donor over HLA mismatched ("alternative") donor sources, with a hierarchical approach to the donor search. More recent data challenge this rubric, particularly in the context of novel graft versus host disease (GVHD) prophylaxis strategies that demonstrate improved outcomes in alternative donor HCT recipients. In this setting, an increased emphasis on non-HLA factors (both donor characteristics and systemic factors) in determining donor selection is now feasible. In this guideline, we review recent evidence from prospective clinical trials as well as high-quality observational studies and provide expert panel recommendations on donor selection algorithms and prioritization in the era of novel GVHD prophylaxis. We then highlight important questions still to be answered in our field.}, }
@article {pmid40619005, year = {2025}, author = {Hullar, MAJ and Kahsai, O and Curtis, KR and Navarro, SL and Zhang, Y and Randolph, TW and Levy, L and Shojaie, A and Kratz, M and Neuhouser, ML and Lampe, PD and Raftery, D and Lampe, JW}, title = {Metabolic plasticity of the gut microbiome in response to diets differing in glycemic load in a randomized, crossover, controlled feeding study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2025.06.026}, pmid = {40619005}, issn = {1938-3207}, abstract = {BACKGROUND: Dietary patterns characterized by low-glycemic, minimally processed plant foods are associated with lower risk of several chronic diseases.
OBJECTIVE: Evaluate the effects of a low glycemic load (LGL) versus a high glycemic load (HGL) dietary pattern on stool bacterial community structure and metabolism.
METHODS: Participants in this crossover-controlled feeding study were healthy men and women (n=69). We identified genera, species, and genes and transcripts of metabolic pathways and bacterial enzymes using 16S rRNA gene, metagenomic and metatranscriptomic sequencing, and bioinformatic analysis.
RESULTS: Overall community structure measured by alpha and beta diversity were not significantly different across the diets although diet did significantly increase the abundance of 13 out of 161 genera (padj<0.05) and 5 species in the LGL and 7 species in the HGL diet. Gene expression in the hexitol fermentation pathway (β=-1.15, SE=0.24 with 95% CI (-1.63, -0.67); padj=0.002) was significantly higher in the HGL diet, whereas expression in the L-lysine biosynthesis pathway (β =0.20, SE=0.05 with 95% CI (0.09, 0.30); padj=0.03); was enriched in the LGL diet. The beta diversity of expressed carbohydrate-active enzymes (CAZymes) was significantly different between the diets (MiRKAT, p<0.001). CAZymes enriched in the HGL diet reflected dietary additives while CAZymes enriched in the LGL diet reflected diverse phytochemical intake. There was a significant interaction between HOMA IR and the Coenzyme A biosynthesis I pathway involved in bacterial fatty acid biosynthesis (padj=0.035) that was positive in the HGL diet (β=0.20, SE=0.09 with 95% CI (0.02, 0.39)) and negative in the LGL diet (β =-0.23, SE=0.09 with 95% CI (-0.40, -0.06)).
CONCLUSION: In healthy humans, diet impacts microbial metabolism and enzymatic activity but not the overall diversity of the gut microbiome. This emphasizes the relevance of dietary components in activating expression of specific bacterial genes and their impact on host metabolism. This trial was registered at clinicaltrials.gov as NCT00622661.}, }
@article {pmid40618773, year = {2025}, author = {White, RG and Churchyard, GJ and Horton, KC and Fiore-Gartland, A and Behr, MA and Clark, RA and Cobelens, F and Ernst, JD and Esmail, H and Garcia-Basteiro, AL and Hadinegoro, SR and Hanekom, WA and Hatherill, M and Hill, PC and Muloiwa, R and Pelzer, PT and Rangaka, L and Rees, H and Schrager, L and Stanley, M and Tufet, M and Wong, EB and Houben, RMGJ}, title = {Evidence required to evaluate the use of bacteriologically confirmed asymptomatic tuberculosis disease as a primary endpoint in prevention of tuberculosis disease vaccine licensure trials.}, journal = {The Lancet. Respiratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2213-2600(25)00164-X}, pmid = {40618773}, issn = {2213-2619}, abstract = {Current licensure trials of new vaccines to prevent tuberculosis disease use bacteriologically confirmed symptomatic tuberculosis disease as the primary endpoint. Globally, the incidence of symptomatic tuberculosis disease is low, making licensure trials large, long, and expensive. New data suggest that bacteriologically confirmed asymptomatic tuberculosis disease might occur more frequently than symptomatic tuberculosis disease. Therefore, if vaccines have efficacy against asymptomatic disease, tuberculosis vaccine licensure trials could include it in the primary endpoint, potentially leading to smaller or shorter trials. We describe the potential benefits and risks of this inclusion in the primary endpoint of tuberculosis vaccine licensure trials. We also simulate licensure trial endpoint accrual and summarise feedback from anonymous regulators and policy makers on the knowledge needed to consider this proposal and research studies needed to fill these evidence gaps. If bacteriologically confirmed asymptomatic tuberculosis disease could be included in the primary endpoint of tuberculosis disease licensure trials, it could lead to cheaper and more rapid tuberculosis vaccine development.}, }
@article {pmid40617679, year = {2025}, author = {Petersdorf, EW}, title = {Semper Progrediens.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {399-400}, doi = {10.1016/j.jtct.2025.06.005}, pmid = {40617679}, issn = {2666-6367}, }
@article {pmid40617637, year = {2025}, author = {Rafati, DM and Wang, Y and Koppayi, AL and Savage, SA and Godley, LA and Williams, KM and Porter, C and Jones, K and Hicks, B and Spellman, SR and He, M and Atshan, R and Bolon, YT and Arrieta-Bolaños, E and Saultz, JN and Benjamin, CL and Lee, SJ and Saber, W and Gadalla, SM}, title = {REMOVED: Conditioning Regimen Considerations for Allogeneic Hematopoietic Cell Transplantation in Recipients with Germline Pathogenic Variants in Base-Excision Repair Pathway Genes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {2S}, pages = {S338}, doi = {10.1016/j.jtct.2025.01.521}, pmid = {40617637}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Transplantation Conditioning/methods ; *DNA Repair/genetics ; Transplantation, Homologous/methods ; *Germ-Line Mutation ; Male ; Female ; Excision Repair ; }, abstract = {This abstract has been removed: please see Elsevier policy on article withdrawal (https://www.elsevier.com/about/policies-and-standards/article-withdrawal). This article has been removed at the request of the author. This abstract has been removed because it was not presented at the 2025 BMT Tandem Meeting.}, }
@article {pmid40617636, year = {2025}, author = {Rafati, DM and Pirsl, F and Katki, HA and Wu, D and Luo, W and Liu, J and Jones, K and Zhou, W and Spellman, SR and Bolon, YT and Lee, SJ and Deeg, HJ and Gupta, V and Saber, W and Gadalla, SM}, title = {REMOVED: Genetic Landscape in Myelofibrosis Impacts Post-Hematopoietic Cell Transplantation Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {2S}, pages = {S337}, doi = {10.1016/j.jtct.2025.01.520}, pmid = {40617636}, issn = {2666-6367}, mesh = {Humans ; *Primary Myelofibrosis/genetics/therapy ; *Hematopoietic Stem Cell Transplantation/methods ; Treatment Outcome ; }, abstract = {This abstract has been removed: please see Elsevier policy on article withdrawal (https://www.elsevier.com/about/policies-and-standards/article-withdrawal). This article has been removed at the request of the author. This abstract has been removed because it was not presented at the 2025 BMT Tandem Meeting.}, }
@article {pmid40617294, year = {2025}, author = {Chloe, TB and Taara, EB and Kenna, S and Lynn, OM and Stephanie, JL}, title = {Serositis associated with chronic graft-versus-host disease.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.07.002}, pmid = {40617294}, issn = {2666-6367}, abstract = {Serositis is a recognized complication associated with chronic graft-versus-host disease (cGVHD) in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Although it is uncommon, serositis after HCT can have significant negative clinical impacts. There are limited data describing the patient population, incidence, risk factors and management strategies of cGVHD-associated serositis. We retrospectively identified 50 adult patients who underwent HCT at the Fred Hutchinson Cancer Center between 1998 and 2021 and developed serositis attributed to cGVHD. Most patients developed pericardial effusions (n=31) and/or pleural effusions (n=38). 94% of patients with pleural effusion and 87% of patients with pericardial effusion received medical management for their serositis. Eleven patients experienced at least one recurrence of serositis. The median overall survival for all serositis types at one-year post-serositis diagnosis was 86%, and 69% for three-years post-serositis diagnosis. Serositis is a serious atypical cGVHD manifestation and prospective data collected from a larger cohort of patients is required to better understand favorable treatment strategies and outcomes of this complication.}, }
@article {pmid40616435, year = {2025}, author = {Huang, Y and Zhang, B and Zhang, L and Mayer, BT and Martin, T and Hahn, W and Hyrien, O and Gelderblom, HC}, title = {Dose finding in early-phase human immunodeficiency virus type 1 prevention monoclonal antibody clinical trials.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745251347280}, doi = {10.1177/17407745251347280}, pmid = {40616435}, issn = {1740-7753}, abstract = {Human immunodeficiency virus type 1 remains a major public health burden with 39 million people living with human immunodeficiency virus type 1 and 1.3 million new diagnoses in 2023, despite the recent approval of multiple antiretroviral-based prevention products. While the development of a safe and effective human immunodeficiency virus type 1 vaccine remains the ultimate goal for controlling the worldwide pandemic, progress has been hindered by unprecedented challenges, including the extraordinary genetic diversity of human immunodeficiency virus type 1, the inability of current vaccines to induce broadly reactive antibody responses, and the lack of clear immune correlates of protection to serve as benchmarks for vaccine development. Passive administration of broadly neutralizing monoclonal antibodies that are engineered versions of naturally occurring antibodies has emerged as a potential complement to current human immunodeficiency virus type 1 prevention modalities. These antibodies are isolated from people with human immunodeficiency virus type 1 and can neutralize a broad range of human immunodeficiency virus type 1 viruses. Importantly, advances in antibody engineering have improved the pharmacokinetics of these monoclonal antibodies, offering potential for lower levels and/or less frequent monoclonal antibody dosing with greater feasibility and accessibility for human immunodeficiency virus type 1 prevention. Evaluating monoclonal antibody candidates in human immunodeficiency virus type 1 prevention trials, dose-finding and optimization requires a careful balance between virus-neutralization coverage, cost considerations, and practical constraints. To achieve this, pharmacokinetic modeling of antibody concentrations over time, combined with pharmacodynamics modeling of the relationship between neuralization titers and prevention efficacy, serves as a core of the statistical framework. In addition, for human immunodeficiency virus type 1 monoclonal antibodies administered to individuals without human immunodeficiency virus type, neutralization titers can be reliably predicted from antibody concentrations, owning to the preservation of neutralization function post-administration of these monoclonal antibodies. Within this framework, the antibody-mediated prevention efficacy trials of VRC01, an human immunodeficiency virus type 1 monoclonal antibody, and a meta-analysis of 16 different monoclonal antibodies in non-human primates provided consistent evidence that neutralization titer is a potential pharmacodynamics biomarker of monoclonal antibody prevention efficacy. These findings support the use of integrated pharmacokinetics/pharmacodynamics modeling as a foundation for dose finding of human immunodeficiency virus type 1 monoclonal antibodies. However, in the context of combination monoclonal antibody regimens, additional challenges arise. The total dose cost, operational feasibility, and the influence of dosing ratios on neutralization breadth and potency across diverse human immunodeficiency virus type 1 viral strains are important areas for further research. While monoclonal antibody clinical trials share some common design features with therapeutic small molecule drug trials, monoclonal antibodies possess unique safety, pharmacokinetics and pharmacodynamics profiles that require dedicated statistical and clinical considerations, particularly when used for prevention of viral infections. In this article, we highlight dose-finding efforts particularly for combination monoclonal antibodies regimens, including the selection of optimal dosing ratio and total dose amount in the context of human immunodeficiency virus type 1 prevention. Looking ahead, future directions in monoclonal antibody-based human immunodeficiency virus type 1 prevention include efforts to enhance dose-associated cost-effectiveness, and the identification and validation of robust pharmacokinetic and pharmacodynamic markers that are predictive of the prevention efficacy of combination monoclonal antibodies.}, }
@article {pmid40616382, year = {2025}, author = {Lakkaraja, M and Baker, KS}, title = {Precision transplant and cell therapies for non-malignant disorders-The path forward.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.20245}, pmid = {40616382}, issn = {1365-2141}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; //American Society of Hematology/ ; }, abstract = {The number of patients undergoing haematopoietic stem cell transplant (HCT) and cell therapies for non-malignant disorders is steadily increasing with more genetic diseases being identified and newer gene therapy products being introduced for various indications. By combining individualized conditioning, novel graft manipulation techniques, using cutting edge methods to monitor post HCT response and offering exceptional survivorship care, one can achieve excellent survival and improved quality of life for these patients.}, }
@article {pmid40614969, year = {2025}, author = {Kennedy, VE and Ahmed, N and Artz, A and Bhatt, NS and Custatis, R and Espinoza-Gutarra, MR and Farhan, S and Ferguson, RJ and Hamilton, B and Katz, H and Kelly, DL and Knight, JM and Lee, C and Lin, A and Lin, R and Mohanraj, L and Munshi, P and Nawas, M and Nelson, AM and Odstracil, S and Olin, R and Phelan, R and Rentscher, KE and Schoemans, H and Sung, A and Taylor, MR and Wood, W and Yuen, CH and Jayani-Kosarzycki, RV}, title = {Assessing Cognitive Function in Transplantation and CAR-T Recipients: Expert Recommendations from the Survivorship, Aging and Biobehavioral Special Interest Groups of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.026}, pmid = {40614969}, issn = {2666-6367}, abstract = {Cognitive impairment is a prevalent yet underexplored comorbidity and complication in hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy. Affecting up to half of patients, cognitive impairment may include acute phases, manifesting as transplant-associated altered mentation and encephalopathy (TAME) or immune effector cell-associated neurotoxicity syndrome (ICANS), and may persist for years post-treatment as cancer-related cognitive impairment (CRCI). Such dysfunction undermines autonomy, healthcare management, work reintegration, and quality of life. This consensus review synthesizes current evidence on CRCI across the timeline of transplant and cellular therapy, organized into pre-, peri-, and post-therapy phases, with additional focus on specific populations, such as older adults and pediatric patients. It highlights gaps in understanding of cognitive impairment risks, trajectory, and impact, alongside the challenges of standardizing assessments in diverse practice settings. Key recommendations, endorsed by the American Society for Transplantation and Cellular Therapy (ASTCT) Aging, Biobehavioral Research, and Survivorship Special Interest Groups, advocate for cognitive assessment pre- and post-therapy using validated instruments, like the Montreal Cognitive Assessment (MoCA) or Blessed Orientation-Memory-Concentration Test (BOMC). We additionally recommend supplementing with patient-reported outcomes (PROs) measures for comprehensive evaluation. If cognitive impairment is identified, we recommend action items, including exclusion of alternative etiologies, reconsideration of therapy or caregiving plan, and referrals for additional evaluation and rehabilitation, among others. Practical guidance for implementation across clinical and research settings is provided, emphasizing the need for multidisciplinary strategies to address identified impairments. This work aims to establish a framework for systematic cognitive monitoring, improving patient outcomes and quality of life while guiding future research to address significant knowledge and implementation gaps.}, }
@article {pmid40614783, year = {2025}, author = {Corn, BW and Paulus, R and Gondi, V and Mehta, MP and Fogh, S and Wefel, JS and Videtic, GM and Sun, A and Yoon, H and Heinzerling, JH and McGarry, RC and Kundapur, V and Devisetty, K and Wu, A and McCarron, EC and Pollock, J and Kanner, AA and Feldman, DB and Pugh, SL and Kachnic, LA and Movsas, B}, title = {"Hope" Drives Quality of Life in Patients with Brain Metastases, But, the "Hope Center" Remains Elusive: An Analysis of NRG-CC003.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.06.3884}, pmid = {40614783}, issn = {1879-355X}, abstract = {PURPOSE: xxxxx randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without Hippocampal Avoidance (HA). "Hopefulness" is a cognitive construct with 3 components: goals, pathways and agency. Hope is measurable with validated instruments. Since hope is cognitive in nature, the existence of a "hope center" in the brain - most likely in the hippocampus - has been hypothesized. One exploratory objective of xxxxx posited that if hope levels were better maintained in patients randomized to PCI+HA, then the hippocampus would be implicated in the mechanism of hopefulness.
METHODS & MATERIALS: PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6-months. Regarding patient reported outcome (PRO) measures, the EORTC QLQ-C30 was administered at baseline and at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients.
RESULTS: Approximately 95% completed the AHS at baseline and 67% filled out the questionnaire at 6-months paralleling the completion rates of the conventional tools for QOL and neurocognition. When comparing hope levels (change from baseline to 6 months) there was no significant difference (p > 0.05) between the two arms of the trial. There was a correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (rho=0.27, p<0.0001) as well as between change in pathways score and QLQ-C30 global health status (rho=0.16, p=0.022).
CONCLUSIONS: It is feasible to study hopefulness in the context of prospective trials conducted within the National Clinical Trials Network (NCTN). The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. For the first time, validated tools established a relationship between hope and quality of life among cancer patients.}, }
@article {pmid40614134, year = {2025}, author = {Marchak, JG and Seidel, KD and Cherven, BO and Klosky, JL and Ritenour, CWM and Leisenring, WM and Sklar, CA and Ford, JS and Krull, KR and Robison, LL and Armstrong, GT and Meacham, LR}, title = {Comprehensive assessment of sexual function in male survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {131}, number = {14}, pages = {e35967}, doi = {10.1002/cncr.35967}, pmid = {40614134}, issn = {1097-0142}, support = {CA21765/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; //Lance Armstrong Foundation/ ; }, mesh = {Humans ; Male ; Adult ; Middle Aged ; Young Adult ; *Neoplasms/complications ; *Sexual Dysfunction, Physiological/epidemiology/etiology ; Surveys and Questionnaires ; *Survivors ; *Cancer Survivors ; Child ; Risk Factors ; *Sexual Dysfunctions, Psychological/epidemiology/etiology ; Sexual Behavior ; }, abstract = {BACKGROUND: Assessment of sexual dysfunction among adult male survivors of childhood cancer has primarily been limited to erectile dysfunction. This study aimed to characterize sexual functioning more comprehensively among a large population of male survivors of childhood cancer.
METHODS: Male survivors (N = 1595, 22.0-59.4 years, median age, 37.8 years) and siblings (N = 269, 21.5-60.8 years, median age, 38.9 years) from the Childhood Cancer Survivor Study completed the Sexual Functioning Questionnaire (SFQ) to assess interest, desire, arousal, satisfaction, activity, orgasm, masturbation, relationship, and problems. Poor sexual functioning was defined as SFQ Total scores >2 standard deviations below siblings' mean. Multivariable logistic regression identified risk factors for poor sexual function.
RESULTS: Survivors (8.3%) were more likely to report poor sexual functioning as compared to siblings (4.9%, odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.4) and reported lower SFQ total scores (p < .001) and lower means on seven subscales. Poor sexual functioning among survivors was associated with older age (40-49 years: OR, 3.81; 95% CI, 1.78-8.18; 50-59 years: OR, 6.45; 95% CI, 2.28-18.30), not being married (OR, 4.39; 95% CI, 2.66-7.26), lower education (OR, 3.07; 95% CI, 1.32-7.14), learning/memory problems (OR, 1.83; 95% CI, 1.02-3.27), and high-dose cranial (≥40 Gy: OR, 3.45; 95% CI, 1.58-7.51) or high-dose testicular (≥10 Gy: OR, 4.16; 95% CI, 1.66-10.39) radiation.
CONCLUSIONS: Adult male survivors report poor sexual functioning at twice the rate expected before age 60 years. High-dose cranial or testicular radiation, as well as social and cognitive factors, contributes to risk. Improved awareness of sexual dysfunction prevalence and risk factors in male childhood cancer survivors can help clinicians better assess and treat those at highest risk.}, }
@article {pmid40613977, year = {2025}, author = {Mezzanotte-Sharpe, J and Hsu, CY and Choi, D and Sheffield, H and Zelinskas, S and Proskuriakova, E and Montalvo, M and Lee, DS and Whisenant, JG and Gaffney, K and Thompson, MS and Blenman, K and Tawagi, K and Symonds, L and Santa-Maria, C and Unni, N and Quiroga, D and Shyr, Y and Kennedy, LC}, title = {Adverse events in patients treated with neoadjuvant chemo/immunotherapy for triple negative breast cancer: results from seven academic medical centers.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {40613977}, issn = {1573-7217}, support = {2T32CA217834-07//VOLT T32/ ; }, abstract = {PURPOSE: The standard-of-care neoadjuvant treatment for early-stage or locally advanced triple negative breast cancer (TNBC) is the KEYNOTE-522 regimen that combines pembrolizumab and chemotherapy. Although this approach has superior response and survival rates, high-grade adverse events (AEs) are common. Real-world data from a diverse patient population is needed to better understand practice patterns and the impact of immunotherapy in TNBC patients.
METHODS: Medical records from TNBC patients were retrospectively reviewed during neoadjuvant and adjuvant treatment with pembrolizumab and chemotherapy. CTCAE version 5.0 was used to grade AEs. Variables were reported with descriptive statistics, and AE, pCR and hospitalization rates were estimated with 95% confidence intervals.
RESULTS: We identified 415 patients from seven academic medical centers; 60% identified as White and 21% as Black. pCR rate was 52%. 88% of patients experienced an AE, 38% experienced a grade 3+ AE, and 31% stopped pembrolizumab early. Hospitalization rate was 26%. There were no statistically significant differences in AE, pCR or hospitalization rates between White and Black patients. Obese patients had a statistically significant higher hospitalization rate (p = 0.014). There were 18 deaths during treatment, mainly from progressive TNBC.
CONCLUSION: This is one of the largest real-world, diverse patient cohorts for TNBC patients treated with chemotherapy and pembrolizumab. pCR rate was lower than that reported in the KEYNOTE-522 study and in smaller real-world studies, potentially due to high rates of pembrolizumab and chemotherapy discontinuation. AEs and hospitalizations were common, with obese patients more likely to be hospitalized than patients with a normal BMI.}, }
@article {pmid40613577, year = {2025}, author = {Fourment, M and Macaulay, M and Swanepoel, CJ and Ji, X and Suchard, MA and Iv, FAM}, title = {torchtree: flexible phylogenetic model development and inference using PyTorch.}, journal = {Systematic biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/sysbio/syaf047}, pmid = {40613577}, issn = {1076-836X}, abstract = {Bayesian inference has predominantly relied on the Markov chain Monte Carlo (MCMC) algorithm for many years. However, MCMC is computationally laborious, especially for complex phylogenetic models of time trees. This bottleneck has led to the search for alternatives, such as variational Bayes, which can scale better to large datasets. In this paper, we introduce torchtree, a framework written in Python that allows developers to easily implement rich phylogenetic models and algorithms using a fixed tree topology. One can either use automatic differentiation, or leverage torchtree's plug-in system to compute gradients analytically for model components for which automatic differentiation is slow. We demonstrate that the torchtree variational inference framework performs similarly to BEAST in terms of speed, and delivers promising approximation results, though accuracy varies across scenarios. Furthermore, we explore the use of the forward KL divergence as an optimizing criterion for variational inference, which can handle discontinuous and non-differentiable models. Our experiments show that inference using the forward KL divergence is frequently faster per iteration compared to the evidence lower bound (ELBO) criterion, although the ELBO-based inference may converge faster in some cases. Overall, torchtree provides a flexible and efficient framework for phylogenetic model development and inference using PyTorch. phylogenetics, Bayesian inference, variational Bayes, PyTorch.}, }
@article {pmid40610289, year = {2025}, author = {Keyes, M and Sturdza, AE and Crook, J and Anderson, B and Boldrini, L and Chino, J and Corradini, S and Deufel, C and Farach, A and Folkert, MR and Frank, SJ and Hannoun-Levi, JM and Hoskin, P and Jurgenliemk-Schulz, I and Kamrava, M and Kollmeier, M and McKee, MM and Iii, POF and Rossi, P and Pieters, BR and Strnad, V and Shah, C and Siebert, FA and Stewart, A and Taggar, AS and Tagliaferri, L and Morton, G}, title = {Joint ABS/GEC-ESTRO Consensus Statement on the objectives of training in brachytherapy for physicians.}, journal = {Brachytherapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.brachy.2025.05.006}, pmid = {40610289}, issn = {1873-1449}, abstract = {Brachytherapy is an essential skill in the practice of radiation oncology and is an important component of high-quality, full-service radiation oncology departments. With rapidly changing technology, the role of brachytherapy is constantly evolving, but it remains critically important for optimal patient care in several disease sites. As a procedural aspect of radiation oncology practice, brachytherapy requires a fundamentally different and more focused training approach, with specific training objectives, a unique knowledge base, and specialized training environment. The existing gap in brachytherapy training and experience is compounded with a lack of standardized training objectives. Consensus statement objectives were in part adapted with permission from the Royal College of Physician and Surgeons of Canada, and then further reviewed, modified and enriched with expert knowledge by all authors. Training objectives were further synchronized with the US Accreditation Council for Graduate Medical Education (ACGME). This ABS/GEC-ESTRO Consensus Statement of training objectives will facilitate brachytherapy training by outlining the necessary knowledge and procedural skills for successful practice in brachytherapy. The final brachytherapy curriculum development for any individual program, country and regions, is the responsibility of the individual programs and licensing jurisdictions and should be tailored to their patient population, available equipment and facilities.}, }
@article {pmid40609744, year = {2025}, author = {Banerjee, R and Amonoo, HL and Barata, A and Bhatt, NS and Espinoza-Gutarra, MR and Jayani-Kosarzycki, RV and Katz, H and Kennedy, VE and Nawas, M and Steineck, A and Wanjiku, C and Costanzo, E and Cusatis, RN and Knight, JM and Schoemans, H and Sidana, S and Wood, WA and Sung, AD and Lee, CJ and Hamilton, BK}, title = {Assessing Quality of Life and Symptoms in Transplantation and CAR-T Recipients: Expert Panel Recommendations from the Survivorship Special Interest Group of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.030}, pmid = {40609744}, issn = {2666-6367}, abstract = {Patient-reported outcomes (PROs) to measure quality of life (QOL) and other symptoms play an increasingly important role in clinical trials and regulatory approvals for hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. However, their adoption has been hindered by wide heterogeneity in the choice of PRO measures for clinical research, including the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT) and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) inventories. Additionally, the potential for PRO integration into routine standard-of-care (SOC) practice for patients undergoing HCT or CAR-T therapy has not yet been realized. As part of a coordinated effort by three American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Groups, we developed best practices for PRO integration in adult and pediatric recipients of HCT and CAR-T therapy. We strongly encourage the use of Patient-Reported Outcomes Measurement Information System (PROMIS) or PRO version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) instruments as the primary PRO measures for most HCT and CAR-T trials. Measures such as the PROMIS-29 inventory can be used for QOL assessments, while PRO-CTCAE item banks can be used for specific symptoms. Rationales for our strong recommendation to move from FACT-BMT and EORTC QLQ-C30 to PROMIS/PRO-CTCAE instruments include: (1) free licensing and ease of implementation, including in electronic medical records; (2) psychometric validation in a variety of oncologic settings, including during inpatient hospitalizations; (3) translation into multiple languages, with validation in both adult and pediatric settings; and (4) adoption into centrally-collected PRO protocols from the Center for International Blood and Marrow Transplant Research for both HCT and CAR-T recipients. Steps to operationalize these PRO measures are discussed, as are methods to migrate existing data from legacy PRO instruments. We similarly recommend the consideration of PRO integration into SOC clinical practice, including the development of threshold-based workflows to both personalize and standardize care in this setting. Other panel recommendations include the use of standardized timepoints for longitudinal PRO assessments and the inclusion of patient advocates when implementing PRO measures. Implementing these steps will improve the ability of PROs to improve outcomes for patients undergoing HCT or CAR-T therapy, both in trials and - more importantly - in SOC practice.}, }
@article {pmid40609573, year = {2025}, author = {Layman, RM and Han, HS and Rugo, HS and Stringer-Reasor, EM and Specht, JM and Dees, EC and Kabos, P and Suzuki, S and Mutka, SC and Sullivan, BF and Gorbatchevsky, I and Wesolowski, R}, title = {Overall survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer treated in a phase 1b trial evaluating gedatolisib in combination with palbociclib and endocrine therapy.}, journal = {The Lancet. Oncology}, volume = {26}, number = {7}, pages = {e332-e333}, doi = {10.1016/S1470-2045(25)00236-0}, pmid = {40609573}, issn = {1474-5488}, }
@article {pmid40609538, year = {2025}, author = {Severson, TM and Minnee, E and Zhu, Y and Schuurman, K and Nguyen, HM and Brown, LG and Hakkola, S and Menezes, R and Gregoricchio, S and Kim, Y and Kneppers, J and Linder, S and Stelloo, S and Lieftink, C and van der Heijden, MS and Nykter, M and van der Noort, V and Sanders, J and Morris, B and Jenster, G and van Leenders, GJ and Pomerantz, M and Freedman, ML and Beijersbergen, RL and Urbanucci, A and Wessels, L and Nelson, PS and Corey, E and Prekovic, S and Zwart, W and Bergman, AM}, title = {Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102215}, doi = {10.1016/j.xcrm.2025.102215}, pmid = {40609538}, issn = {2666-3791}, abstract = {Androgen receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase 2 clinical trial, we epigenetically profile enhancer/promoter activities with acetylation of lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identify a distinct subset of H3K27ac-differentially marked regions that are associated with treatment responsiveness, which we successfully validate in mCRPC patient-derived xenograft (PDX) models. In silico analyses reveal histone deacetylase (HDAC)3 to critically drive resistance to hormonal interventions, which we validate in vitro. Critically, we identify the pan-HDAC inhibitor vorinostat to be effective in decreasing tumor cell proliferation, both in vitro and in vivo. Moreover, we uncover evidence for HDAC3 working together with glucocorticoid receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate the rationale for therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.}, }
@article {pmid40609469, year = {2025}, author = {Chen, J and Hart, JE and VoPham, T and Elliott, EG and Jones, RR and Ward, MH and Laden, F and Birmann, BM}, title = {Ambient dioxin exposure and incidence of lymphoid malignancies in large prospective US cohorts of female nurses.}, journal = {Journal of hazardous materials}, volume = {495}, number = {}, pages = {139115}, doi = {10.1016/j.jhazmat.2025.139115}, pmid = {40609469}, issn = {1873-3336}, abstract = {BACKGROUND: Limited evidence exists from prospective cohorts on residential dioxin exposure and incident non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). We assessed the associations in two US nationwide cohorts - the Nurses' Health Study (NHS, 1986-2012) and NHSII (1989-2019).
METHODS: We estimated residential proximity, duration of residence and emissions from industrial dioxin-emitting facilities within 3 km, 5 km, and 10 km radii. Outcomes included overall NHL, major NHL subtypes, and MM. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) with 95 % confidence intervals (CIs) and meta-analyzed cohort-specific results.
RESULTS: We observed 984 NHL and 227 MM cases in NHS (1,921,802 person-years), and 396 NHL and 61 MM cases in NHSII (2,845,710 person-years). We did not observe consistent associations between dioxin exposure and overall NHL or MM incidence. Results were heterogeneous across major NHL subtypes. Increased follicular lymphoma incidence was suggestively associated with residential proximity to dioxin-emitting facilities (HRyes vs. no and 95 % CI: 1.26, 0.95 -1.68) and duration of residence near these facilities (HR≤median vs. non-exposed and 95 % CI: 1.44, 0.98 -2.12) and significantly with dioxin emission levels (HR≤median vs. non-exposed and 95 % CI: 1.52, 1.07 -2.16) within 3 km. These positive associations remained suggestive for up to 10 km.
CONCLUSION: Dioxin exposure showed no consistent association with overall NHL or MM, but a positive association with follicular lymphoma was suggested.}, }
@article {pmid40608157, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, AB and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology}, volume = {33}, number = {1}, pages = {14}, pmid = {40608157}, issn = {1573-6849}, support = {R35 GM149357/NH/NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; DP5 OD029630/OD/NIH HHS/United States ; DP5-OD029630/NH/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35GM134842/NH/NIH HHS/United States ; }, mesh = {*Centromere/metabolism/genetics ; *Microtubules/metabolism ; Kinetochores/metabolism ; *Kluyveromyces/genetics/metabolism ; Nucleosomes/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Chromosome Segregation ; Centromere Protein A ; Thermotolerance ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast, which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere, but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid40607811, year = {2025}, author = {Simonich, CAL and McMahon, TE and Ju, X and Yu, TC and Brunette, N and Stevens-Ayers, T and Boeckh, MJ and King, NP and Greninger, AL and Bloom, JD}, title = {RSV F evolution escapes some monoclonal antibodies but does not strongly erode neutralization by human polyclonal sera.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0053125}, doi = {10.1128/jvi.00531-25}, pmid = {40607811}, issn = {1098-5514}, abstract = {Vaccines and monoclonal antibodies targeting the respiratory syncytial virus (RSV) fusion protein (F) have recently begun to be widely used to protect infants and high-risk adults. Some other viral proteins evolve to erode polyclonal antibody neutralization and escape individual monoclonal antibodies. However, the impact of RSV F evolution on antibody neutralization is not yet thoroughly understood. Here, we develop an experimental system for measuring neutralization titers against RSV F using pseudotyped lentiviral particles. This system is easily adaptable to evaluate neutralization of relevant clinical strains. We apply this system to demonstrate that the natural evolution of RSV F leads to escape from some monoclonal antibodies, but at most modestly affects neutralization by polyclonal serum antibodies. Overall, our work sheds light on RSV antigenic evolution and describes a tool to measure the ability of antibodies and sera to neutralize contemporary RSV strains.IMPORTANCEWe describe an efficient approach to measure how antibodies inhibit infection by historical and recent human strains of respiratory syncytial virus (RSV). This approach is useful for understanding how viral evolution affects antibody immunity. We apply this approach to demonstrate that RSV evolution can escape some monoclonal antibodies, but polyclonal serum antibodies are less impacted by viral evolution. This information is relevant given the recent development of RSV preventative measures, including monoclonal antibodies and vaccines.}, }
@article {pmid40605797, year = {2025}, author = {Orozco, JJ and Matesan, MC and Lundberg, SJ and Haaf, RL and Miyaoka, RS and Fisher, DR and Gooley, TA and Green, DJ and Sandmaier, BM and Martin, PS and Gopal, AK}, title = {Pretargeted Anti-CD20 Radioimmunotherapy with scFv Fusion Protein Safely Combines with BEAM and ASCT in patients with High-Risk B-cell Lymphomas.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1158/1535-7163.MCT-24-0550}, pmid = {40605797}, issn = {1538-8514}, abstract = {Despite new therapies, many patients with NHL relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pre-targeted radioimmunotherapy (PRIT), when combined with BEAM and autologous stem cell transplantation (ASCT) for NHL patients. High-risk NHL patients received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y), or with indium-111 (111In for imaging) on day -14. BEAM chemotherapy started day -7 before stem cell infusion. Three NHL patients (MCL, transformed DLBCL, and de novo DLBCL), ages 52-62 years, were treated with 30, 50, or 70 mCi (1110, 1850, or 2590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic (PK) studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 min after infusion (14.8 - 49.4 % ID), with only 0.82 - 2.59 % ID after 72 hours. Uptake was preferential at bone marrow (1.73 - 5.96 cGy/mCi injected) and spleen (2.4 - 4.17 cGy/mCi injected) compared to lungs (0.19 - 0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the 3 enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. PK, dosimetry, and outcomes data support that B9E9-FP PRIT and 90Y-augmented ASCT DOTA-Bt is feasible.}, }
@article {pmid40605713, year = {2025}, author = {Danilov, AV and Li, H and Shadman, M and Rimsza, L and Zebari, A and Smith, SM and LeBlanc, M and Friedberg, JW and Carlson, C and Song, JY}, title = {Minimal residual disease status predicts outcomes in patients with follicular lymphoma treated with chemo-immunotherapy on the SWOG S0016 trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288057}, pmid = {40605713}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid40605619, year = {2025}, author = {Pearson, RA and Krish, KN and Whatney, WE and Jaoko, W and Mandaliya, K and Overbaugh, J and Graham, SM and McClelland, RS and Hicks, SL and Maurer, J and Scharer, CD and Day, CL}, title = {Single-cell transcriptomics reveals depletion and dysregulation of Mycobacterium tuberculosis-specific Th1 and Th17 cells early after acquisition of HIV.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf354}, pmid = {40605619}, issn = {1537-6613}, abstract = {HIV significantly increases the risk of developing tuberculosis (TB) and is associated with impaired CD4 T cell responses to Mycobacterium tuberculosis (Mtb). We evaluated the frequency and functional capacity of Mtb-specific CD4 T cells in individuals with and without HIV using flow cytometry and performed single-cell RNA sequencing on these cells longitudinally in a subset of individuals before and after acquisition of HIV. Our findings reveal preferential depletion and functional impairment of Mtb-specific CD4 T cells early after acquisition of HIV, characterized by reduced cytokine production, loss of effector functions, and transcriptional dysregulation. Mtb-specific Th1 and Th17 cells decreased, whereas TCF7+ stem-like cells were enriched following acquisition of HIV. Pathway analysis revealed upregulation of hypoxia and WNT signaling, and downregulation of cell adhesion, migration, antigen processing, and cytokine signaling pathways. These findings provide novel insights into HIV-mediated dysregulation of CD4 T cell responses to Mtb.}, }
@article {pmid40603473, year = {2025}, author = {Banjoko, AW and Ng'uni, T and Naidoo, N and Ramsuran, V and Hyrien, O and Ndhlovu, ZM}, title = {High resolution class I HLA-A, -B, and -C diversity in Eastern and Southern African populations.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {23667}, pmid = {40603473}, issn = {2045-2322}, support = {SANTHE COL018//Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE)/ ; INV-027499/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; INV-048833//Bill and Melinda Gates Foundation/ ; R01A1181690//National Institutes of Health, NIH/NIAID/ ; INV-027090/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *Genetic Variation ; Gene Frequency ; Haplotypes ; *Black People/genetics ; *HLA-A Antigens/genetics ; *HLA-B Antigens/genetics ; Alleles ; *HLA-C Antigens/genetics ; Linkage Disequilibrium ; Africa, Southern ; Genetics, Population ; Africa, Eastern ; }, abstract = {Africa, being one of the most genetically diverse regions in the world, remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data. The extensive genetic variation in HLA alleles across the region underscores the need for population-specific immunogenetic data to guide T-cell vaccine development. This study analysed Class I HLA data from Eastern and Southern African populations to assess regional genetic diversity. Analyses included allele and haplotype frequency distributions, deviations from Hardy-Weinberg equilibrium, linkage disequilibrium, and homozygosity test of neutrality across various populations. To further contextualise African HLA diversity, comparisons were made among African populations and also with African American and European American populations using the Hellinger diversity index and multidimensional scaling methods. The results revealed that South African populations exhibited an estimated average of 34.1% genetic diversity with respect to other African populations. Rwanda demonstrated an estimated 26.9% genetic diversity, Kenya (26.5%), Zambia (26.5%), and Uganda (24.7%). Additionally, in-country analyses revealed variations in HLA diversity among different tribes within each country. The estimated average in-country diversity was 51% in Kenya, 35.8% in Uganda, and 33.2% in Zambia. These results reveal various levels of genetic diversity among African populations. The highlighted differences in HLA Class I allele frequencies between Eastern and Southern African populations compared to US populations, demonstrate that it is inappropriate to extrapolate HLA data from US populations including that of African Americans when designing T-cell-inducing vaccines tailored to African populations. Our findings underscore the urgent need to generate high-resolution HLA data to guide vaccine development tailored to African populations.}, }
@article {pmid40601110, year = {2025}, author = {Hyde, ET and Evenson, KR and Howard, AG and Parada, H and Di, C and LaMonte, MJ and Bellettiere, J and Cuthbertson, CC and Lee, IM and LaCroix, AZ}, title = {Sitting time and risk of cancer incidence and cancer mortality in postmenopausal women: the Women's Health Accelerometry Collaboration.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40601110}, issn = {1573-7225}, support = {T32HL07989/HL/NHLBI NIH HHS/United States ; 75N92021D00002, HL153462, HL151885, HL150170, and HL130591/HL/NHLBI NIH HHS/United States ; U54 CA285117 & U54 CA285115//SDSU/UCSD Cancer Center Comprehensive Partnership/ ; P30 AG059299/AG/NIA NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; 31KT1501//Tobacco-Related Disease Research Program/ ; }, abstract = {PURPOSE: Few studies have explored whether accelerometer-measured sedentary behavior increases cancer risk. We examined the associations of accelerometer-measured daily sitting time and mean sitting bout duration classified by the Convolutional Neural Network Hip Accelerometer Posture (CHAP) machine-learned algorithm with incidence of any cancer, incidence of 13 physical activity-related cancers, and cancer mortality among postmenopausal women.
METHODS: We used data from 22,097 women (mean age = 73.3 years, standard deviation [SD] = 6.7) in the Women's Health Accelerometry Collaboration, a consortium of two US-based cohort studies of postmenopausal women: the Women's Health Study and the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Women who completed hip-worn triaxial accelerometry for ≥ 4 of 7 consecutive days were included. Associations between sedentary behaviors and physician-adjudicated invasive cancer incidence and mortality were tested using Cox regression.
RESULTS: Women were followed on average 8.0 years to identify cancer cases (n = 1,861) and deaths (n = 601). Overall, mean sitting time was 567 (SD = 113) min/day and mean sitting bout duration was 12.8 (SD = 4) min/bout. In covariate-adjusted models, one-SD increment higher in sitting time was associated with a 6% increased risk of incident cancer (hazard ratio [HR] = 1.06, 95% CI: 1.01-1.11); associations were similar for bout duration (HR = 1.05, 95% CI: 1.00-1.10). Estimates were similar for the 13 physical activity-related cancers (sitting time: HR = 1.10, 95% CI: 1.04-1.17; bout duration: HR = 1.08, 95% CI: 1.02-1.14) and for cancer mortality (sitting time: 1.06, 95% CI: 0.98-1.16; bout duration: HR = 1.05, 95% CI: 0.97-1.13).
CONCLUSION: Among postmenopausal women, sedentary behavior was associated with increased cancer risk, particularly for physical activity-related cancers and cancer mortality.}, }
@article {pmid40600502, year = {2025}, author = {Stansfield, SE and Moore, M and Jamieson, L and Meyer-Rath, G and Johnson, LF and Kaftan, D and Bershteyn, A and Smith, J and Cambiano, V and Bansi-Matharu, L and Phillips, A and Heitner, J and Barnabas, RV and Hanscom, B and Donnell, DJ and Boily, MC and Dimitrov, D}, title = {Estimated impact of long-acting injectable PrEP in South Africa: a model comparison analysis.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 2}, number = {Suppl 2}, pages = {e26453}, pmid = {40600502}, issn = {1758-2652}, support = {UM1 068617//the NIH NIAID/ ; R01 AI179417/AI/NIAID NIH HHS/United States ; 019496//Bill and Melinda Gates Foundation/ ; INV-007145/GATES/Gates Foundation/United States ; MR/T042796/1/MRC_/Medical Research Council/United Kingdom ; MR/X020258/1//MRC Centre for Global Infectious Disease Analysis/ ; //UK Medical Research Council/ ; //Global Health EDCTP3 Joint Undertaking/ ; }, mesh = {South Africa/epidemiology ; *Pre-Exposure Prophylaxis/methods ; *HIV Infections/prevention & control/epidemiology/transmission ; Humans ; *Anti-HIV Agents/administration & dosage ; Male ; Female ; *Pyridones/administration & dosage ; Tenofovir/administration & dosage ; Adult ; Injections ; Emtricitabine/administration & dosage ; Diketopiperazines ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) in two clinical trials. This analysis projects the impact of expanding PrEP coverage with CAB-LA in South Africa between 2022 and 2042.
METHODS: Three independently calibrated models of HIV transmission in South Africa (Synthesis, EMOD-HIV, Thembisa) projected HIV acquisitions and effective coverage (average PrEP coverage across exposure groups, weighted by HIV incidence in the absence of PrEP in each group) over 20 years under multiple scenarios of PrEP expansion compared to no PrEP expansion. PrEP expansion scenarios differed in targeted overall coverage, speed of expansion, coverage of high-exposure groups, and relative coverage of women and men.
RESULTS: Achieving 5% PrEP coverage with CAB-LA by 2032 prioritizing high-exposure groups resulted in 49% (Synthesis), 18% (EMOD-HIV), and 8% (Thembisa) effective coverage and averted a median of 43%, 29% and 10% of new HIV acquisitions, respectively. Similar expansion with TDF/FTC resulted in lower impact by 19 percentage points (pp), 18pp and 3pp, respectively. Increasing CAB-LA coverage to 15% led to an additional 7pp, 12pp and 16pp, respectively, of HIV acquisitions averted. Achieving 5% CAB-LA coverage expanding to women only resulted in a lower impact by 16pp (Synthesis) and 13pp (EMOD-HIV), and a higher impact by 2pp (Thembisa). Scenarios with similar effective coverage resulted in comparable impact estimates across models.
CONCLUSIONS: Offering CAB-LA in South Africa may substantially impact the HIV epidemic based on these projections. Effective coverage proved to be a good predictor of intervention effectiveness.}, }
@article {pmid40600473, year = {2025}, author = {Noller, K and Botsis, T and Camara, PG and Ciotti, L and Cooper, LA and Goecks, J and Griffith, M and Haas, BJ and Ideker, T and Karchin, R and Kontos, D and Lai, J and Marcus, D and Meyer, CA and Naegle, K and Pati, S and Peters, B and Pratt, D and Raphael, BJ and Reich, M and Savova, GK and Wright, C and Fertig, EJ and Bakas, S}, title = {Informatics at the Frontier of Cancer Research.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-24-2829}, pmid = {40600473}, issn = {1538-7445}, abstract = {Digitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterization, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of cancer research.}, }
@article {pmid40598755, year = {2025}, author = {Grinsztejn, B and Appay, V and Bekker, LG and Beyrer, C and Donnell, D and Sanchez, J and Canagasabey, D and Coutinho, C and Ganor, Y and Muturi-Kioi, V and Ortblad, KF and Cooney, E and Devisich, G and Ellenberg, P and Ghiglione, Y and K'Orimba, K and Ssemambo, PK and Ludwig-Barron, NT and Mielke, DK and Mullick, R and Muthui, MK and Radusky, PD and Sendaula, E and Tirmizi, SRH and Sanchez, AVM and Vega, J and Pebody, R}, title = {The science at HIVR4P 2024: The era of choice in biomedical HIV prevention.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {7}, pages = {e70001}, pmid = {40598755}, issn = {1758-2652}, support = {//Roger Pebody and Dr Wendy Smith/ ; //International AIDS Society/ ; }, mesh = {Humans ; AIDS Vaccines/administration & dosage/immunology ; Anti-HIV Agents/therapeutic use ; *HIV Infections/prevention & control ; Peru ; *Pre-Exposure Prophylaxis/methods ; Congresses as Topic ; }, abstract = {INTRODUCTION: HIVR4P 2024, the 5th HIV Research for Prevention Conference, took place in Lima, Peru, 6-10 October 2024. The conference focused on new developments in HIV prevention from basic research to new product development and implementation science.
METHODS: Sessions were assigned to one of five tracks: basic science; pre-exposure prophylaxis (PrEP) and antiretroviral (ARV)-based prevention; vaccines and broadly neutralizing antibodies (bNAbs); applied and implementation science; and other prevention modalities and cross-cutting issues. A team of rapporteurs covered each track and identified conference highlights.
RESULTS: Strategies to elicit bNAb responses by vaccination are advancing to clinical trials, while combination bNAbs show promise as an alternative to ARV-based products. There is promising diversity in the PrEP product pipeline and twice-yearly lenacapavir has demonstrated exceptional efficacy, but barriers to widespread access and implementation remain, compounded by new challenges from the significant policy changes and funding reductions of the new US administration. Innovative ways of delivering PrEP to vulnerable communities that could benefit are being explored and, in some cases, have been successfully implemented.
DISCUSSION: Choice in HIV prevention products and differentiated delivery models that enable clients to select options that meet their preferences and changing needs is essential. Additionally, the involvement of the community throughout the design, implementation and dissemination process is necessary to maximize the impact of HIV prevention. Ensuring equitable access in a rapidly changing context will involve policy changes, partnerships with local organizations and addressing social determinants that impact health outcomes.
CONCLUSIONS: We are in an era with more tools than ever before to prevent HIV acquisition; now, we need to facilitate collaborations between diverse stakeholders, including researchers, community members, policymakers, healthcare providers and funders. The future of HIV prevention should lie in a holistic approach that respects individual choice, enhances service accessibility and is flexible to meet evolving challenges and opportunities. However, policy changes since the conference ended have profoundly altered the HIV prevention landscape and threaten the advances described in this report.}, }
@article {pmid40598383, year = {2025}, author = {Mangale, DI and Heitner, J and Ortblad, KF and Mogere, P and Kiptinness, C and Mugo, NR and Baeten, JM and Ngure, K and Barnabas, R}, title = {Opportunity for cost savings with a novel differentiated model of PrEP delivery: a comparative costing analysis of six-month PrEP supported by interim HIV self-testing and standard of care PrEP dispensing in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {865}, pmid = {40598383}, issn = {1472-6963}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; R01 MH113572/MH/NIMH NIH HHS/United States ; R01MH113572/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/economics/methods ; *HIV Infections/prevention & control/diagnosis/economics ; *Cost Savings ; *Anti-HIV Agents/economics/therapeutic use/administration & dosage ; Male ; *Self-Testing ; Female ; }, abstract = {BACKGROUND: Cost remains an important barrier to HIV pre-exposure prophlyaxis (PrEP) delivery in Africa. Simplified delivery models that reduce costs without compromising PrEP outcomes are needed. The JiPime-JiPrEP trial tested a model of six-month PrEP dispensing supported with interim HIV self-testing (HIVST) and found non-inferior HIV testing, PrEP refilling, and adherence compared to three-month PrEP dispensing and quarterly clinic visits, the standard-of-care (SOC). We estimated the cost of this novel differentiated PrEP delivery model compared to SOC in Kenya.
METHODS: Using activity-based micro-costing (payer perspective) and time-and-motion observations, we estimated the cost of PrEP delivery (per client-month) in the intervention and SOC between May 2018 to December 2019. Data from budgets and expense reports, published documents, and interviews informed our estimates. We calculated costs over a one-year horizon for: 1) the trial scenario (i.e., costs within the trial), and 2) the Ministy of Health (MOH) scenario (i.e., hypothetical costs at public clinics). Estimates were in 2019 US dollars and excluded research-related costs.
RESULTS: The mean personnel time attributable to PrEP delivery was 76 minutes per visit and 152 minutes projected over a year in the intervention and 54 minutes per visit and 282 minutes per year in the SOC. In the trial scenario, PrEP delivery cost $17.73 per client-month in the intervention (n=2039 PrEP-months) and $25.50 in the SOC (n=913 PrEP-months). The projected cost of PrEP delivery in the MOH scenario was $11.94 in the intervention and $14.76 in the SOC, with the addition of HIVST kits in the intervention more than offset by personnel savings. In this scenario, personnel (intervention: 55%; SOC: 44%) and medication (intervention: 16%; SOC: 32%) were the primary cost drivers. Including serum creatine testing twice a year in the MOH scenario resulted in a slight increase in the cost of PrEP delivery in the intervention ($12.88 per client-month) versus SOC ($16.17 per client-month).
CONCLUSIONS: Six-month PrEP with interim HIVST demonstrated lower costs than three-month dispensing, with decreased personnel time. Scale-up of PrEP delivery requires efficient use of limited resources; the savings in this model of PrEP delivery could be redirected towards currently unmet medical needs.
CLINIAL TRIAL NUMBER: NCT03593629|| https://www.
CLINICALTRIALS: gov/ with the Clinical Trial Registry (Registration date: 2018-07-20).}, }
@article {pmid40595741, year = {2025}, author = {Zheng, Y and Caron, DP and Kim, JY and Jun, SH and Tian, Y and Mair, F and Stuart, KD and Sims, PA and Gottardo, R}, title = {ADTnorm: robust integration of single-cell protein measurement across CITE-seq datasets.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5852}, pmid = {40595741}, issn = {2041-1723}, support = {U19 AI128949/AI/NIAID NIH HHS/United States ; T32 AI106711/AI/NIAID NIH HHS/United States ; K99 HG012797/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; HG012797//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Single-Cell Analysis/methods ; Humans ; Antibodies/immunology ; Transcriptome ; *Epitopes/genetics/immunology ; Gene Expression Profiling/methods ; *Membrane Proteins/genetics/metabolism ; High-Throughput Nucleotide Sequencing/methods ; COVID-19/virology ; }, abstract = {Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm, a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations with negative- and positive-expression of surface protein markers across 13 public datasets, effectively removing technical variation across batches and improving cell-type separation. ADTnorm enables efficient integration of public CITE-seq datasets, each with unique experimental designs, paving the way for atlas-level analyses. Beyond normalization, ADTnorm includes built-in utilities to aid in automated threshold-gating as well as assessment of antibody staining quality for titration optimization and antibody panel selection. Applying ADTnorm to an antibody titration study, a published COVID-19 CITE-seq dataset, and a human hematopoietic progenitors study allowed for identifying previously undetected phenotype-associated markers, illustrating a broad utility in biological applications.}, }
@article {pmid40595413, year = {2025}, author = {Luecken, MD and Gigante, S and Burkhardt, DB and Cannoodt, R and Strobl, DC and Markov, NS and Zappia, L and Palla, G and Lewis, W and Dimitrov, D and Vinyard, ME and Magruder, DS and Mueller, MF and Andersson, A and Dann, E and Qin, Q and Otto, DJ and Klein, M and Botvinnik, OB and Deconinck, L and Waldrant, K and Yasa, SN and Szałata, A and Benz, A and Li, Z and , and Bloom, JM and Pisco, AO and Saez-Rodriguez, J and Wulsin, D and Pinello, L and Saeys, Y and Theis, FJ and Krishnaswamy, S}, title = {Defining and benchmarking open problems in single-cell analysis.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {40595413}, issn = {1546-1696}, support = {T15//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 860329 Marie-Curie ITN "STRATEGY-CKD"//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 1F31CA257625//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 1SF3822N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; 101054957//European Commission (EC)/ ; 101054957//European Commission (EC)/ ; }, }
@article {pmid40593602, year = {2025}, author = {Cuénod, A and Chac, D and Khan, AI and Chowdhury, F and Hyppa, RW and Markiewicz, SM and Rice, A and Kholwadwala, A and Calderwood, SB and Ryan, ET and Harris, JB and LaRocque, RC and Bhuiyan, TR and Smith, GR and Qadri, F and Lypaczewski, P and Weil, AA and Shapiro, BJ}, title = {Prevalent chromosome fusion in Vibrio cholerae O1.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5830}, pmid = {40593602}, issn = {2041-1723}, support = {P500PB_214356//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; T32 HD007233/HD/NICHD NIH HHS/United States ; R01 AI106878/AI/NIAID NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; K08 AI123494/AI/NIAID NIH HHS/United States ; R56 AI106878/AI/NIAID NIH HHS/United States ; R37 AI106878/AI/NIAID NIH HHS/United States ; }, mesh = {*Chromosomes, Bacterial/genetics ; *Vibrio cholerae O1/genetics/isolation & purification/pathogenicity ; *Cholera/microbiology/transmission ; Humans ; Bangladesh ; Biofilms/growth & development ; Virulence Factors/genetics ; Genome, Bacterial ; }, abstract = {Two circular chromosomes are a defining feature of the bacterial family Vibrionaceae, including the pathogen Vibrio cholerae, with rare reports of isolates with a single, fused chromosome. Here, we use long-read sequencing to analyse 467 V. cholerae O1 isolates from 47 cholera patients and household contacts in Bangladesh. We identify several independent chromosome fusion events that are likely transmissible within a household. Fusions occur in a 12 kilobase-pair homologous sequence shared between the two chromosomes and are stable for at least 200 generations under laboratory conditions. We find no detectable effect of fusion on V. cholerae growth, virulence factor expression, or biofilm formation. The factors promoting fusion, affecting chromosome stability, and subtle phenotypic or clinical consequences merit further investigation.}, }
@article {pmid40593437, year = {2025}, author = {Grivas, P and Moon, HH}, title = {A Podcast on Real-World Evidence with Avelumab First-Line Maintenance and Treatment Sequencing in Locally Advanced or Metastatic Urothelial Carcinoma.}, journal = {Targeted oncology}, volume = {}, number = {}, pages = {}, pmid = {40593437}, issn = {1776-260X}, abstract = {Avelumab first-line maintenance is an approved treatment for cisplatin-eligible or -ineligible patients with advanced urothelial carcinoma (UC) who are progression free following first-line platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 phase 3 trial. In recent years, an increasing number of real-world studies have examined the effectiveness and safety of avelumab first-line maintenance in heterogeneous populations from different countries, expanding the clinical evidence base. In this podcast, we discuss findings from these real-world studies, which have complemented clinical trials and provided additional insights about overall effectiveness, treatment sequencing involving second-line enfortumab vedotin monotherapy or other options, and healthcare resource utilization. We also briefly discuss the evolving treatment landscape in advanced UC in addition to benefits and limitations of real-world studies in general. Overall, across multiple studies involving more than 3000 patients worldwide, real-world outcomes with avelumab first-line maintenance treatment have been consistent with findings from the JAVELIN Bladder 100 trial, confirming the clinical benefits of this treatment approach for patients with advanced UC who are encountered in day-to-day practice.}, }
@article {pmid40592341, year = {2025}, author = {Clark, ML and Simeonov, KP and Mowel, WK and Michieletto, MF and Joannas, L and Wright, JM and Erickson, I and Johnson, LR and Krishnan, R and de la Fuente-Núñez, C and Minn, AJ and Henao-Mejia, J}, title = {Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.06.006}, pmid = {40592341}, issn = {1097-4180}, abstract = {Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.}, }
@article {pmid40590852, year = {2025}, author = {Levis, MJ and Hamadani, M and Logan, BR and Jones, RJ and Singh, AK and Litzow, MR and Wingard, JR and Papadopoulos, EB and Perl, AE and Soiffer, RJ and Ustun, C and Ueda Oshima, M and Uy, GL and Waller, EK and Vasu, S and Solh, MM and Mishra, A and Muffly, LS and Kim, HJ and Stelljes, M and Najima, Y and Onozawa, M and Thomson, KJ and Chen, C and Hasabou, N and Rosales, M and Hill, JE and Gill, SC and Nuthethi, R and King, D and Mendizabal, AM and Devine, SM and Horowitz, MM and Chen, YB}, title = {Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016306}, pmid = {40590852}, issn = {2473-9537}, abstract = {We conducted a post-hoc analysis of data from BMT CTN 1506 (MORPHO), a randomized trial of gilteritinib versus placebo as post-transplantation maintenance for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 co-mutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD-negative pre-HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC versus RIC. NPM1 co-mutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. Only in participants who were NPM1 wild-type at diagnosis and were FLT3-ITD MRD-positive prior to HCT did MAC appear superior to RIC in preventing relapse. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from myeloablative conditioning, and that, much like AML therapy prior to HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. (NCT02997202).}, }
@article {pmid40590661, year = {2025}, author = {Søgaard, MT and Tseng, D and Gibbs, S and Wu, W and Nolan, LG and Yang, PY and Lai, M and Cao, J and Pipavath, S and Mayer-Blackwell, K and Newell, EW and Houghton, AM and Payne, KK and Chiou, SH and Nair, VS}, title = {T cell receptor profiling of blood to detect lung cancer.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-24-1109}, pmid = {40590661}, issn = {2326-6074}, abstract = {The blood T cell receptor (TCR) repertoire broadly reflects current and lifetime immune responses against infectious pathogens and cancer, but the circulating T cell repertoire remains a largely untapped resource for cancer biomarker studies due to repertoire complexity and limited profiling data. Here, we investigated the use of blood TCR sequencing for early detection of lung cancer. We sequenced the leukocyte fraction of peripheral blood from 633 individuals divided into a case-control (n=511) and a lung cancer screening cohort (n=122) representing over 12.6 million unique clonotypes. Based on the TCR repertoires in these individuals, we devised a Tumor Immune Lymphocyte Score (TILS) using either TCR specificity groups (TILS-A) or highly recurrent, 'public' TCR clonotypes (TILS-B) capable of detecting lung cancer. TILS-A consisted of 125 TCR specificity groups that outperformed the TILS-B classifier of 49 public, TCR(?)-V(?)-defined clonotypes for cancer detection. TILS classifiers provided predictive value after accounting for age, smoking status and nodule size in the lung cancer screening cohort and improved cancer prediction for individuals with indeterminate lung cancer risk. In the subgroup analysis, TILS-A was associated with lung cancer in both early- and late-stage disease, had improved accuracy when accounting for HLA status and was validated in an external dataset studying lung cancer initiation. Collectively, these data suggest that profiles of the circulating T cell response can provide value for lung cancer detection and supports its use as a diagnostic tool.}, }
@article {pmid40590452, year = {2025}, author = {Brown, TT and Arao, RF and Warsi, M and Phanuphak, N and Vasconcelos, R and Oyedele, T and Sullivan, PA and Hanscom, B and Rooney, JF and Rinehart, AR and McCauley, M and Grinsztejn, B and Landovitz, RJ}, title = {Bone Changes With Long-Acting Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention in Cisgender Men and Transgender Women: HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf221}, pmid = {40590452}, issn = {1537-6591}, abstract = {In a randomized clinical trial, pre-exposure prophylaxis (PrEP) with long-acting cabotegravir (CAB-LA) had a better bone safety profile than tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) over 105 weeks. For individuals with low bone mineral density or other fracture risk factors, CAB-LA PrEP should be considered over TDF-based PrEP. Clinical Trials Registration. clinicaltrials.gov (NCT02720094).}, }
@article {pmid40589281, year = {2025}, author = {Wright, JD and Prest, MT and Ferris, JS and Chen, L and Xu, X and Rouse, KJ and Melamed, A and Hur, C and Heckman-Stoddard, BM and Samimi, G and Bickell, NA and Layne, TM and Myers, ER and Havrilesky, LJ and Blank, SV and Stout, NK and Hazelton, WD and Kong, CY and Elkin, EB}, title = {Projected Trends in the Incidence and Mortality of Uterine Cancer in the United States.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {7}, pages = {1156-1166}, pmid = {40589281}, issn = {1538-7755}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; 1U01 CA265739//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Female ; *Uterine Neoplasms/mortality/epidemiology ; Incidence ; United States/epidemiology ; Middle Aged ; Aged ; Adult ; White People/statistics & numerical data ; Black or African American/statistics & numerical data ; White ; }, abstract = {BACKGROUND: To develop a natural history model for uterine cancer calibrated to population-based incidence and mortality data to project future trends in the disease through 2050.
METHODS: We developed a state-transition microsimulation model of uterine cancer. The model begins at 18 years of age and simulates Black and White patients, includes transition states for precursor lesions, and separately models endometrioid and nonendometrioid tumors. The model was calibrated to population-based incidence and mortality data using parameter extrapolation.
RESULTS: The model closely fit population-based incidence and mortality data of uterine cancer. From 2020 to 2050, the incidence of uterine cancer is projected to increase in White women to 74.2 cases per 100,000 (compared with 57.7 cases per 100,000 in 2018) and increase to 86.9 per 100,000 (compared with 56.8 cases per 100,000 in 2018) in Black women. Among White women, incidence-based mortality will increase from 6.1 per 100,000 in 2018 to 11.2 per 100,000 in 2050, whereas incidence-based mortality in Black women will increase from 14.1 per 100,000 to 27.9 per 100,000. Endometrioid tumors are expected to increase considerably in both White and Black women; White women will experience only a slight increase in nonendometrioid tumors, whereas the incidence of these tumors will increase substantially in Black women.
CONCLUSIONS: The incidence and mortality of uterine cancer are projected to increase substantially over the next three decades. Black women will experience a disproportionate increase in the disease.
IMPACT: Projecting the incidence and mortality of uterine cancer can facilitate future cancer control efforts.}, }
@article {pmid40588476, year = {2025}, author = {Banerjee, R and Hosoya, H and Mikkilineni, L and Hansen, DK and Wolf, JL and Lin, Y}, title = {Managing IEC-associated enterocolitis following CAR-T therapy in multiple myeloma.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {112}, pmid = {40588476}, issn = {2044-5385}, }
@article {pmid40588371, year = {2025}, author = {Patel, SP and Fisher, J and Chae, YK and Soto, LS and Kasi, A and Konda, B and Walshauser, M and Parra, E and Zhang, J and Duault, C and Gonzalez-Kozlova, E and Manyam, G and Zhang, J and Chen, H and Duose, DY and Laberiano Fernandez, C and Luthra, R and Al-Atrash, G and Kim-Schulze, S and Maecker, HT and Wistuba, II and Gnjatic, S and Lee, JJ and Zhang, J and Magner, CM and Chen, HX and Sharon, E and Othus, M and Ryan, CW and Blanke, C and Haymaker, CL and Kurzrock, R}, title = {Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {6}, pages = {}, pmid = {40588371}, issn = {2051-1426}, support = {UG1 CA233331/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; U24 CA224319/CA/NCI NIH HHS/United States ; R33 CA263705/CA/NCI NIH HHS/United States ; U01 DK124165/DK/NIDDK NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U24 CA224316/CA/NCI NIH HHS/United States ; U24 CA224285/CA/NCI NIH HHS/United States ; U10 CA180828/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U24 CA224309/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; P30 CA196521/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Pancreatic Neoplasms/drug therapy/mortality/pathology ; Female ; Middle Aged ; Aged ; Adult ; *CTLA-4 Antigen/antagonists & inhibitors ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Nivolumab/therapeutic use/pharmacology ; *Neuroendocrine Tumors/drug therapy ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Ipilimumab/therapeutic use/pharmacology ; }, abstract = {PURPOSE: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.
EXPERIMENTAL DESIGN: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.
RESULTS: 19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited.
CONCLUSIONS: Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients.
TRIAL REGISTRATION NUMBER: NCT02834013.}, }
@article {pmid40586142, year = {2025}, author = {Glover, R and Yeboah, B and Vassallo, RR and Stolla, M and Panch, SR and Khan, J and Kogler, VJ and Luckey, CJ and Gorham, JD}, title = {It is time to eliminate the one-hour corrected count increment in the diagnostic workup of platelet transfusion refractoriness.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18327}, pmid = {40586142}, issn = {1537-2995}, }
@article {pmid40585005, year = {2025}, author = {Brittain, JS and Tsui, J and Inward, R and Gutierrez, B and Mwanyika, G and Tegally, H and Huynh, T and Githinji, G and Tessema, SK and McCrone, JT and Bhatt, S and Dasgupta, A and Ratcliffe, S and Kraemer, MUG}, title = {GRAPEVNE - Graphical Analytical Pipeline Development Environment for Infectious Diseases.}, journal = {Wellcome open research}, volume = {10}, number = {}, pages = {279}, pmid = {40585005}, issn = {2398-502X}, abstract = {The increase in volume and diversity of relevant data on infectious diseases and their drivers provides opportunities to generate new scientific insights that can support 'real-time' decision-making in public health across outbreak contexts and enhance pandemic preparedness. However, utilising the wide array of clinical, genomic, epidemiological, and spatial data collected globally is difficult due to differences in data preprocessing, data science capacity, and access to hardware and cloud resources. To facilitate large-scale and routine analyses of infectious disease data at the local level (i.e. without sharing data across borders), we developed GRAPEVNE (Graphical Analytical Pipeline Development Environment), a platform enabling the construction of modular pipelines designed for complex and repetitive data analysis workflows through an intuitive graphical interface. Built on the Snakemake workflow management system, GRAPEVNE streamlines the creation, execution, and sharing of analytical pipelines. Its modular approach already supports a diverse range of scientific applications, including genomic analysis, epidemiological modeling, and large-scale data processing. Each module in GRAPEVNE is a self-contained Snakemake workflow, complete with configurations, scripts, and metadata, enabling interoperability. The platform's open-source nature ensures ongoing community-driven development and scalability. GRAPEVNE empowers researchers and public health institutions by simplifying complex analytical workflows, fostering data-driven discovery, and enhancing reproducibility in computational research. Its user-driven ecosystem encourages continuous innovation in biomedical and epidemiological research but is applicable beyond that. Key use-cases include automated phylogenetic analysis of viral sequences, real-time outbreak monitoring, forecasting, and epidemiological data processing. For instance, our dengue virus pipeline demonstrates end-to-end automation from sequence retrieval to phylogeographic inference, leveraging established bioinformatics tools which can be deployed to any geographical context. For more details, see documentation at: https://grapevne.readthedocs.io.}, }
@article {pmid40581741, year = {2025}, author = {Harlass, M and Knudsen, AB and Nieboer, D and van Duuren, LA and Kuntz, KM and Rutter, CM and Nascimento de Lima, P and Collier, N and Ozik, J and Hahn, AI and Alarid-Escudero, F and Zauber, AG and Inadomi, JM and Meester, RGS and Lansdorp Vogelaar, I}, title = {Benefits of colorectal cancer screening using FIT with varying positivity thresholds by age and sex.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf149}, pmid = {40581741}, issn = {1460-2105}, abstract = {BACKGROUND: Fecal immunochemical test (FIT) performance for colorectal cancer (CRC) screening varies by age and sex, yet most FIT-based screening programs use uniform thresholds. This study assessed the potential benefits of stratifying FIT thresholds based on age and sex.
METHODS: We conducted a meta-analysis of FIT sensitivity and specificity at various positivity thresholds by age and sex. We then used these estimates in two microsimulation models of CRC and projected lifetime clinical outcomes, incremental costs, and quality-adjusted life-years gained (QALYG) from age- and sex-stratified FIT strategies. FIT thresholds ranged from 10 to 50 µg hemoglobin/g feces (µg/g).
RESULTS: For current uniform FIT screening (20 µg/g), models projected 85.67 to 122.15 QALYG at incremental costs of -$982 to $504 per 1,000 individuals compared to no screening. At equivalent costs to current uniform screening, only one model found stratified FIT approaches cost-effective, yielding a marginal increase of 1.04 and 1.10 QALYG/1,000 females and males, respectively. At a willingness-to-pay threshold of $100,000/QALYG, both models found stratified FIT cut-offs to be the best strategy, with cut-offs being equal or higher for men and lowest at older ages. Uniform strategies showed comparable effectiveness, falling within one quality-adjusted life day per person of efficient strategies at up to $112 more per person. Results were sensitive to FIT test performance characteristics and one-time setup costs.
CONCLUSION: Stratifying FIT thresholds by age and sex may be cost-effective compared to current screening. However, the gain in expected health benefits with stratified FIT screening is likely small.}, }
@article {pmid40581613, year = {2025}, author = {Maurice, NJ and Erickson, JR and DeJong, CS and Mair, F and Taber, AK and Frutoso, M and Islas, LV and Vigil, ALBG and Lawler, RL and McElrath, J and Newell, E and Sullivan, LB and Shree, R and McCartney, SA}, title = {Cytokine and metabolite networks shape T cell residency and functionality at the term human maternal-fetal interface.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {}, number = {}, pages = {}, doi = {10.1093/jimmun/vkaf093}, pmid = {40581613}, issn = {1550-6606}, support = {R21 AI144677/NH/NIH HHS/United States ; F31 HD098769/NH/NIH HHS/United States ; F99 CA245735/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; //Andy Hill Endowment Distinguished Researcher/ ; //Institute of Translational Health Sciences/ ; K12 HD000849/HD/NICHD NIH HHS/United States ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //Burroughs Wellcome Fund/ ; //Doris Duke Foundation/ ; }, abstract = {Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI), which affect T cell programming, but the identities (i.e. memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as proinflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of costimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although proinflammatory molecules elicit T cell effector functions, we show that additional cytokine (transforming growth factor β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, these data demonstrate that T cells at the MFI are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments in which they are enriched.}, }
@article {pmid40581329, year = {2025}, author = {Kalkeri, R and Zhu, M and Cloney-Clark, S and Parekh, A and Gorinson, D and Cai, Z and Cai, MR and Mahato, S and Chau, G and Babu, TM and Wald, A and Ramanathan, P and Aurelia, LC and Selva, KJ and Marchese, AM and Fries, L and Dunkle, LM and Chung, AW and Plested, JS}, title = {Anti-spike IgG4 and Fc effector responses: The impact of SARS-CoV-2 vaccine platform-specific priming and immune imprinting.}, journal = {The Journal of infection}, volume = {91}, number = {2}, pages = {106543}, doi = {10.1016/j.jinf.2025.106543}, pmid = {40581329}, issn = {1532-2742}, abstract = {Proportional increases in anti-Spike (S) IgG4 associated with decreased Fc effector functions have been reported following repeated mRNA, but not recombinant protein-based (rS) (NVX-CoV2373, Novavax, Inc.), SARS-CoV-2 vaccination. We demonstrate the first evidence of a negative correlation between anti-S IgG4 and neutralizing antibody (nAb), as well as antibody-dependent surrogate Fc effector functions. Priming with two NVX-CoV2373 vaccines followed by a third dose was associated with higher IgG1 and IgG3, lower IgG4, higher nAb titers and surrogate Fc effector functions versus mRNA. Immune imprinting of anti-S IgG4 and nAbs, and Fc effector function imprinting after mRNA priming was observed. This effect was partially overcome by updated XBB.1.5 protein subunit vaccination, but not by ancestral vaccine strains. We establish correlation of anti-S IgG4 responses to reduced nAbs and surrogate Fc effector functions and demonstrate the impact of additional booster vaccination on subsequent immune response and Fc effector functions in the context of ancestral and XBB.1.5 strains.}, }
@article {pmid40581305, year = {2025}, author = {Khawaja, F and Zamora, D and Yong, MK and Hakki, M and Goscicki, BK and Danziger-Isakov, L and Lin, A and Carpenter, PA and Boeckh, M and Papanicolaou, GA and Dadwal, SS and Chemaly, RF}, title = {American Society for Transplantation and Cellular Therapy Series #11: Updated Cytomegalovirus Guidelines in Hematopoietic Cell Transplant and Cellular Therapy Recipients.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.025}, pmid = {40581305}, issn = {2666-6367}, abstract = {The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with the society's Transplant Infectious Diseases Special Interest Group to update its previous infectious disease guidelines for the prevention and management of cytomegalovirus (CMV) infection and disease following hematopoietic cell transplantation (HCT)[1]. The two updates, published in 2021, focused on the prevention and management of CMV infection, respectively, including refractory and resistant CMV infections. To best serve clinical providers, each standalone topic in the infectious diseases series has been published in a concise format of frequently asked questions (FAQs). Adult and pediatric infectious diseases and HCT content experts developed the FAQs and the answers; recommendations were graded according to their strength (A-E) and the level of the supporting evidence (I-III). Several advances in CMV prevention and management since 2021 warranted an update to the original third and fourth topics in the series. This eleventh topic in the series focuses on new antiviral treatments for CMV, expanded indications of existing antiviral therapy for the prevention of CMV, and the treatment of CMV in special populations such as CAR T-cell therapy recipients and pediatric transplant recipients.}, }
@article {pmid40580948, year = {2025}, author = {Khor, S and Carlson, JJ and Basu, A and Bansal, A and Yu, K and Fedorenko, CR and Ramsey, S and Shankaran, V}, title = {The association between new cancer therapy innovations and financial toxicity.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf152}, pmid = {40580948}, issn = {1460-2105}, abstract = {BACKGROUND: Recent advancements in cancer treatments have improved survival rates, but rising costs associated with these innovations raise concerns about their financial impact on patients. This study investigates the trade-off between improved survival and the financial toxicity over time in advanced non-small cell lung cancer (NSCLC).
METHODS: We conducted a retrospective cohort study using linked data from the Western Washington SEER cancer registry and TransUnion credit records, focusing on adults diagnosed with advanced NSCLC, bladder, uterine, head and neck, and liver cancers between 2013 and 2017. Financial toxicity was assessed through major adverse financial events (AFEs), including collections, charge offs, liens, delinquent payments, foreclosures, repossessions, and bankruptcies. Multivariable multinomial logistic regression evaluated trends in a composite outcome of survival and AFEs for NSCLC patients within two years post-diagnosis. A falsification test evaluated a negative control group of advanced cancers lacking new therapies.
RESULTS: Our study included 6548 patients (mean age 69; 42% female; 86% non-Hispanic White). Two-year survival for NSCLC patients increased from 15.2% to 19.2% between 2013 and 2017 (mean change 4.0%pt, 95%CI 0.7, 7.3). The proportion of survivors without AFEs increased by 2.2%pt (95%CI -0.6, 5.1), while those alive with major AFEs increased by 1.9%pt (95%CI 0.02, 3.6). This trend was absent in the negative control group.
CONCLUSIONS AND RELEVANCE: The trade-off between survival gains and increased economic hardships linked to treatment innovations underscores the need to expand our focus beyond clinical outcomes and implement protective measures that ensure healthcare advancements promote population health without inducing financial distress.}, }
@article {pmid40579877, year = {2025}, author = {Dudakov, JA and van den Brink, MRM}, title = {Burning Down the House: Thymic Repair and Regeneration After Acute Damage.}, journal = {Immunological reviews}, volume = {332}, number = {1}, pages = {e70050}, doi = {10.1111/imr.70050}, pmid = {40579877}, issn = {1600-065X}, support = {R01-HL123340/HL/NHLBI NIH HHS/United States ; R01-HL145276/HL/NHLBI NIH HHS/United States ; R01-HL147584/HL/NHLBI NIH HHS/United States ; R01-HL165673/HL/NHLBI NIH HHS/United States ; R35-HL-171556/HL/NHLBI NIH HHS/United States ; P01-CA023766/CA/NCI NIH HHS/United States ; R01-CA228308/CA/NCI NIH HHS/United States ; R01-CA228358/CA/NCI NIH HHS/United States ; P01-AG052359/AG/NIA NIH HHS/United States ; U01-AI70035//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Thymus Gland/physiology/immunology/radiation effects ; *Regeneration ; Animals ; Signal Transduction ; Cytokines/metabolism ; }, abstract = {The thymus is extremely sensitive to insult but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage such as ionizing radiation leads to prolonged T cell lymphopenia for which there is currently no therapeutic treatment. We and others have been focusing in recent years on untangling the cellular and molecular mechanisms underlying endogenous thymic regeneration in the hope of being able to exploit them for clinical benefit. To date, multiple molecular mechanisms have been identified that are centered on several distinct cell axes, including interleukin-22 produced by innate lymphoid cells, BMP4 by endothelial cells, and type 2 cytokines from eosinophils, ILCs, and Tregs. Notably, one of the uniting triggers for these pathways of repair centers on the balance of cell death detection. In this review, we will highlight the current state of play with regard to cellular and molecular pathways of regeneration as well as the mechanisms triggering them. We will also highlight recent work that sheds light on the limitations of thymus repair and speculate as to what will be needed for an effective thymus-boosting therapy.}, }
@article {pmid40578716, year = {2025}, author = {Morrell, ED and Cheng, GS}, title = {Lumpers vs. Splitters: The Search for Treatable Traits in Post-Transplant BOS.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.healun.2025.06.010}, pmid = {40578716}, issn = {1557-3117}, }
@article {pmid40578660, year = {2025}, author = {Mitsunami, M and Soria-Contreras, DC and Ortiz-Panozo, E and Harris, HR and Missmer, SA and Chavarro, JE}, title = {Soy consumption and the risk of laparoscopically confirmed endometriosis in a prospective cohort study.}, journal = {Fertility and sterility}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.fertnstert.2025.06.028}, pmid = {40578660}, issn = {1556-5653}, abstract = {OBJECTIVE: To investigate the association of soy and isoflavone intake with the risk of laparoscopically confirmed endometriosis.
DESIGN: The Nurses' Health Study II, a prospective cohort study from 1991 to 2021.
SUBJECTS: 82,084 premenopausal participants aged 27-44 years in 1991 EXPOSURE: Soy and isoflavone intake was evaluated from 1991 and every 4 years using a food frequency questionnaire.
MAIN OUTCOME MEASURES: Self-reported laparoscopically confirmed endometriosis in biennial follow-up questionnaires. Cox proportional hazard models with age in months were used to calculate hazard ratios and 95% confidence intervals for laparoscopically-confirmed endometriosis. Restricted cubic splines were used to examine the possibility of non-linear relations between isoflavone intake and the risk of endometriosis.
RESULTS: 3,829 incident cases of laparoscopically confirmed endometriosis were reported over 1,038,888 person-years of follow-up (incidence rate = 369 per 100 000 person-years). Increasing soy intake by 1 serving per week was associated with a 8% lower risk of laparoscopically confirmed endometriosis (Hazard ratio=0.92, 95% confidence interval [0.87-0.98]). This association was present among participants without a concurrent report of infertility (Hazard ratio=0.92, 95% confidence interval [0.86, 0.99]) although not among participants with a concurrent infertility diagnosis (Hazard ratio=0.97, 95% confidence interval [0.83, 1.13], Test for heterogeneity 1.00). There was evidence of a non-linear inverse association of isoflavones intake with the risk of laparoscopically confirmed endometriosis (P, non-linearity = 0.02), in which the inverse association between isoflavones and endometriosis was approximately linear up until an intake of 4mg/day (∼95[th] percentile of intake), which plateaued thereafter.
CONCLUSION: In a population with a modest intake of soy products, consistent with levels seen in other Western populations, soy intake is associated with a lower risk of laparoscopically confirmed endometriosis.}, }
@article {pmid40578047, year = {2025}, author = {Ssenyonga, N and Stiller, CA and Marcos-Gragera, R and Kuehni, CE and Saint-Jacques, N and Bulliard, JL and Redaniel, MT and Nakata, K and Schwartz, S and De, P and Ragusa, R and Troussard, X and Curado, MP and Girardi, F and Maynadié, M and Valkov, M and Guilloteau, A and Lima, C and Coleman, MP and Allemani, C and , }, title = {Conditional survival of children, adolescents and young adults (0-24 years) diagnosed with leukaemia during 2000-2014 world-wide: (CONCORD-3).}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {225}, number = {}, pages = {115445}, doi = {10.1016/j.ejca.2025.115445}, pmid = {40578047}, issn = {1879-0852}, abstract = {BACKGROUND: Population-based survival estimates provide valuable insights into cancer care patterns world-wide. Access to optimal treatment leads to better outcomes, however, treatment pathways vary globally. Conditional survival is the probability that patients who have already survived for a given number of years since diagnosis will live for an additional number of years. It is a useful proxy to assess the success of initial treatment or remission of leukaemia.
METHODS: We analysed data for 164,563 patients aged 0-24 years diagnosed during 2000-2014, from 258 population-based cancer registries in 61 countries. Using the Pohar-Perme estimator, we estimated net survival at five years, conditional on surviving at least one year, and at 10 years conditional on surviving five years. To control for background mortality, we used life tables of all-cause mortality by single year of age, sex, country and calendar year. All-ages survival estimates were standardised to the marginal age distribution.
FINDINGS: During 2010-2014, age-standardised five-year conditional net survival ranged from 61.8 % in Mexico to 90 % or more in 20 countries. By 2010-2014, five-year conditional survival in most high-income countries exceeded 90 % for children, but not for older patients, and for acute myeloid leukaemia it was typically 5-10 % lower than for lymphoid leukaemia. Ten-year conditional survival was 90 % or higher in most countries, with less variation world-wide.
INTERPRETATION: World-wide variation in survival was less marked for patients who survived the first year(s) after diagnosis. Notable gains occurred in countries with initially lower five-year survival (e.g., China or Mexico), where legislative changes contributed to improved access to treatment for young patients with cancer. Nonetheless, inequalities persisted between high-income and low- and middle-income countries. Population-based cancer registry data remain essential to monitor further improvements.
FUNDING: Children with Cancer UK; the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute and the American Cancer Society.}, }
@article {pmid40577227, year = {2025}, author = {Perazzolo, S and Flexner, CW and Stephen, ZR and Acosta, EP and Bender Ignacio, RA and Ho, RJY}, title = {Long-acting Injectable Containing Lopinavir Eliminates Reliance on Ritonavir Pharmacokinetic Enhancement.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf319}, pmid = {40577227}, issn = {1537-6613}, abstract = {High-extraction protease inhibitors (e.g., for HIV and COVID-19) typically require ritonavir to enhance bioavailability by overcoming first-pass metabolism. However, in the long-acting subcutaneous injectable dosage form TLC-ART 101, lopinavir persisted in plasma for 57 days, while ritonavir was detectable for only 3-7 days. The remarkable duration of lopinavir suggests that ritonavir may be unnecessary in long-acting injectable products, potentially reducing side effects and drug-drug interactions.}, }
@article {pmid40576898, year = {2025}, author = {Goodsell, KE and Chauhan, SSB and Pillarisetty, VG and Sham, JG}, title = {Somatostatin Analogs for Preventing Postoperative Pancreatic Fistula: Past Evidence Reveals New Opportunities.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {40576898}, issn = {1534-4681}, abstract = {Postoperative pancreatic fistula (POPF) is the defining complication following pancreatectomy. The incidence of POPF after pancreatic resection remains high even at experienced centers, with associated patient morbidity, increased healthcare costs, and poorer oncologic outcomes. There is evidence that POPF is more frequent after distal pancreatectomy. On the basis of the premise that reduction in pancreatic exocrine secretion reduces the risk of fistula formation, somatostatin analogs (SSA) to prevent POPF and its sequelae have been studied for more than 30 years. However, evidence regarding their efficacy remains mixed. Early multicenter randomized control trials demonstrated a benefit of octreotide in reducing POPF, although subsequent single-center studies failed to confirm these results. Despite additional studies demonstrating a significant reduction in POPF with the use of newer SSAs including pasireotide and lanreotide, surgical practices in the use of somatostatin analogs in preventing POPF are highly variable. Herein, we review three decades of available data on SSA for POPF prophylaxis and highlight the need for pragmatic, focused, and data-driven design for future trials with modern agents.}, }
@article {pmid40576840, year = {2025}, author = {Mayer, J and Blanco-Melo, D and Coffin, JM and Gifford, RJ and Johnson, WE and Lindemann, D and Peeters, M and Sato, K and Stoye, J and Tachedjian, G and Hatziioannou, T}, title = {2024 taxonomy update for the family Retroviridae.}, journal = {Archives of virology}, volume = {170}, number = {8}, pages = {164}, pmid = {40576840}, issn = {1432-8798}, mesh = {*Retroviridae/classification/genetics ; Genome, Viral ; Phylogeny ; Terminology as Topic ; Humans ; }, abstract = {The Retroviridae are a family of viruses that reverse transcribe their RNA genome and integrate the resulting double-stranded DNA copy into the genome of the host cell. Retroviruses are well-documented pathogens that have been associated with a variety of diseases. The International Committee on Taxonomy of Viruses (ICTV) currently lists 65 species of retroviruses. As required by the ICTV, we have converted the species nomenclature to a binomial format comprised of the genus and a freeform epithet. Assigning binomial species names to classify new retroviruses will be facilitated when following the epithet rules described herein.}, }
@article {pmid40576634, year = {2025}, author = {Figueiredo, JC and Redwood, D and Li, L and Donato, E and Fort, D and Fox, EE and Grady, WM and Green, H and Harrison, TA and Haupt, C and Hsu, L and Hullar, MAJ and Huyghe, JR and Johnson, W and Koehne, AL and LaBrie, SD and Lakey, MA and Lin, M and Loroña, NC and Maresh, GA and Matrana, M and Mizrahi, JD and Nash, SH and Nguyen, NT and Paruch, JL and Phipps, AI and Qu, C and Randolph, TW and Romo, S and Thomas, CE and Thomas, S and Tiesinga, J and Whitlow, C and Yeung, CCS and Yin, H and Zibilich, CM and Li, CI and Thomas, TK and Peters, U}, title = {The Translational Research Program in Cancer Differences across Populations.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1711}, pmid = {40576634}, issn = {1538-7755}, abstract = {BACKGROUND: Colorectal cancer (CRC) incidence and mortality vary substantially across populations. The Translational Research Program in Cancer Differences across Populations (TRPCDP) was established in 2020 to address differences in CRC incidence and mortality rates within the United States.
METHODS: TRPCDP centralized data acquisition and harmonization across three sites in the U.S. to create a well-annotated resource of CRC tumors across four populations: African American/Black, Alaska Native, Hispanic/Latino/a, and non-Hispanic White. Using a case-control framework, patients with lethal CRC were matched to two controls with non-lethal CRC. Formalin-fixed paraffin-embedded tumor and normal tissue were retrieved and sent for centralized pathology review, followed by DNA and RNA extraction and tissue microarray development. Multi-omics and spatial profiling are underway to evaluate the transcriptome, proteome, and microbiome. Patient demographic and clinical data were obtained by medical record review, patient self-report, or linkage to cancer registries. Additional health-related factors were assessed using geospatial linkage.
RESULTS: The virtual biorepository includes 7,181 patients [African American (n=1,345), Alaska Native (n=1,640), Hispanic (n=1,659), and non-Hispanic White (n=2,537)]. Tissue blocks (1,594 tumor, 728 normal colon) were selected for 938 patients. To date, DNA and RNA have been extracted (n=831) and tissue microarrays have been constructed (n=414). Transcriptomic, spatial tumor profiling (multiplex immunofluorescence, PhenoCycler, GeoMx) and microbiome data (16S rRNAseq, ddPCR) are available.
CONCLUSION: The TRPCDP has developed a clinically annotated biorepository for future molecular epidemiology studies.
IMPACT: TRPCDP is a unique program that supports collaborative research, community engagement, and pipeline development for the next generation of scientists.}, }
@article {pmid40576334, year = {2025}, author = {Lee, EM and Srinivasan, S and Purvine, SO and Fiedler, TL and Leiser, OP and Proll, SC and Minot, SS and Djukovic, D and Raftery, D and Johnston, C and Fredricks, DN and Deatherage Kaiser, BL}, title = {Syntrophic bacterial and host-microbe interactions in bacterial vaginosis.}, journal = {The ISME journal}, volume = {19}, number = {1}, pages = {}, pmid = {40576334}, issn = {1751-7370}, support = {P41 GM103493/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; R01 AI061628/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; S10OD021562/RI/ORIP NIH HHS/United States ; R01AI061628/NH/NIH HHS/United States ; GM103493/GM/NIGMS NIH HHS/United States ; U19 AI113173/NH/NIH HHS/United States ; }, mesh = {Female ; *Vaginosis, Bacterial/microbiology ; Humans ; Vagina/microbiology ; *Host Microbial Interactions ; *Bacteria/metabolism/classification/genetics/isolation & purification ; Formates/metabolism ; Adult ; Putrescine/metabolism ; Proteomics ; Microbiota ; Bacterial Proteins/metabolism ; }, abstract = {Bacterial vaginosis (BV) is a common, polymicrobial condition of the vaginal microbiota that is associated with symptoms such as malodor and excessive discharge, along with increased risk of various adverse sequelae. Host-bacteria and bacteria-bacteria interactions are thought to contribute to the condition, but many of these functions have yet to be elucidated. Using untargeted metaproteomics, we identified 1068 host and 1418 bacterial proteins in a set of cervicovaginal lavage samples collected from 20 participants with BV and 9 who were negative for the condition. We identified Dialister micraerophilus as a major producer of malodorous polyamines and identified a syntrophic interaction between this organism and Fannyhessea vaginae that leads to increased production of putrescine, a metabolite characteristic of BV. Although formate synthesis has not previously been noted in BV, we discovered diverse bacteria associated with the condition express pyruvate formate-lyase enzymes in vivo and confirm these organisms secrete formic acid in vitro. Sodium hypophosphite efficiently inhibited this function in multiple taxa. We also found that the fastidious organism Coriobacteriales bacterium DNF00809 can metabolize formic acid secreted by Gardnerella vaginalis, representing another syntrophic interaction. We noted an increased abundance of the host epithelial repair protein transglutaminase 3 in the metaproteomic data, which we confirmed by enzyme-linked immunosorbent assay. Other proteins identified in our samples implicate Finegoldia magna and Parvimonas micra in the production of malodorous trimethylamine. Some bacterial proteins identified represent novel targets for future therapeutics to disrupt BV communities and promote vaginal colonization by commensal lactobacilli.}, }
@article {pmid40571676, year = {2025}, author = {Muskara, A and Parthasarathy, PB and Oyarbide, U and Ma, Y and Ganguly, S and Imamura, J and Liao, R and Rubin, BP and Macaskill, A and Murphy, ES and Anderson, PM and Gryder, BE and Scott, JG and Zahler, SG and Mian, OY}, title = {Transcriptomic Profiling of Relapsed Rhabdomyosarcoma: Pre- and Post-Treatment Tissue Analysis Reveals Molecular Characteristics of Treatment Failure.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e31864}, doi = {10.1002/pbc.31864}, pmid = {40571676}, issn = {1545-5017}, support = {//VeloSano Foundation Research/ ; P30CA043703//Case Comprehensive Cancer Center NIH/ ; P30CA043703//Case Comprehensive Cancer Center NIH/ ; //Case Comprehensive Cancer Center, Case Western Reserve University/ ; L30CA220908//NIH/NCI/ ; }, abstract = {BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Historically classified based on histology, advances in molecular profiling have allowed further sub-classification, which has improved risk stratification. Although molecular profiling has improved our understanding of disease progression and risk, the molecular evolution of therapy resistance in RMS remains poorly characterized. Transcriptomic profiling of patients with high-risk, relapsed RMS was undertaken with the goal of uncovering insights into the biology of RMS treatment failure.
PROCEDURE: Formalin-fixed, paraffin-embedded (FFPE) tissue samples from patients with relapsed RMS who had samples archived at diagnosis and relapse were obtained. Histologic subtype and PAX3/7::FOXO1 fusion status were confirmed. Transcriptomic profiling of the FFPE tissue samples was performed using the high-throughput genomics (HTG) whole transcriptome panel.
RESULTS: We identified 11 patients with relapsed RMS who had FFPE tissue samples archived at diagnosis and relapse following multimodality therapy. All patients were stratified as high risk, including five with PAX3/7::FOXO1 fusion-positive RMS (FP-RMS) and six with PAX3/7::FOXO1 fusion-negative RMS (FN-RMS). The transcriptomic analysis revealed that the myogenesis pathway and markers associated with myogenic differentiation were enriched pre-treatment in patients with FP-RMS and enriched post-treatment in patients with FN-RMS. Post-treatment enrichment of the inflammatory response pathway was observed in both FP-RMS and FN-RMS samples.
CONCLUSIONS: Using a probe-based transcriptome panel to characterize matched pre- and post-treatment tissue samples from patients with RMS, we report that relapsed RMS follows a fusion status-dependent evolutionary trajectory, marked by differential expression of myogenesis-associated genes, myogenic differentiation markers, and inflammatory response pathways.}, }
@article {pmid40570746, year = {2025}, author = {Giacani, L and Romeis, E and Haynes, A and Molini, BJ and Tantalo, LC and Xu, LH and Trejos, AT and Keane, J and Mohamed, Z and Armstrong, TD and Wieland, BA and Phung, Q and Vyshenska, D and Campbell, VL and Godornes, C and Koelle, DM and Reid, TB and Wang, Y and Vorobieva, AA and Wald, A and Lieberman, NAP and Greninger, AL}, title = {Immunization with full-length TprC variants induces a broad response to surface-exposed epitopes of the Treponema pallidum repeat protein family and is partially protective in the rabbit model of syphilis.}, journal = {Vaccine}, volume = {61}, number = {}, pages = {127406}, doi = {10.1016/j.vaccine.2025.127406}, pmid = {40570746}, issn = {1873-2518}, abstract = {An effective vaccine against syphilis could aid current control measures to reduce the incidence of infection. Protective immunity from the syphilis agent, Treponema pallidum subsp. pallidum (T. pallidum), is associated with pathogen clearance by phagocytosis, supporting that immunization with an effective vaccine candidate should elicit opsonic antibodies to key epitopes at the host-pathogen interface. The T. pallidumrepeat (Tpr) proteins are putative β-barrel outer membrane porins with ten predicted extracellular loops. Here, we immunized three groups of eight rabbits with either a combination of three recombinant variants of the full-length TprC antigen, the TprD2 protein, or the conserved NH2-terminal region of TprK, with the latter antigen already known to induce incomplete protection in immunized rabbits. Compared to unimmunized controls, rabbits immunized with the three TprC variants or the TprK fragment exhibited attenuated primary chancres, reduced treponemal burden at the challenge sites, and limited pathogen dissemination to lymph nodes. Immunization with TprD2, alone did not produce comparable results. Strong humoral and cellular responses against TprC and TprK were elicited by immunization, and functional analyses supported the induction of opsonizing antibodies. Epitope mapping performed using TprC- and TprK-specific synthetic peptides and phage immunoprecipitation-sequencing identified a subset of highly reactive sequences and demonstrated immunity to predicted surface-exposed epitopes across multiple Tpr paralogs, which explained the significant, albeit incomplete protection measured post-challenge. These data advance TprC and TprK as syphilis vaccine candidates and highlight several correlates of their protection that deserve further examination.}, }
@article {pmid40569916, year = {2025}, author = {Ortblad, KF and Brown, ER and Heffron, R and Ngure, K and Mujugira, A and Donnell, D}, title = {Research designs to generate evidence of HIV post-exposure prophylaxis effectiveness for new long-acting agents.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26475}, pmid = {40569916}, issn = {1758-2652}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; K24 MH123371/MH/NIMH NIH HHS/United States ; K24 MH123371/NH/NIH HHS/United States ; R00 MH121166/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention & control/drug therapy ; *Post-Exposure Prophylaxis/methods ; *Research Design ; *Anti-HIV Agents/administration & dosage/therapeutic use ; Treatment Outcome ; Pre-Exposure Prophylaxis ; }, abstract = {INTRODUCTION: New longer-acting antiretroviral (ARV) drugs-that is single doses with antiviral activity for at least a month-are being utilized for HIV treatment and pre-exposure prophylaxis (PrEP) but have not been explored for post-exposure prophylaxis (PEP). A "one-and-done" simplification of PEP has the potential to serve the HIV prevention needs of individuals not being met with traditional services and expand overall biomedical HIV prevention coverage. We discuss challenges with the assessment of PEP effectiveness in human trials and potential study designs that could generate evidence needed to inform the use of new, single-administered, long-acting ARVs for PEP.
DISCUSSION: Challenges with determining the effectiveness of new long-acting PEP agents in human trials include the low likelihood of observing an HIV acquisition and the short period for outcome assessment (likely 1 month) following PEP administration. Additional challenges include recruiting individuals in the brief window in which they could benefit (<72 hours of a potential HIV exposure) and ethics of conducting informed consent during a period of high stress/vulnerability. Consequently, design approaches where the efficacy goal is to establish that the HIV incidence rate following PEP administration (of the standard or a novel agent) approaches zero should be considered. HIV RNA testing conducted within 5 days of a potential exposure could define prevention per exposure. Novel recruitment venues-such as community-based retail or online pharmacies-could be used to reach individuals after a potential exposure. Potential study designs include one- or two-arm individual-level product assignment aimed at demonstration of short-course efficacy or longer-term effectiveness compared to a background rate; cluster-randomized controlled trials of recruitment venues; and novel individual-level approaches that either do not or do utilize randomization in combination with choice, enabling assessment of preferences and effectiveness.
CONCLUSIONS: Over the past decade, multiple new HIV PrEP products-but no new PEP products-have been developed to meet the diverse needs of individuals seeking HIV prevention services. Challenges exist with generating PEP effectiveness evidence, but they are not insurmountable. Effectiveness research on new PEP products could advance the number of HIV prevention options available.}, }
@article {pmid40569884, year = {2025}, author = {Roche, SD and Omollo, V and Mogere, P and Asewe, M and Gakuo, S and Banerjee, P and Harkey, K and Sharma, M and Pintye, J and Mugambi, ML and Shah, P and Odoyo, J and Ong'wen, P and Were, D and Bukusi, EA and Ngure, K and Ortblad, KF}, title = {A modified pharmacy provider-led delivery model of oral HIV pre- and post-exposure prophylaxis in Kenya: a pilot study extension.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26467}, pmid = {40569884}, issn = {1758-2652}, support = {INV-033052/GATES/Gates Foundation/United States ; R34 MH120106/MH/NIMH NIH HHS/United States ; R00MH121166/MH/NIMH NIH HHS/United States ; R01HD108041//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Anti-HIV Agents/administration & dosage/therapeutic use ; *HIV Infections/prevention & control ; Kenya/epidemiology ; Pharmacies ; Pilot Projects ; *Post-Exposure Prophylaxis/methods ; *Pre-Exposure Prophylaxis/methods ; }, abstract = {INTRODUCTION: Private pharmacies in Africa reach individuals with ongoing and periodic HIV risk, yet few countries currently leverage pharmacies as an HIV service delivery platform. We conducted a 6-month pilot to evaluate a model for pharmacy provider-led delivery of HIV pre- and post-exposure prophylaxis (PrEP and PEP) in Kenya.
METHODS: At 12 private pharmacies in Kisumu and Kiambu Counties, licensed pharmacy providers initiated and managed eligible clients ≥18 years on PrEP and PEP under remote clinician supervision (NCT04558554); four of these pharmacies additionally offered sextually transmitted infection (STI) testing. PrEP/PEP clients were scheduled for follow-up 1 month later and then quarterly (PrEP clients only). Primary outcomes included PrEP and PEP initiation and continuation during the pilot period. Client and providers rated the model across multiple constructs of acceptability and feasibility from established frameworks.
RESULTS: From January to July 2022, 1028 clients interested in PrEP, PEP and/or STI testing were screened and 829 initiated one or more service: 661 PrEP, 162 PEP and 52 STI testing. About half of clients (48%, 398/829) were male, most were unmarried (78%, 644/829) and PrEP-naïve (89%, 737/829), and the median age was 25 years (IQR 22-31). Most PrEP clients reported inconsistent condom use (88%, 581/661) or sex with partners of unknown HIV status (70%, 460/661) in the past 6 months. Most PEP clients reported condomless sex (48%, 78/162) or a condom break (46%, 75/162) in the past 72 hours; 4% (6/162) reported sexual assault. Among PrEP clients eligible for a refill, 73% (479/658) refilled at least once and 60% (197/328) twice. Among PEP clients eligible for follow-up, 44% (65/148) completed follow-up HIV testing and 20% (30/148) transitioned to PrEP. Among STI clients, 19% (10/52) tested positive for gonorrhoea (n = 7) and/or chlamydia (n = 5). Most clients and providers (≥92%) found the delivery model and its implementation strategies acceptable. All providers (n = 12) thought it was possible to deliver PrEP and PEP at pharmacies in Kenya.
CONCLUSIONS: Pharmacy PrEP/PEP delivery achieved high uptake, continuation and acceptability among eligible clients that could benefit, highlighting the potential of pharmacies to expand HIV prevention service coverage in Kenya, particularly to individuals not accessing these services at clinics.}, }
@article {pmid40569864, year = {2025}, author = {Kiptinness, C and Naik, P and Kareithi, T and Thuo, N and Okello, P and Culquichicon, C and Rafferty, M and Abdulrashid, S and Jomo, E and Nyamasyo, N and Wood, T and Mendonca, R and Malen, RC and Dettinger, JC and Pintye, J and Mwangi, J and Stergachis, A and Onentia, J and Curran, K and Mugambi, ML and Were, D and Ngure, K and Sharma, M and Ortblad, KF and , }, title = {Online delivery of oral HIV pre- and post-exposure prophylaxis: findings from the ePrEP Kenya pilot.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26468}, pmid = {40569864}, issn = {1758-2652}, support = {INV-037646/GATES/Gates Foundation/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; K01 MH115789/MH/NIMH NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Anti-HIV Agents/administration & dosage/therapeutic use ; *HIV Infections/prevention & control ; Kenya ; Pilot Projects ; *Post-Exposure Prophylaxis/methods ; *Pre-Exposure Prophylaxis/methods ; *Telemedicine ; }, abstract = {INTRODUCTION: The expansion of telecommunication networks and smartphones in many African countries could be leveraged to deliver HIV prevention products directly to consumers. In collaboration with a private e-commerce platform and online pharmacy in Kenya, MYDAWA, we piloted a new model of HIV pre- and post-exposure prophylaxis (PrEP/PEP) delivery.
METHODS: In the ePrEP Kenya pilot (NCT05377138), individuals living in Nairobi and Mombasa Counties could complete a free telehealth visit with a remote clinician to assess eligibility for online PrEP/PEP (i.e. ≥18 years; no medical contraindications). Eligible individuals could order HIV testing services-courier delivered to clients' choice location-for a fee of 250 KES (∼$2 USD) for self-testing or 150 KES (∼$1 USD) for provider-administered rapid diagnostic testing. Following confirmation of clients' HIV-negative status (via an uploaded test result image), free PrEP/PEP drugs from government supply were courier delivered with or separately from HIV testing services. Clients paid a delivery fee ≤149 KES (∼$1 USD) per courier visit.
RESULTS: From October 2022 to December 2023, we screened 2257 individuals and enrolled 1915. Most PrEP/PEP clients were men (63%, 1428/1915), ≥25 years (72%, 1631/1915) and never married (80%, 1796/1915); few had ever used PrEP (3%, 48/1915) or PEP (14%, 263/1915). At enrolment, 227 (12%) were preliminarily eligible for PrEP and 1688 (88%) for PEP. Among PrEP-eligible clients, 89% (203/227) completed HIV testing and 92% (208/227) received PrEP; among PEP-eligible clients, 92% (1551/1688) completed HIV testing and 92% (1549/1688) received PEP. Most PrEP/PEP clients completed HIV testing within 6 hours of their telehealth visit (53%, 927/1757) and had drugs delivered with testing services (88%, 1546/1757). Among PrEP clients eligible for follow-up, 47% (120/256) continued PrEP and 4% (10/256) initiated PEP following PrEP discontinuation. Among PEP clients eligible for follow-up, 7% (99/1428) repeated PEP use and 6% (83/1428) transitioned from PEP to PrEP.).
CONCLUSIONS: Online PrEP/PEP delivery could expand access to prevention services by reaching individuals not engaged in existing delivery platforms. The uptake of online PEP was five times greater than PrEP, underscoring an unmet demand for PEP and highlighting the potential for online pharmacies to deliver time-sensitive PEP services.}, }
@article {pmid40569643, year = {2025}, author = {Rashidi, A}, title = {Microbiota and chronic GVHD: a plasmablast link.}, journal = {Blood}, volume = {145}, number = {26}, pages = {3073-3075}, doi = {10.1182/blood.2025029521}, pmid = {40569643}, issn = {1528-0020}, }
@article {pmid40569290, year = {2025}, author = {Biernacki, MA and Lok, J and Foster, KA and Cummings, C and Busch, S and Black, RG and Ray, S and Baquero Galvis, L and Monahan, T and Oh, ST and Oehler, VG and Stirewalt, DL and Wu, D and Deeg, HJ and Doulatov, S and Bleakley, M}, title = {SF3B1K700E neoantigen is a CD8+ T-cell target shared across human myeloid neoplasms.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-24-0091}, pmid = {40569290}, issn = {2326-6074}, abstract = {Acquired mutations in spliceosome genes in early hematopoietic stem/progenitor cells are common events in myelodysplastic neoplasms (MDS) and related myeloid malignancies. Mutations in the spliceosome factor subunit B1 (SF3B1) gene occur in ≥20% of MDS cases at conserved hotspots and in early neoplastic clones as driver events. Neoantigens from aberrant SF3B1 proteins could serve as shared T-cell therapy targets for SF3B1-mutated myeloid neoplasms. We identified a candidate neoantigen from the prevalent SF3B1K700E variant using in silico predictions of epitope processing and presentation, then validated presentation and immunogenicity in vitro. CD8+ T cells recognizing SF3B1K700E demonstrated high functional avidity and killed neoplastic myeloid cell lines and primary cells in an antigen-specific manner. We then sequenced, cloned, and transduced a SF3B1K700E-specific T-cell receptor (TCR) into 3rd-party T cells and confirmed that TCR transfer conferred antigen specificity and killing of neoplastic myeloid cells in vitro and in vivo. The data indicate that the SF3B1K700E neoantigen represents a promising T-cell target for patients with SF3B1-mutated MDS and acute myeloid leukemia.}, }
@article {pmid40569102, year = {2025}, author = {Cheng, GS and Sheshadri, A and Turner, J and Williams, KM and Hsu, JL and Agoritsas, T and Ali, MH and Bondeelle, L and Bouguet, G and Chanez, P and Cooke, KR and Galban, CJ and Goldfarb, S and Hallstrand, TS and Johnson, S and Lam, DCL and Michonneau, D and O'Dwyer, DN and Paczesny, S and Sharifi, H and Todd, JL and Wolff, D and Yadav, H and Yanik, GA and Bergeron, A}, title = {Addressing Knowledge Gaps in the Early Detection of Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation. An Official American Thoracic Society Research Statement.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1164/rccm.202506-1352ST}, pmid = {40569102}, issn = {1535-4970}, abstract = {BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a late onset noninfectious pulmonary complication of allogeneic hematopoietic cell transplantation (HCT) that is often diagnosed in advanced stage with severe lung impairment. Increasing utilization of HCT for the treatment of hematologic diseases worldwide translates to an increasing burden of BOS, particularly for the community pulmonologist. Early recognition of BOS, which offers the best opportunity to mitigate morbidity and mortality, is hampered by incomplete knowledge of the clinical course and disease process. The goal of this research statement is to survey our current understanding of BOS and to define the research agenda for the early detection of BOS.
METHODS: We convened a multidisciplinary panel that included community representatives for an in-depth survey of the published literature followed by an online workshop.
RESULTS: Major knowledge gaps were identified within interrelated themes of natural history and pathogenesis, risk factors, and the clinical diagnostic approach.
CONCLUSIONS: This statement reflects the detailed assessment of identified knowledge gaps with associated key research questions, as well as a proposed research roadmap to stimulate cross-disciplinary collaborations from pre-clinical to clinical investigations.}, }
@article {pmid40568722, year = {2025}, author = {Hogan, LE and Bhatla, T and Xu, X and Gore, L and Raetz, EA and Bhojwani, D and Teachey, DT and Hunger, SP and Loh, ML and Brown, PA and Ji, L}, title = {Severe toxicity and poor efficacy of reinduction chemotherapy are associated with overall poor outcomes in relapsed B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group AALL1331 trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.287386}, pmid = {40568722}, issn = {1592-8721}, abstract = {Children's Oncology Group AALL1331 utilized an intensive chemotherapy induction (Block 1) based on UK ALLR3 induction for children, adolescents, and young adults with acute lymphoblastic leukemia in first relapse, followed by risk-stratified therapy. High/intermediate risk patients were subsequently randomized to receive 2 blocks of chemotherapy or 2 blocks of blinatumomab followed by hematopoietic stem cell transplant. Low risk patients were randomized to chemotherapy or chemotherapy cycles intercalated with three blinatumomab blocks. Patients who had an early treatment failure were eligible to receive blinatumomab for up to 2 salvage cycles. We reviewed Block 1 responses, risk stratification, randomization rates, adverse events (AE), and event-free survival and overall survival for all enrolled patients. AALL1331 enrolled 661 patients: 24 died during Block 1 and 42 experienced early treatment failure. Overall, 531/661 (80.3%) attained complete remission with 586 risk-assigned and only 471 were randomized. Of 532 patients with marrow involvement, 290 (54.5%) were minimal residual disease positive (≥0.01%) after Block 1. Grade 3/4/5 AE occurred in Block 1 in 44.9, 24.1, and 3.6% patients respectively, with febrile neutropenia, infections, and sepsis most frequent. Notably, 190 enrolled patients (28.7%) did not proceed with post-induction therapy, including 115 (17.4%) risk stratified but not randomized. These patients had dismal survival. More effective and less toxic reinduction strategies are needed for B-ALL in first relapse. Trial Registration Number: NCT02101853.}, }
@article {pmid40568668, year = {2025}, author = {Mendez, JS and Queme, B and Fu, Y and Morrison, J and Lewinger, JP and Kawaguchi, E and Mi, H and Obón-Santacana, M and Moratalla-Navarro, F and Martín, V and Moreno, V and Lin, Y and Bien, SA and Qu, C and Su, YR and White, E and Harrison, TA and Huyghe, JR and Tangen, CM and Newcomb, PA and Phipps, AI and Thomas, CE and Conti, DV and Wang, J and Platz, EA and Keku, TO and Newton, CC and Um, CY and Kundaje, A and Shcherbina, A and Murphy, N and Gunter, MJ and Dimou, N and Papadimitriou, N and Bézieau, S and van Duijnhoven, FJ and Männistö, S and Rennert, G and Wolk, A and Hoffmeister, M and Brenner, H and Chang-Claude, J and Tian, Y and Le Marchand, L and Cotterchio, M and Tsilidis, KK and Bishop, DT and Melaku, YA and Lynch, BM and Buchanan, DD and Ulrich, CM and Ose, J and Peoples, AR and Pellatt, AJ and Li, L and Devall, MA and Campbell, PT and Albanes, D and Weinstein, SJ and Berndt, SI and Gruber, SB and Ruiz-Narvaez, E and Song, M and Joshi, AD and Drew, DA and Petrick, JL and Chan, AT and Giannakis, M and Hsu, L and Peters, U and Gauderman, WJ and Stern, MC}, title = {Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40568668}, support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; U2C CA252971/CA/NCI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; U54 CA233465/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions.
METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk.
RESULTS: A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (p = 0.003). When variants in the TGF-β pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat.
CONCLUSIONS: This pathway-based interaction analysis revealed a significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk.
IMPACT: These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.}, }
@article {pmid40564099, year = {2025}, author = {Wang, H and Wang, C and Qin, R and He, J and Zhang, X and Ma, C and Li, S and Fan, L and Wang, L and Cao, L}, title = {Integrative Analysis of Plasma Proteomics and Transcriptomics Reveals Potential Therapeutic Targets for Psoriasis.}, journal = {Biomedicines}, volume = {13}, number = {6}, pages = {}, pmid = {40564099}, issn = {2227-9059}, support = {82304250//National Natural Science Foundation of China/ ; 82273734//National Natural Science Foundation of China/ ; YQ2022H005//Heilongjiang Province Natural Science Foundation/ ; }, abstract = {Background Psoriasis (PsO): is an immune-mediated inflammatory disease that imposes a significant burden on patients. Many patients experience relapse or inadequate responses, and PsO subtypes also lack effective therapies, highlighting the need for new therapeutic targets. Methods: We performed a proteome-wide Mendelian randomization (MR) to explore potential therapeutic targets for PsO. Protein quantitative trait loci (pQTLs) data were obtained from the Pharma Proteomics Project (54,219 UK Biobank participants, 2923 proteins), and PsO phenotype and subtype data were sourced from FinnGen (10,312 cases; 397,564 controls) for discovery. Replication MR utilized integrated protein data (Iceland and Norfolk) and phenotype data from multiple databases (UK Biobank and GWAS Catalog). Reverse MR and colocalization were used to support causal relationships. Single-cell RNA-seq analysis revealed distinct expression patterns of protein-coding genes across different cell types in PsO biopsy samples and normal skin tissues. Protein-protein interactions (PPI) and molecular docking were used to evaluate druggability. Results: MR analysis identified 13 proteins significantly associated with PsO risk (p < 2.56×10-5), including 10 proteins associated with PsO subtypes. Decreased levels of eight proteins (IFNLR1, APOF, TDRKH, DDR1, HLA-E, LTA, MOG, and ICAM3) and increased levels of five proteins (IFNGR2, HCG22, IL12B, BTN3A2, and TRIM40) showed protective effects against PsO progression. Robust colocalization (PPH4 > 0.9) identified IFNLR1, IFNGR2, APOF, and TDRKH as top candidates. Single-cell RNA sequencing analysis revealed that IFNLR1, IFNGR2, LTA, TDRKH, and DDR1 were specifically expressed in T cells of psoriatic biopsy specimens compared to healthy controls. Molecular docking indicated the druggability of IFNLR1 and IFNGR2. Conclusions: We identified several potential therapeutic targets for PsO, with IFNLR1, IFNGR2, APOF, and TDRKH emerging as promising candidates, particularly IFNLR1 and IFNGR2, which are associated with the IFN family. These findings may provide new perspectives on PsO therapy and pathogenesis.}, }
@article {pmid40562770, year = {2025}, author = {Dima, D and Vazquez-Martinez, MA and Davis, JA and Goel, U and Afrough, A and Sannareddy, A and Pasvolsky, O and Razzo, B and Banerjee, R and Khouri, J and Grajales-Cruz, A and Lieberman-Cribbin, A and Rana, MS and Julian, K and DeJarnette, S and Portuguese, AJ and Gaballa, MR and De Avila, G and Susaniba Adaniya, S and Raza, S and Herr, MM and Ouchveridze, E and Richards, T and Hosoya, H and Mikkilineni, L and Kaur, G and Castaneda Puglianini, O and Rossi, A and Lin, Y and Atrash, S and Sborov, D and Shain, KH and Voorhees, PM and Richard, S and Garfall, AL and Hansen, DK and Sidana, S and Patel, KK and Cowan, AJ and Anderson, LD and Lee, HC and Anwer, F and Ferreri, CJ and Shune, L}, title = {Outcomes of teclistamab in patients with relapsed/refractory multiple myeloma with prior exposure to BCMA-directed therapy: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {111}, pmid = {40562770}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; Male ; Female ; Middle Aged ; Aged ; *B-Cell Maturation Antigen/antagonists & inhibitors ; Retrospective Studies ; Adult ; Aged, 80 and over ; Treatment Outcome ; United States ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; }, abstract = {Data describing outcomes of teclistamab in multiple myeloma patients with prior exposure to BCMA-directed therapy (BCMA-DT) are limited. The goal of this multicenter retrospective analysis was to report the efficacy and safety of standard-of-care teclistamab in patients with prior BCMA-DT. A total of 385 patients were included, of whom 193 (50%) had received prior BCMA-DT, including 47 (24%) patients with prior antibody-drug conjugate (ADC)-only, 99 (51%) with chimeric antigen receptor T-cell therapy (CAR T)-only, 36 (19%) with both ADC and CAR T, 6 (3%) with bispecific antibody-only, and 5 (3%) with other combinations. Most safety parameters between cohorts were comparable. The prior BCMA-DT cohort had a lower overall response rate (ORR: 48.7% versus 61.5%; p = 0.012), and median progression-free survival (PFS: 4.6 versus 8.2 months; p = 0.017) compared to the cohort without prior BCMA-DT. However, in multivariable analysis, despite a clear trend, ultimately receipt of a prior BCMA-DT was not independently associated with ORR or PFS (p = 0.057 and p = 0.1, respectively). No significant differences in PFS were noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Using the maximally selected rank statistics method, the optimal cut-off for time from the last BCMA-DT exposure to teclistamab initiation was identified as 8.7 months. Patients with >8.7 months between their last exposure to prior BCMA-DT and teclistamab initiation had a significantly improved median PFS with teclistamab (8.1 months, 95% CI: 4.6-11.7) compared to patients with <8.7 months (2.5 months, 95% CI: 1.1-5.7), p = 0.001. Altogether, our findings support the use of teclistamab as a viable treatment option in patients previously exposed to BCMA-DT.}, }
@article {pmid40562030, year = {2025}, author = {Banerjee, R and Yamshon, S}, title = {Double trouble: Non-relapse mortality with bispecific antibodies in lymphoma and myeloma.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {7}, pages = {2966-2967}, doi = {10.1016/j.ymthe.2025.06.014}, pmid = {40562030}, issn = {1525-0024}, }
@article {pmid40561681, year = {2025}, author = {Coleman, RL and Fleming, GF and Brady, MF and Swisher, EM and Steffensen, KD and Friedlander, M and Okamoto, A and Moore, KN and Leath, CA and Cella, D and Sun, Z and Patel, S and Tang, Z and Ratajczak, CK and Aghajanian, C and Bookman, MA}, title = {Veliparib concomitant with first-line chemotherapy and as maintenance therapy in ovarian cancer: Final overall survival and disease-related symptoms results.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {225}, number = {}, pages = {115587}, doi = {10.1016/j.ejca.2025.115587}, pmid = {40561681}, issn = {1879-0852}, abstract = {INTRODUCTION: In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial.
METHODS: This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints.
RESULTS: In the intention-to-treat population (N = 1140), median OS was 59.2 months (95 % confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance.
CONCLUSION: No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.}, }
@article {pmid40561385, year = {2025}, author = {Zeiser, R and Russo, D and Ram, R and Hashmi, SK and Chakraverty, R and Middeke, JM and Musso, M and Giebel, S and Uzay, A and Langmuir, P and Hamad, N and Burock, K and Gowda, M and Stefanelli, T and Lee, SJ and Teshima, T and Locatelli, F}, title = {Ruxolitinib in Patients With Corticosteroid-Refractory or Corticosteroid-Dependent Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of the Phase III REACH3 Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2402477}, doi = {10.1200/JCO-24-02477}, pmid = {40561385}, issn = {1527-7755}, abstract = {In REACH3 (ClinicalTrials.gov identifier: NCT03112603), ruxolitinib was investigated versus best available therapy (BAT) for 3 years in patients with steroid-refractory/dependent chronic graft-versus-host-disease (SR/D-cGVHD). Patients received ruxolitinib (10 mg twice daily) or BAT for 24 weeks; thereafter (weeks 24-156), patients continued randomized treatment, entered long-term survival follow-up, or crossed over from BAT to ruxolitinib. In 329 randomly assigned patients (ruxolitinib: 165; BAT: 164), the median failure-free survival (FFS) was 38.4 months for ruxolitinib versus 5.7 months for BAT (hazard ratio, 0.36 [95% CI, 0.27 to 0.49]). Median duration of response (DOR) was not reached for ruxolitinib versus 6.4 months for BAT. Ruxolitinib-treated patients had a higher probability of FFS (ruxolitinib: 56.5%; BAT: 18.2%) and maintaining a response (ruxolitinib: 59.6%; BAT: 26.7%) at 36 months. Median overall survival was not reached. Nonrelapse mortality and malignancy relapse/recurrence events were low. In 70 patients who crossed over to ruxolitinib, the overall response rate (50.0%) at week 24 and best overall response (81.4%) during the crossover period were consistent with the primary analysis of randomly assigned patients. No new safety signals were observed. Ruxolitinib provided longer FFS and DOR than BAT, demonstrating sustained efficacy and manageable safety over 3 years of follow-up in patients with SR/D-cGVHD.}, }
@article {pmid40561376, year = {2025}, author = {Bardia, A and Rugo, HS and Sedrak, MS and Loibl, S and Tolaney, SM and Punie, K and Hurvitz, SA and Kalinsky, KM and Cortés, J and O'Shaughnessy, JA and Dieras, V and Piccart-Gebhart, MJ and Dasgupta, A and Kaushik, A and Lai, C and Shi, L and Brufsky, A}, title = {Q-TWiST Analysis to Assess Benefit-Risk of Sacituzumab Govitecan in Previously Treated Patients With Metastatic Triple-Negative Breast Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400806}, doi = {10.1200/OP-24-00806}, pmid = {40561376}, issn = {2688-1535}, abstract = {PURPOSE: In ASCENT, sacituzumab govitecan (SG) showed significantly longer overall survival and progression-free survival than chemotherapy of physician's choice with similar rates of treatment-emergent adverse events (TEAEs) in previously treated patients with metastatic triple-negative breast cancer (mTNBC). We assessed the benefit-risk of SG versus chemotherapy by integrating patient preferences (health utilities) with clinical benefits in this analysis.
METHODS: Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) methodology was used to compare treatments where survival was partitioned into three health states using the intention-to-treat ASCENT population: (1) toxicity (grade ≥3 TEAE after random assignment and before disease progression), (2) TWiST (progression-free period without grade ≥3 TEAE), and (3) relapse (disease progression until death or end of follow-up, whichever came first). Health state utilities were derived from published literature. Q-TWiST was calculated as utility-weighted sum of mean health state durations. The established threshold for relative Q-TWiST improvement considered clinically important is 10% and clearly clinically important is 15%.
RESULTS: SG had significantly longer Q-TWiST (8.3 months; 95% CI, 7.6 to 9.1 months) than chemotherapy (4.8 months; 95% CI, 4.3 to 5.4 months) in patients with mTNBC, a difference of 3.5 months (95% CI, 2.6 to 4.4 months; P < .0001). Relative Q-TWiST improvement with SG was 39.5%, exceeding the clearly clinically important threshold. Q-TWiST benefits of SG over chemotherapy increased over the available 31-month follow-up. Restricted mean time with toxicity was numerically higher with SG versus chemotherapy; this difference stabilized with longer follow-up.
CONCLUSION: The Q-TWiST analysis supports a positive benefit-risk ratio for SG versus chemotherapy in patients with previously treated mTNBC. Net benefits of SG continued to accrue over time.}, }
@article {pmid40561372, year = {2025}, author = {Calverley, DC and Leader, A and Cheong, MA and Sanfilippo, KM and Mason, G and Lyman, GH and Kuderer, NM}, title = {Inconsistent and Inaccurate Cancer Clinical Trial Reporting of Venous and Arterial Thrombotic Events: An Urgent Call to Action.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500489}, pmid = {40561372}, issn = {1527-7755}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, }
@article {pmid40558267, year = {2025}, author = {Terashima, M and Nakayama, K and Ugai, S and Lee, HY and Tsukumo, Y and Suzuki, E and Mizuno, H and Song, M and Sasamoto, N and Kawachi, I and Ugai, T}, title = {Global Incidence Trend of Early-Onset Obesity-Related and Non-Obesity-Related Cancers.}, journal = {Current oncology (Toronto, Ont.)}, volume = {32}, number = {6}, pages = {}, pmid = {40558267}, issn = {1718-7729}, support = {R50 CA274122/CA/NCI NIH HHS/United States ; R50 CA274122/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/epidemiology/etiology ; *Obesity/complications/epidemiology ; Incidence ; Female ; Male ; Adult ; Age of Onset ; Middle Aged ; Global Health ; Young Adult ; }, abstract = {The global rise in obesity prevalence and the incidence of early-onset cancer (diagnosed between 20 and 49 years of age) is a serious public health concern. We, therefore, evaluated the recent global trends in the incidence of early-onset obesity-related cancers and compared them to those of non-obesity-related cancers. We obtained age-standardized incidence rates of early-onset cancers diagnosed between 2000 and 2012 in 44 countries from the Cancer Incidence in Five Continents database. Using joinpoint regression models, we calculated the average annual percentage changes (AAPCs) and their corresponding 95% confidence intervals (95% CIs) for combined and individual categories of obesity-related cancers (11 and 9 cancer types in females and males, respectively) and non-obesity-related cancers (12 cancer types in both females and males). Differences in the AAPC were assessed by comparing 95% CIs, where nonoverlapping 95% CIs were considered statistically significantly different. We observed statistically significant positive AAPCs for early-onset obesity-related cancers in all available countries combined among females (global AAPC, 4.3%; 95% CI, 4.1-4.6%) and males (global AAPC, 1.4%; 95% CI, 1.2-1.7%). When analyzed by countries, we observed statistically significant positive AAPCs in 26 countries among females and 11 countries among males. AAPCs for early-onset obesity-related cancers were statistically significantly higher than those of non-obesity-related cancers in several regions, especially North America and Oceania. In conclusion, this study indicates that the incidence of early-onset obesity-related cancers exhibited a more pronounced increasing trend than non-obesity-related cancers among both sexes in many countries and regions.}, }
@article {pmid40556953, year = {2025}, author = {Mda, P and Mngadi, K and Zhang, B and Burnham, R and Juraska, M and Hyrien, O and Garrett, N and Dubula, T and Toni, S and Joseph, S and Kotze, P and Buchbinder, S and Takalani, A and Tomaka, F and Luedtke, A and Willems, W and Swann, E and Hutter, J and Gelderblom, H and McElrath, MJ and Lavreys, L and Stranix-Chibanda, L and Roxby, AC and Bekker, LG and Gray, GE}, title = {Pregnancy and contraceptive use among participants of childbearing potential in the HVTN 705 HIV vaccine trial in Southern Africa.}, journal = {Frontiers in reproductive health}, volume = {7}, number = {}, pages = {1565933}, pmid = {40556953}, issn = {2673-3153}, abstract = {BACKGROUND: HIV vaccine trial participants include sexually active cisgender females who agree to avoid pregnancy during the active vaccination period. Nevertheless, some pregnancies occur in almost all studies. We examined contraceptive use, pregnancy incidence, and the relationship between pregnancy and HIV seroconversion in one HIV vaccine trial.
METHODS: We performed an exploratory analysis of data collected for HVTN 705/HPX2008, a phase IIb HIV vaccine trial enrolling cisgender women across 23 sites in five southern African countries. Baseline characteristics and contraceptive use were assessed among participants who became pregnant and those who did not during the active vaccination phase (months 0-15). Pregnancy incidence rates were calculated for this phase and the duration of follow up (36 months). Cox regression analysis was used to assess factors associated with incident pregnancy.
RESULTS: There were 2,636 participants who received at least one vaccine or placebo dose (mean age: 23 years, standard deviation: 3 years). At enrolment, when contraception was required, 62.9% reported using injectable contraceptives. Overall pregnancy rate was 2.95 per 100 person-years (95% CI: 2.40, 3.58), with 101 pregnancies reported by month 15. Cumulative incidence of pregnancy at month 15 was similar between trial arms (log-rank p = 0.688). Each additional year of age was associated with an 8% decrease in pregnancy incidence (p = 0.014). Women aged 31-35 years had the lowest pregnancy incidence [1.75 (0.48, 4.48) per 100 person-years]. In a Cox regression analysis covering months 0-15, all contraceptive methods significantly reduced the incidence of pregnancy compared to no contraceptive use. Oral contraception was associated with the least reduction in pregnancy risk; implants were associated with the most reduction in pregnancy risk (p < 0.001).
CONCLUSIONS: In HVTN 705/HPX2008, higher incidence of pregnancy was associated with younger age and oral contraception (compared to other methods). These data may inform future designs of HIV prevention or vaccine trials.}, }
@article {pmid40555394, year = {2025}, author = {Iqbal, M and Kumar, A and Dreger, P and Chavez, J and Sauter, CS and Sureda, AM and Bachanova, V and Maziarz, RT and Dreyling, M and Smith, SM and Jacobson, C and Glass, B and Casulo, C and Oluwole, OO and Montoto, S and Advani, R and Cohen, J and Salles, G and Hamad, N and Kuruvilla, J and Kahl, BS and Shadman, M and Kanate, AS and Budde, LE and Kamdar, M and Flowers, C and Hamadani, M and Kharfan-Dabaja, MA}, title = {Corrigendum to 'Clinical Practice Recommendations for Hematopoietic Cell Transplantation.' Transplant Cell Ther. 2024 Sep;30(9):832-843.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.022}, pmid = {40555394}, issn = {2666-6367}, }
@article {pmid40554677, year = {2025}, author = {Venkataraman, V and Abrams, HR and Shulman, DS and Loggers, ET and Pollack, SM and Paulson, KG and Wagner, MJ}, title = {Effect of HLA restriction on racial and ethnic disparities in access to immune therapies for advanced synovial sarcoma.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyaf193}, pmid = {40554677}, issn = {1549-490X}, abstract = {PURPOSE: Synovial sarcoma (SS) is aggressive with poor outcomes. Cellular therapies are now FDA approved for advanced disease, but are restricted to certain HLA-A*02 alleles. We estimate eligibility to cellular therapies by race and ethnicity.
MATERIALS AND METHODS: Demographic and clinical features of SS cases from 2001 to 2020 were obtained from the United States Cancer Statistics (USCS; NPCR-SEER). Survival analyses were performed overall and by races/ethnicity. The proportion eligible for cellular therapy was estimated by races/ethnicity using previously published data on HLA-A*02 status and MAGE-A4 positivity.
RESULTS: From 2001 to 2020, 10,605 patients (48% female, 64% Non-Hispanic White, 17% Hispanic) with SS were identified. The incidence rate was 1.5-1.8/million/person-years and was stable over time, corresponding to an average 530 new cases annually. The most common primary site was the extremity (n = 5,877; 58%), and most patients presented with localized disease (n = 5,753; 54%). The 5-year cause-specific survival was 60% across all races/ethnicities and 79% for localized, 57% for regional, 12% for distant disease. Differences by race and ethnicity were found in the proportions of patients expected to be eligible for HLA-restricted cellular therapies targeting MAGE-A4. People of European/European descent had the highest estimated proportion (25-39%), and people of Asian/Pacific Islander descent had the lowest (11-17%).
CONCLUSION: Engineered T-cells targeting MAGE-A4 have shown encouraging safety and efficacy in advanced SS; however, eligibility restrictions will lead to racial and ethnic disparities. HLA-independent solutions must be developed to counter disparities and ensure all patients have access.}, }
@article {pmid40554428, year = {2025}, author = {Bhatt, NS and Borogovac, A and Efebera, YA and DeSalvo, AM and Devine, SM and Foley, A and Stewart, V and Hamilton, BK and Heuer, M and Molfenter, T and Plastaras, JP and Ragon, BK and Wall, SA and Broglie, L and Juckett, MB and Khera, N and Horowitz, MM and DeZern, AE}, title = {Upfront Alternative Donor HCT in Severe Aplastic Anemia: Gaps and Opportunities to Translate Evidence into Practice.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015405}, pmid = {40554428}, issn = {2473-9537}, abstract = {Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as post-transplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underutilized as upfront therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights where gaps remain. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.}, }
@article {pmid40554417, year = {2025}, author = {Sharifi, H and Moss, CT and Musa, Z and Bell, A and O'Donnell, C and Borges, C and Matthaiou, EI and Johnston, L and Galban, C and Sheshadri, A and Yanik, GA and Cheng, GS and Hsu, JL}, title = {Pirfenidone for the treatment of bronchiolitis obliterans syndrome related to chronic graft-versus-host disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016122}, pmid = {40554417}, issn = {2473-9537}, abstract = {Bronchiolitis obliterans syndrome (BOS) is a severe form of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic cell transplantation (HCT) with five-year survival of 40%. Currently, there is no curative therapy for BOS. Pre-clinical data suggest that pirfenidone, an anti-fibrotic drug, may benefit small airway fibrosis in HCT-associated BOS. A single-arm, open-label, 56-week phase 1 trial with 56-month extension evaluated pirfenidone's tolerability, safety, and efficacy in BOS patients. Efficacy was measured using pulmonary function tests (PFT), quantitative CT (qCT) scans, patient reported outcomes (PRO), cGVHD indices, and laboratory tests. Lung function trajectory was assessed by change in regression slopes before and during treatment. Baseline qCT metrics, including percentage normal lung, air trapping, volume change (Jacobian), and heterogeneity of volume change (Jacobian variance) were analyzed by participant response. Among 30 participants, 25 completed the 56-week trial, and 10 continued into the extension. Overall, 63% tolerated the recommended dose without safety concerns. There was significant improvement in the percent predicted forced expiratory volume in 1 second (P=0.00267) when analyzing all participants and improvement in individual PFT trend for 41.3% of participants. Quantitative CT analysis by lobe showed healthier lungs in the upper lobes of responders. Significant improvements were noted in liver function tests, PRO related to physical functioning and shortness of breath, and cGVHD skin indices. These findings indicate that pirfenidone is safe and tolerable in BOS patients post-HCT and may improve lung function and symptoms. Further trials are warranted to evaluate the efficacy of pirfenidone as a treatment for BOS after HCT. (NCT03315741).}, }
@article {pmid40553813, year = {2025}, author = {Barta, JA and Arenberg, D and Backhus, L and Detterbeck, F and Gould, MK and Nair, VS and Pasquinelli, M and Powell, CA and Sandler, K and Silvestri, G and Triplette, M and Vachani, A and Wiener, RS and Mazzone, PJ}, title = {Components Necessary for High-Quality Lung Cancer Screening: A 10-Year Update.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2025.06.006}, pmid = {40553813}, issn = {1931-3543}, abstract = {Lung cancer screening (LCS) has evolved over the past decade with research advances and clinical experience helping to define target populations for screening, improve lung nodule detection and management, and identify structural components of programs that improve the quality of screening delivery. The 2015 American College of Chest Physicians and American Thoracic Society Policy Statement, Components Necessary for High-Quality Lung Cancer Screening, identified nine essential components for high-quality LCS. Ten years later, optimizing the balance between the benefits and harms of LCS and ensuring equitable screening among all population groups remain fundamental objectives. In this 2025 update we aim to summarize new knowledge and highlight critical components that are needed for providing high-quality LCS. A multidisciplinary group of LCS experts was assembled to review evidence from the past ten years. The original components were reviewed and updated to develop eight refined components that should be considered essential structural elements of screening programs. Each component recommended by the authors is supported by an evidence update. Applying this framework will allow screening programs across the country to ensure implementation of high-quality, net-benefit LCS.}, }
@article {pmid40550509, year = {2025}, author = {Munoz, FM and Parameswaran, L and Gundacker, H and Posavad, CM and Badell, ML and Bunge, K and Mulligan, MJ and Olson-Chen, C and Novak, RM and Brady, RC and DeFranco, E and Gerber, JS and Pasetti, M and Shriver, MC and Coler, RN and Larsen, SE and Suthar, MS and Moreno, A and Miedema, J and Sui, Y and Richardson, BA and Piper, J and Beigi, R and Neuzil, KM and Brown, ER and Cardemil, CV and , }, title = {Infant Antibodies After Maternal COVID-19 Vaccination During Pregnancy or Postpartum.}, journal = {Pediatrics}, volume = {156}, number = {1}, pages = {}, doi = {10.1542/peds.2024-070175}, pmid = {40550509}, issn = {1098-4275}, mesh = {Humans ; Female ; Pregnancy ; Prospective Studies ; *Antibodies, Viral/blood ; *COVID-19 Vaccines/immunology/administration & dosage ; *COVID-19/prevention & control/immunology ; Infant ; *Postpartum Period/immunology ; Infant, Newborn ; *Immunity, Maternally-Acquired ; *Antibodies, Neutralizing/blood ; Adult ; SARS-CoV-2/immunology ; Male ; Vaccination ; }, abstract = {BACKGROUND AND OBJECTIVE: We describe the kinetics of maternally derived antibodies in infants in the first 6 months of life following 2- or 3-dose maternal vaccination during pregnancy or postpartum.
METHODS: This prospective, multicenter cohort study enrolled infants born to mothers vaccinated with 2- (n = 280) or 3-dose (boosted) monovalent messenger RNA vaccines in pregnancy (n = 202) or to mothers vaccinated postpartum (n = 36) from July 2021 to January 2022. Binding (immunoglobulin G to S and receptor-binding domain), pseudovirus, and live neutralizing antibody (nAb) geometric mean titers (GMTs) to vaccine and Omicron BA.1/BA.5 strains were measured at birth and 2 and 6 months of age. Antibody half-life and the effect of maternal or infant COVID-19 infection were assessed.
RESULTS: Significantly higher GMTs of binding antibody and nAb to all antigens were present at birth and 2 months in infants of boosted mothers (P < .01) and higher titers to the vaccine strain, but not Omicron BA.1 and BA.5, persisted up to 6 months of age in infants of boosted mothers compared with the other groups (P < .01). Higher infant antibody titers at delivery and 6 months of age were associated with a booster dose during pregnancy and maternal prenatal and infant COVID-19 infection. Maternal infection status or vaccine regimen did not influence the half-life of infant antibodies.
CONCLUSIONS: A maternal COVID-19 booster in pregnancy results in significantly higher functional antibody titers in infants compared with 2 doses in pregnancy or postpartum. High titers at birth and maternal hybrid immunity result in persistently elevated titers in infants for 6 months.}, }
@article {pmid40549982, year = {2025}, author = {El-Jawahri, A and LeBlanc, TW and Kavanaugh, A and Webb, J and Fausto, J and Traeger, L and Greer, JA and Jackson, V and Horick, N and Rabideau, DJ and Fenech, A and Newcomb, R and Ufere, NN and Caruso, E and Pepper, J and DeFilipp, Z and Chen, YB and Lee, SJ and Temel, JS}, title = {Multisite Randomized Trial of Inpatient Palliative Care Intervention for Patients Undergoing Hematopoietic Stem Cell Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500378}, doi = {10.1200/JCO-25-00378}, pmid = {40549982}, issn = {1527-7755}, abstract = {PURPOSE: Patients undergoing hematopoietic stem cell transplantation (HSCT) and their caregivers endure immense physical and psychological symptoms, which result in quality-of-life (QOL) impairments during HSCT.
METHODS: We conducted a multisite randomized trial among adults undergoing autologous or allogeneic HSCT at three academic institutions. Patients were randomly assigned to an inpatient palliative care (PC) intervention or usual care. Intervention patients met with PC clinicians twice weekly during the HSCT hospitalization. Patients assigned to usual care could be referred to PC as per standard of care. We assessed QOL (patient: Functional Assessment of Cancer Therapy-Bone Marrow Transplant; caregiver: Caregiver-Oncology-QOL), depression and anxiety symptoms (Hospital-Anxiety-and-Depression-Scale), and patients' post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist) at baseline, week 2, and 3 and 6 months post-HSCT. The primary end point was patients' QOL at week 2 during hospitalization when patients experience their QOL nadir. We used linear regression, adjusting for baseline scores, to evaluate the effect of the intervention on patient-reported outcomes at week 2. We used linear mixed-effect models to assess the effect of the intervention on study outcomes longitudinally.
RESULTS: We enrolled 68.7% (360/524) of eligible patients between October 2018 and July 2022. Compared with those receiving usual care, patients receiving the intervention reported better QOL (adjusted mean difference [B], 6.3; SE, 0.1; P < .001), lower depression (B, -1; SE, 0.4; P = .026), and fewer PTSD symptoms (B, -1.9; SE, 0.9; P = .046) at week 2. Patient-reported anxiety did not differ significantly between groups at week 2. In longitudinal analyses, patients receiving the intervention reported a steeper decline in PTSD symptoms over 6 months post-HSCT (slope difference, -0.9; SE, 0.7; P = .012). All other patient-reported outcomes did not differ longitudinally between the groups.
CONCLUSION: PC led to substantial improvements in patients' QOL, depression, and PTSD symptoms with sustained effects on PTSD symptoms up to 6 months post-HSCT.}, }
@article {pmid40549387, year = {2025}, author = {Marrero, RJ and Shastri, VM and Nicolet, D and Mrózek, K and Walker, CJ and Blum, WG and Powell, BL and Kolitz, JE and Moore, JO and Uy, GL and Stock, W and Carroll, AJ and Byrd, JC and Aplenc, R and Cooper, TM and Gamis, AS and Wu, H and Pounds, S and Wang, YC and Alonzo, TA and Meshinchi, S and Eisfeld, AK and Kolb, EA and Lamba, JK}, title = {Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2516296}, pmid = {40549387}, issn = {2574-3805}, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/drug therapy/mortality ; Adolescent ; Male ; Female ; Child ; Young Adult ; Adult ; Child, Preschool ; *Cytarabine/therapeutic use ; *Antimetabolites, Antineoplastic/therapeutic use ; Infant ; *Pharmacogenetics ; Treatment Outcome ; Cohort Studies ; Infant, Newborn ; }, abstract = {IMPORTANCE: Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts.
OBJECTIVE: To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts.
This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025.
EXPOSURES: Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols.
MAIN OUTCOMES AND MEASURES: ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status.
RESULTS: The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P < .001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P = .04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients.
CONCLUSIONS AND RELEVANCE: In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.}, }
@article {pmid40549281, year = {2025}, author = {Yi, JC and Walsh, CA and Chow, EJ and Baker, KS and Mendoza, JA and Cole, A}, title = {Primary care providers and their needs caring for cancer survivors: a qualitative study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {40549281}, issn = {1932-2267}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {PURPOSE: To enhance survivorship care, we explored primary care providers' (PCPs) preferences and needs related to treatment summary and survivorship care plans (TS/SCPs) as a communication tool and PCPs' general thoughts related to barriers in managing the care of cancer survivors.
METHODS: We conducted semi-structured qualitative interviews via video with PCPs within primary care practice networks in the Pacific Northwest. A codebook was developed with the interview guide as a template. Directed content analysis was used to analyze PCP reported challenges, supports needed, and TS/SCP feedback.
RESULTS: Qualitative interviews were conducted with 18 PCPs. The majority were female (72%) and non-Hispanic White (94%), with 56% from urban areas and with varied amounts of time in clinical practice (median 4.5 years, range 0.5-47). PCPs reported common challenges caring for cancer survivors (e.g., unsure what surveillance is needed) and supports needed to improve care (e.g., further PCP education). PCPs also described preferred information to include in TS/SCPs (e.g., surveillance schedule) and format (e.g., in the electronic health record). They also reported that e-consultation could be useful in communication with other health care providers about any questions, CONCLUSIONS: PCPs want further education and support about cancer surveillance guidelines and managing long-term effects in survivors. Having TS/SCP information easy to find in the EHR was mentioned by the PCPs as something that would improve their care of cancer survivors.
Providing PCPs with more education and tools in the EHR could lead to improved care of cancer survivors.}, }
@article {pmid40549085, year = {2025}, author = {Goodsell, KE and Sham, JG}, title = {ASO Author Reflections: Reasonable Doubt: The Case for Somatostatin Analogs in Pancreas Surgery Remains Unsettled.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {40549085}, issn = {1534-4681}, }
@article {pmid40549080, year = {2025}, author = {Fernandez, M and Todeschini, L and Keenan, BP and Rosenberg, D and Hernandez, S and Zampese, M and Qiao, G and Pollini, T and Maker, AV}, title = {ASO Visual Abstract: Novel Computational Analysis Identifies Cytotoxic Lymphocyte-to-Monocyte Balance in Tumors as a Predictor of Recurrence-Free Survival in Colorectal Carcinoma.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1245/s10434-025-17700-3}, pmid = {40549080}, issn = {1534-4681}, }
@article {pmid40548935, year = {2025}, author = {Readshaw, JJ and Doyle, LA and Puiu, M and Kelly, A and Nelson, A and Kaiser, AJ and McGuire, SF and Peralta Acosta, J and Smith, DL and Stoddard, BL and Kaiser, BK and Blower, TR}, title = {PglZ from Type I BREX phage defence systems is a metal-dependent nuclease that forms a sub-complex with BrxB.}, journal = {Nucleic acids research}, volume = {53}, number = {12}, pages = {}, pmid = {40548935}, issn = {1362-4962}, support = {BB/T008695/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; //Lister Institute Prize Fellowship to A.K. and T.R.B./ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; R35GM148166/GF/NIH HHS/United States ; R15GM140375//BKK/ ; R15 GM140375/GM/NIGMS NIH HHS/United States ; R01GM105691/GF/NIH HHS/United States ; //New England Biolabs/ ; BB/Y003659/1//responsive mode/ ; //Fred Hutchinson Cancer Center/ ; R35 GM148166/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {*Bacteriophages/genetics ; *Bacterial Proteins/metabolism/chemistry/genetics ; Models, Molecular ; *Viral Proteins/metabolism/chemistry ; Metals/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; }, abstract = {BREX (Bacteriophage Exclusion) systems, identified through shared identity with Pgl (Phage Growth Limitation) systems, are a widespread, highly diverse group of phage defence systems found throughout bacteria and archaea. The varied BREX Types harbour multiple protein subunits (between four and eight) and all encode a conserved putative phosphatase, PglZ, and an equally conserved, putative ATPase, BrxC. Almost all BREX systems also contain a site-specific methyltransferase, PglX. Despite having determined the structure and fundamental biophysical and biochemical behaviours of several BREX factors (including the PglX methyltransferase, the BrxL effector, the BrxA DNA-binding protein, and a commonly-associated transcriptional regulator, BrxR), the mechanism by which BREX impedes phage replication remains largely undetermined. In this study, we identified a stable BREX sub-complex of PglZ:BrxB, generated and validated a structural model of that protein complex, and assessed the biochemical activity of PglZ from BREX, revealing it to be a metal-dependent nuclease. PglZ can cleave cyclic oligonucleotides, linear oligonucleotides, plasmid DNA and both non-modified and modified linear phage genomes. PglZ nuclease activity has no obvious role in BREX-dependent methylation, but does contribute to BREX phage defence. BrxB binding does not impact PglZ nuclease activity. These data contribute to our growing understanding of BREX phage defence.}, }
@article {pmid40548549, year = {2025}, author = {Chao, ST and Berkowitz, A and Harris, EER and Henderson, MA and Lo, SS and Pacella, M and Palmer, J and Saeed, H and Simone, CB and Ziemer, BP and Small, W and Schechter, NR}, title = {ACR-ARS Practice Parameter for the Performance of Stereotactic Body Radiation Therapy.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000001224}, pmid = {40548549}, issn = {1537-453X}, abstract = {OBJECTIVES: This practice parameter was revised collaboratively by the American College of Radiology (ACR) and American Radium Society (ARS). Stereotactic body radiation therapy (SBRT) precisely delivers higher dose(s) of radiation in 5 of fewer fractions, compared with conventional radiation. Given the complexity and technical nature of this treatment technique, practice parameters are needed to provide guidance to physicians and physicists.
METHODS: This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS.
RESULTS: Workflow, qualifications/responsibilities of personnel, quality control, and treatment delivery/verification are reviewed. Notable elements of SBRT include image guidance, immobilization, and motion management, with the treatment planning goal of minimizing the volume of normal tissue exposed to medium and high dose levels and maximizing dose safely to the target. Specialized training is encouraged, as some technologies are not used in standard treatments.
CONCLUSIONS: This practice parameter provides direction on key components recommended for SBRT and may be used as a guide to physicians and physicists wanting to provide this treatment to their patients.}, }
@article {pmid40546794, year = {2025}, author = {Unger, JM and Andrews, HS and Levit, LA and McKelvey, BA and Stewart, M and Canin, B and Flaherty, K and Kimball, D and Miller, T and Onitilo, A and Bruinooge, S and Garrett-Mayer, E and Schenkel, C}, title = {Impact of the COVID-19 Pandemic Mitigation Strategies on Cancer Treatment Trials: A Meta-Analysis of Industry and National Cancer Institute Studies.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2500021}, pmid = {40546794}, issn = {2994-9750}, abstract = {PURPOSE: The onset of the COVID-19 pandemic in early 2020 disrupted the conduct of cancer clinical trials. In response, federal agencies allowed more flexibility for trial recruitment and patient follow-up. A key question is whether the benefits of adopting these strategies outweigh the potential detriments to quality metrics.
METHODS: A joint ASCO and Friends of Cancer Research task force invited industry and National Cancer Institute trial sponsors to contribute deidentified trial-level aggregate data on enrollment, major protocol deviations, dropouts, and severe adverse events (Common Terminology Criteria for Adverse Events grade 3-5). These quality metrics were examined as proportions of participants at risk during the pre-COVID-19 (January 2017-February, 2020), initial wave (March-April, 2020), initial recovery (May-December, 2020), and secondary recovery (January 2021-December 2022) periods. Multilevel beta-regression was used, adjusting for phase; study and sponsor were treated as random effects. Indicator variables were used with pre-COVID-19 as the reference.
RESULTS: Ten sponsors contributed 67 analyzable trials with N = 12,000 US-based participants. Enrollment odds decreased 49% in the initial wave (odds ratio [OR], 0.51 [95% CI, 0.30 to 0.86], P = .01) but recovered to pre-COVID-19 levels by 2021-2022 (OR, 1.01 [95% CI, 0.56 to 1.81], P = .97). Major protocol deviations, dropouts, and severe toxicity all had a lower incidence in the initial wave compared with pre-COVID-19; these outcomes were also less frequent (P < .05) in the initial recovery period but returned to pre-COVID-19 levels by 2021-2022.
CONCLUSION: In this multicollaborator evaluation, large declines in enrollment, major protocol deviations, dropouts, and severe toxicity during the acute phase of the pandemic all returned to pre-COVID-19 levels by 2021-2022. These findings highlight the impact of the temporary disruption to trial conduct during the pandemic's peak, but suggest that pandemic-related procedural flexibility did not result in long-term reduced data quality. Sponsors and regulators should consider broader adaptation of trial flexibilities moving forward.}, }
@article {pmid40546726, year = {2025}, author = {Iyer, SP and Dakhil, S and Shinohara, MM and Zain, J and Acosta, M and Foss, F}, title = {Pralatrexate injection combined with oral leucovorin for mucositis management in PTCL/CTCL treatment: a multicenter phase 2 trial.}, journal = {Blood neoplasia}, volume = {2}, number = {1}, pages = {100055}, pmid = {40546726}, issn = {2950-3280}, abstract = {Pralatrexate (Folotyn) is an antifolate indicated for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), and although durable clinical benefit has been demonstrated, oral and gastrointestinal mucositis and/or skin reactions are frequent toxicity complications associated with pralatrexate treatment. Leucovorin (d,l-folinic acid) administration has been used as a standard rescue for patients receiving high-dose methotrexate therapy and has recently been studied in patients with PTCL and cutaneous T-cell lymphoma receiving pralatrexate. We describe results from a multicenter, phase 2, single-arm, open-label trial, conducted with the primary objective of evaluating the effect of leucovorin in preventing or reducing the incidence of grade 2 or higher oral mucositis associated with pralatrexate treatment in cycle 1. Patients were administered pralatrexate, 30 mg/m[2] as an IV push, once weekly for 6 weeks in each cycle, followed by a week of rest (no treatment). Leucovorin 25 mg tablets were administered 3 times daily for 2 days (a total of 6 doses [150 mg cumulative weekly dose]), initiated 24 hours (±2 hours) after each pralatrexate dose. The evaluable population included 34 patients, with a mean age of 63.7 years and 60% males, of whom 2 (5.9%) developed grade 2 oral mucositis during the study period (P < .0001) and there were no reports of grade 3 or higher oral mucositis. Dose modifications, including omissions, delays, or reductions, due to oral mucositis were limited to 1 patient. Coadministration of leucovorin resulted in a significant reduction in mucositis and can be considered a prophylactic therapy in patients receiving pralatrexate treatment. This trial was registered at www.clinicaltrials.gov as #NCT02106650.}, }
@article {pmid40546723, year = {2025}, author = {Davids, MS and Ambrose, J and de Nigris, E and Prescott, J and Leng, S and Farooqui, MZH and Gandra, SR and Zettler, CM and Fernandes, LL and Wang, CK and Shadman, M}, title = {Real-world characteristics, treatment patterns, and outcomes of patients with 2 or more LOTs for CLL/SLL in the United States.}, journal = {Blood neoplasia}, volume = {2}, number = {1}, pages = {100047}, pmid = {40546723}, issn = {2950-3280}, abstract = {The development of targeted agents for chronic lymphocytic leukemia (CLL) has transformed the treatment paradigm for patients with CLL. Because of this evolving treatment landscape, contemporaneous evidence was needed related to US treatment patterns and outcomes among patients treated in the real-world. Using COTA's electronic health records-based database, we examined characteristics, treatment patterns, and outcomes of patients receiving ≥2 lines of therapy (LOTs). A total of 1283 adult patients with CLL were identified who initiated second LOT (2L) between 1 January 2014 and 30 June 2022. Of those patients, 542 (42.2%) later received third-line (3L) therapy, of whom 228 (42.1%) went on to receive fourth-line (4L) therapy. Overall, >18% of patients died after 2L initiation and before 3L initiation, and more than a quarter died before 4L initiation. Most patients were White (77.7%), male (60.6%), aged ≥65 years (68.8%), and treated in a community practice setting (87.8%). From 2014 to 2023, the use of chemoimmunotherapy in any ≥2L LOT decreased, whereas use of Bruton tyrosine kinase inhibitor and B-cell lymphoma 2 inhibitor therapy increased. Across endpoints, median times to event(s) were generally shorter with each subsequent LOT received, both in the overall population and among patients receiving a given therapy in different LOTs. With a median follow-up time from 2L initiation of 38.0 months, median real-world time to next treatment, progression-free survival, and overall survival was 31.9, 33.8, and 80.1 months, respectively. Despite great advancements in CLL treatments since 2014, unmet need persists for patients receiving late LOT.}, }
@article {pmid40545568, year = {2025}, author = {Gupta, M and Schoettler, ML and Brazauskas, R and Bo-Subait, S and Orozco, G and Battiwalla, M and Buchbinder, D and Hamilton, BK and Savani, BN and Schoemans, H and Sorror, ML and Ahmed, S and Badawy, SM and Bhushan, V and Birdsey, K and Couriel, D and Doherty, EE and Donato, M and Farag, SS and Gutman, J and Horwitz, M and El Jurdi, N and Maakaron, JE and Maziarz, RT and Pineiro, L and Schiller, G and Weisdorf, DJ and William, BM and Shaw, BE and Phelan, R and Porter, DL and Abt, PL and Levine, M}, title = {Risk Factors for Solid Organ Graft Failure and Death in Hematopoietic Cell Transplant Recipients Undergoing Solid Organ Transplantation: A Retrospective Center for International Blood and Marrow Transplant Research and Organ Procurement and Transplantation Network Study.}, journal = {Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1097/TP.0000000000005397}, pmid = {40545568}, issn = {1534-6080}, abstract = {BACKGROUND: There is a growing population of hematopoietic cell transplantation (HCT) survivors who later require a solid organ transplant (SOT). However, there are limited data on survival, risk factors (RFs) for SOT graft loss, and death.
METHODS: This is a retrospective Center for International Blood and Marrow Transplant Research study that included recipients of HCT followed by SOT between 2001 and 2017. HCT data were merged with data from the Organ Procurement and Transplantation Network.
RESULTS: Eighty patients underwent autologous (45%) or allogeneic (55%) HCT followed by single SOT. Common indications for HCT included leukemia/myelodysplastic syndrome (45%) and plasma cell disorders (38.8%). The median time from HCT to SOT was 47.7 mo. There were 49 kidney, 26 thoracic, and 5 liver transplants. Overall survival from SOT was significantly different by organ (P = 0.01). Three-year overall survival by organ type was 85% among kidney, 70.7% among thoracic, and 30% among liver SOT recipients. Significant RFs for death included lymphoma versus plasma cell disorders and SOT type; thoracic and liver SOT carried a greater risk of death than kidney SOT. There was no significant difference in SOT failure incidence by SOT type; 3-y overall incidence was 27.8%. RFs for SOT graft loss included lymphoma, liver SOT, and positive recipient cytomegalovirus status at SOT.
CONCLUSIONS: In this study, liver SOT recipients had inferior outcomes. However, renal and thoracic SOT recipients after HCT have acceptable outcomes compared with those of the general SOT population, and thus, SOT should be considered a viable treatment option in these patients.}, }
@article {pmid40545567, year = {2025}, author = {Gupta, M and Schoettler, ML and Orozco, G and Brazauskas, R and Bo-Subait, S and Battiwalla, M and Buchbinder, D and Hamilton, BK and Savani, BN and Schoemans, H and Sorror, ML and Ahmed, S and Badawy, SM and Bhushan, V and Birdsey, K and Couriel, D and Doherty, EE and Donato, M and Farag, SS and Gutman, J and Horwitz, M and El Jurdi, N and Maakaron, JE and Maziarz, RT and Pineiro, L and Schiller, G and Weisdorf, DJ and William, BM and Shaw, BE and Phelan, R and Porter, DL and Levine, M and Abt, PL}, title = {Risk Factors for Solid Organ Graft Failure and Death in Solid Organ Transplant Recipients Undergoing Hematopoietic Cell Transplantation: A Retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) and Organ Procurement and Transplantation Network (OPTN) Study.}, journal = {Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1097/TP.0000000000005377}, pmid = {40545567}, issn = {1534-6080}, abstract = {BACKGROUND: There is a growing population of solid organ transplant (SOT) survivors who subsequently require a hematopoietic cell transplant (HCT), although there are limited data on survival, risk factors for SOT graft loss, and death in this cohort.
METHODS: This retrospective Center for International Blood and Marrow Transplant Research study included recipients of SOT followed by HCT between 1989 and 2017. HCT data were merged with organ transplant data from the Organ Procurement and Transplantation Network.
RESULTS: Eighty-three patients with an SOT underwent an HCT. Organs transplanted included heart/lung (thoracic, n = 15), kidney (n = 42), and liver (n = 26); 24 patients (29%) received a living donor graft and 59 (71%) a deceased graft. Forty-one patients (49.4%) received an allogeneic HCT and 42 (50.6%) an autologous HCT. Three-year overall survival (OS) from HCT in the entire cohort was 38.6%. There were no significant differences in OS by SOT type, although 3-y OS appeared lowest in the kidney SOT group at 29.9%, compared with liver SOT at 40.6% and thoracic SOT at 58.2%. The incidence of SOT graft failure 3 y post-HCT was 59.1%. There were no significant differences in SOT graft failure by organ type: 3-y failure probability 67.2% for kidney, 56.5% for liver, and 46.2% for thoracic. Shared risk factors for death and graft failure included HCT indication (leukemia, lymphoma, and nonmalignant diseases), HCT type (allogeneic), and SOT type (kidney).
CONCLUSIONS: Although some SOT recipients may benefit from HCT, the incidence of SOT graft failure was high and OS was poor, particularly after allogeneic HCT.}, }
@article {pmid40545000, year = {2025}, author = {Farhan, S and Kennedy, VE and Espinoza-Gutarra, MR and Lust, H and Bobillo, MSO and Lin, AY and Olin, RL and Lin, RJ and Rentscher, KE and Taylor, MR and Mohanraj, L and Wood, WA and Murthy, HS and Ahmed, N and Dueck, AC and Phelan, R and Kelly, DL and Yuen, C and Munshi, PN and Schoemans, H and Hamilton, BK and Lee, C and Sung, AD}, title = {Assessing Physical Function in Transplantation and CAR-T Recipients: Expert Recommendations from the Survivorship, Aging and Biobehavioral Special Interest Groups of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.017}, pmid = {40545000}, issn = {2666-6367}, abstract = {The past few decades have witnessed significant advancements in stem cell transplant and cell therapy (TCT). This allowed their expanded use in older patients and those with comorbidities with favorable outcomes. However, these procedures carry significant risks, such as graft-versus-host disease, infection, cytokine release syndrome, and immune effector cell-associated neurotoxicity. Therefore, physical function assessment is crucial to assess patient fitness and potential optimization before and after TCT. The existence of diverse assessment tools makes implementation, comparison, and sharing knowledge among centers difficult. This paper proposes a tiered approach aiming to harmonize physical assessment in TCT. This allows healthcare facilities to prioritize recommended assessments based on their current capabilities and resources. TCT patients should receive comprehensive physical assessment pre- and post-TCT using a combination of both patient-reported and objective measures. For patient-reported measures, the Patient-Reported Outcomes Measurement Information System can be considered. For objective measures, we recommend considering a physical performance assessment (e.g., gait speed) or muscle strength assessment (e.g., hand grip), if feasible. Albumin and C reactive protein are also informative in predicting the risk of non-relapse mortality. Other composite tools, questionnaire libraries, biomarkers, imaging, and wearables can be added according to research and clinic needs. A care workflow needs to be in place in case any impairment is found during the evaluation with goals of increasing physiology reserve and mitigating stressors. This tiered approach will increase awareness and adoption of these tools and hence improve patient care, facilitate data sharing, and enhance collaboration in this field.}, }
@article {pmid40544344, year = {2024}, author = {Gilbert, PB and Peng, J and Han, L and Lange, T and Lu, Y and Nie, L and Shih, MC and Waddy, SP and Wiley, K and Yann, M and Zafari, Z and Ghosh, D and Follmann, D and Juraska, M and Díaz, I}, title = {A surrogate endpoint-based provisional approval causal roadmap, illustrated by vaccine development.}, journal = {Biostatistics (Oxford, England)}, volume = {26}, number = {1}, pages = {}, pmid = {40544344}, issn = {1468-4357}, support = {//National Institute of Allergy and Infectious Diseases/ ; /VA/VA/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; /NH/NIH HHS/United States ; //United States Government/ ; R37AI054165/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers ; *Clinical Trials, Phase III as Topic/methods ; *Endpoint Determination/methods ; *Vaccines ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; Biostatistics ; }, abstract = {For many rare diseases with no approved preventive interventions, promising interventions exist. However, it has proven difficult to conduct a pivotal phase 3 trial that could provide direct evidence demonstrating a beneficial effect of the intervention on the target disease outcome. When a promising putative surrogate endpoint(s) for the target outcome is available, surrogate-based provisional approval of an intervention may be pursued. Following the general Causal Roadmap rubric, we describe a surrogate endpoint-based provisional approval causal roadmap. Based on an observational study data set and a phase 3 randomized trial data set, this roadmap defines an approach to analyze the combined data set to draw a conservative inference about the treatment effect (TE) on the target outcome in the phase 3 study population. The observational study enrolls untreated individuals and collects baseline covariates, surrogate endpoints, and the target outcome, and is used to estimate the surrogate index-the regression of the target outcome on the surrogate endpoints and baseline covariates. The phase 3 trial randomizes participants to treated vs. untreated and collects the same data but is much smaller and hence very underpowered to directly assess TE, such that inference on TE is based on the surrogate index. This inference is made conservative by specifying 2 bias functions: one that expresses an imperfection of the surrogate index as a surrogate endpoint in the phase 3 study, and the other that expresses imperfect transport of the surrogate index in the untreated from the observational to the phase 3 study. Plug-in and nonparametric efficient one-step estimators of TE, with inferential procedures, are developed. The finite-sample performance of the estimators is evaluated in simulation studies. The causal roadmap is motivated by and illustrated with contemporary Group B Streptococcus vaccine development.}, }
@article {pmid40544207, year = {2025}, author = {Fernandez, M and Todeschini, L and Keenan, BP and Rosenberg, D and Hernandez, S and Zampese, M and Qiao, G and Pollini, T and Maker, AV}, title = {Novel Computational Analysis Identifies Cytotoxic Lymphocyte-to-Monocyte Balance in Tumors as a Predictor of Recurrence-Free Survival in Colorectal Carcinoma.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {40544207}, issn = {1534-4681}, support = {R37CA238435//Basic Research Laboratory/ ; }, abstract = {The microenvironment and immune infiltrate population of colorectal tumors can serve as a stronger predictor of patient survival than microsatellite-status or traditional T- or N-staging. This study aimed to leverage transcriptomic techniques to identify specific immune cell populations and their ratios associated with cancer recurrence in colorectal cancer patients. The goal was to identify patients who could benefit from early adjuvant interventions, identify those at higher risk of recurrence for surveillance, and identify potential combinatorial immunotherapy strategies tailored to this disease. We found that a lower ratio of cytotoxic lymphocyte: monocytic lineage cells, and not microsatellite-status, was associated with cancer recurrence. Additional differential gene expression analysis of the monocytic lineage demonstrated that genes specifically associated with tumor associated macrophages and a protumoral phenotype were overexpressed in the tumor microenvironment in patients that went on to have recurrent disease. Gene Ontology analysis revealed that pathways associated with pro-tumoral extracellular matrix remodeling were suppressed in tumors exhibiting a high cytotoxic lymphocyte: monocytic lineage ratio, suggesting a diminished propensity for tumor progression. The development of these prognostic markers not only associates with colorectal cancer recurrence, aiding in risk stratification and guiding adjuvant therapy decisions for resected early-stage patients, but also suggests that effective colon cancer treatments will likely require a combination of cytotoxic T-cell-directed immunomodulation and targeted inhibition of tumor-associated macrophages.}, }
@article {pmid40543709, year = {2025}, author = {Brehm, V and Wang, Z and Rocha, L and Jones, B and Jenq, RR and Chang, CC and Cheng, GS and Hsu, J and Sharifi, H and Yanik, G and Luna, L and Waqar, A and Zaveri, J and Dickey, BF and Bashoura, L and Shpall, EJ and Zinter, M and O'Dwyer, D and Champlin, RE and Chen, G and Alousi, A and Paczesny, S and Peterson, CB and Sheshadri, A}, title = {Inflammatory markers and microbiome dysbiosis in hematopoietic cell transplant recipients with lung graft-versus-host disease.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.020}, pmid = {40543709}, issn = {2666-6367}, abstract = {Bronchiolitis obliterans (BOS) is a manifestation of pulmonary chronic graft versus host disease (cGVHD) and is a devastating complication of allogenic hematopoietic stem cell transplantation (HCT). Early detection and treatment of BOS may improve outcomes, but biomarkers which accurately identify BOS early are lacking. We aimed to determine whether certain validated cGVHD markers could also accurately diagnose BOS as compared to patients without BOS and with or without extrapulmonary cGVHD. In addition, we sought to determine whether dysbiosis of gut or oral microbiomes was associated with BOS or with inflammatory biomarkers. We enrolled 43 allogenic HCT recipients, of whom 16 had BOS. For each patient, we obtained pulmonary function tests, measured the levels of nine serum biomarkers utilizing enzyme linked immunosorbent assays, and analyzed both the oral and gut microbiome using microbial DNA amplification and sequencing. We compared biomarker levels to lung function, both at baseline and over time, as well as to microbiome diversity. Higher IL1RL1 (p = 0.002) and IL-17 (p = 0.041) at enrollment were negatively correlated with FEV1% lung function over time. Increases in IL1RL1 (p = 0.035), IL-17 (p = 0.009), and WFDC2 (p = 0.045) levels over time were associated with worsened lung function/FEV1% over time. There were minimal correlations between gut microbiome diversity and lung function or serum biomarkers. Oral microbiome alpha diversity was lower in subjects with BOS than without (p = 0.00057), and oral beta diversity was associated with FEV1% and with levels of several biomarkers. Our pilot study suggests that certain serum cGVHD markers may identify allogeneic HCT recipients at higher risk for pulmonary impairment over time, and should be followed with robust, controlled studies.}, }
@article {pmid40543557, year = {2025}, author = {Nunley, BE and Weixler, A and Kim, HG and Xie, H and Sereewit, J and Hajian, P and Ellis, S and Mills, MG and Pérez-Osorio, AC and Goya, S and Gov, J and Dewar, R and Fernandes, G and Templeton, KE and Maloney, DM and Greninger, AL and Roychoudhury, P}, title = {Clinical Performance Evaluation of a Tiling Amplicon Panel for Whole-Genome Sequencing of Respiratory Syncytial Virus.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmoldx.2025.05.005}, pmid = {40543557}, issn = {1943-7811}, abstract = {Accurate genomic characterization of respiratory syncytial virus (RSV) is crucial for studies of epidemiology and viral evolution, including monitoring potential escape from newly authorized vaccines and prophylactic monoclonal antibodies. We adapted a viral genome tiling amplicon panel (UW-ARTIC) and developed a custom bioinformatic pipeline for high-throughput, cost-effective sequencing of both RSV-A and RSV-B subgroups. We established genome acceptability criteria and determined the performance characteristics of the panel, including assay sensitivity, specificity, breadth of genome recovery, accuracy, and precision, using contrived and remnant clinical specimens. High-quality genomes (>95% genome completeness; >500× and >1000× average depth for whole genome and fusion gene, respectively) were recovered from samples with cycle threshold ≤ 30 (approximately 594 and 2004 copies per reaction for RSV-A and RSV-B, respectively). Minor variants were accurately identified at >5% allele frequency. The assay showed high accuracy when compared with Sanger, shotgun metagenomic, and hybridization capture-based sequencing, as well as high repeatability and reproducibility. The UW-ARTIC RSV panel has utility for cost-effective RSV genome recovery in public health, clinical, and research applications. It has been used to generate US Food and Drug Administration-reportable data for clinical trials of RSV antiviral products, with robust performance in global samples from as recently as the 2023/2024 season. Continued genomic surveillance and future updates to primers will be essential for continued recovery of genomes as RSV continues to evolve.}, }
@article {pmid40542813, year = {2025}, author = {Kouwenberg, TW and van Dalen, EC and Mulder, RL and Armenian, S and Feijen, EAM and Chow, EJ and Kosmidis, H and Vormoor-Bürger, BJ and Kiyotani, C and Nathan, PC and Kapusta, L and Grotenhuis, HB and Engels, FK and Teske, AJ and Tragiannidis, A and Slieker, MG and Ozono, S and Nohria, A and Sláma, T and Skinner, R and Hudson, MM and Kremer, LCM and Ehrhardt, MJ and Mavinkurve-Groothuis, AMC}, title = {IGHG Recommendations for Anthracycline and Anthraquinone Cardiac Dysfunction Equivalence Ratios After Childhood Cancer: JACC: CardioOncology Expert Panel.}, journal = {JACC. CardioOncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaccao.2025.05.009}, pmid = {40542813}, issn = {2666-0873}, abstract = {Anthracycline and anthraquinone agents are major contributors to cancer therapy-related cardiac dysfunction in childhood cancer. However, evidence-based equivalence ratios for estimating individual risk have not been incorporated into international surveillance guidelines. The International Late Effects of Childhood Cancer Guideline Harmonization Group systematically reviewed the literature on equivalence ratios for doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone. Based on available evidence, benefit-harm considerations, and expert consensus, the panel concluded that the risk of cardiac dysfunction is lower with daunorubicin and higher with mitoxantrone compared with doxorubicin (moderate-quality evidence; strong recommendation). The panel recommends using an approximate ratio of 0.6 to convert daunorubicin to a doxorubicin-equivalent dose and a ratio of 10.5 for mitoxantrone (low-quality evidence; moderate recommendation). No recommendation was made for epirubicin or idarubicin due to inconclusive evidence.}, }
@article {pmid40542609, year = {2025}, author = {Menz, BD and Modi, ND and Abuhelwa, AY and Kuderer, NM and Lyman, GH and Swain, SM and Kichenadasse, G and Shahnam, A and Haseloff, M and Vitry, A and Rammant, E and Ramsey, I and Chan, RJ and McKinnon, RA and Rowland, A and Sorich, MJ and Hopkins, AM}, title = {Patient-reported outcome thresholds and their associations with survival, adverse events, and quality of life in a pooled analysis of breast cancer trials.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70020}, pmid = {40542609}, issn = {1097-0215}, support = {APP2008119//National Health and Medical Research Council/ ; APP2030913//National Health and Medical Research Council/ ; RSP-117-FY2023//Tour de Cure/ ; 2023-S-DTFA-005//Hospital Research Foundation/ ; }, abstract = {Researchers at the EORTC recently recommended clinical thresholds for the QLQ-C30 to facilitate actionable insights in clinical practice. We evaluate the distribution of these thresholds and associations with outcomes in breast cancer. Data were pooled from two early-stage and six advanced-stage breast cancer trials. EORTC thresholds were applied to available QLQ-C30 data to identify clinically important PRO domains. Associations between the number of clinically important PRO domains at baseline with overall survival (OS), invasive-disease-free survival (IDFS), progression-free survival (PFS), grade ≥3 adverse events (AEs), and serious AEs were evaluated using Cox-regression. Data from 8544 breast cancer patients, of whom 2428 (41%) of the 5893 early-stage and 1486 (56%) of the 2651 advanced-stage patients reported ≥3 clinically important PRO domains. In the early-stage, each additional clinically important PRO domain was associated with worsened grade ≥3 AEs (HR, 1.03 [95%CI, 1.01-1.04], p = 0.001) and serious AEs (1.05 [1.03-1.07], p < 0.001). In the advanced-stage, each additional clinically important PRO domain was associated with worsened OS (1.05 [1.03-1.07], p < 0.001), PFS (1.03 [1.01-1.04], p = 0.002), grade ≥3 AEs (1.04 [1.02-1.06], p < 0.001), and serious AEs (1.07 [1.04-1.11], p < 0.001). A substantial proportion of breast cancer patients report clinically important PRO domains at baseline, with increasing numbers associated with worsening AEs, survival, and quality-of-life.}, }
@article {pmid40541542, year = {2025}, author = {Gee-Rodriguez, K and Indorf, A and Swisher, EM and Bialick, K and Banda, K}, title = {Human epidermal growth factor receptor 2 targeted agents in gynecologic cancers: an updated review.}, journal = {International journal of gynecological cancer : official journal of the International Gynecological Cancer Society}, volume = {}, number = {}, pages = {101948}, doi = {10.1016/j.ijgc.2025.101948}, pmid = {40541542}, issn = {1525-1438}, abstract = {Human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic target across several solid tumor types and is associated with advanced disease and aggressive biology among gynecologic cancers. Experts have recommended HER2 testing algorithms to guide the treatment of advanced or recurrent endometrial cancers, but these guidelines utilize an outdated version of the recommendations for HER2 testing in breast cancers. Additionally, similar consensus guidelines do not exist for HER2 testing and reporting in ovarian or cervical cancers, leading to inconsistent HER2 measurement in clinical trials and real-world practice across all 3 gynecologic cancer types. Nonetheless, accumulating data support the efficacy of HER2-targeted treatment in gynecologic cancers, generating urgency to standardize HER2 measurement for these cancers. Practitioners also need to gain familiarity with the potential impacts on cardiac and respiratory function and the concomitant drug interactions of existing and developing HER2-targeted therapies. This review clarifies HER2 terminology and testing, discusses completed and ongoing clinical trials, and synthesizes recommendations for the use of HER2-directed agents in gynecologic cancers.}, }
@article {pmid40540800, year = {2025}, author = {Tsilifis, C and Raedler, J and Renke, J and Medinger, M and Laberko, A and Haraldsson, Á and Patel, N and Ciznar, P and Wong, M and Keogh, SJ and Gray, PE and Mitchell, R and Bigley, V and Elcombe, SE and Hauck, F and Albert, MH and Tholouli, E and Herwadkar, A and Elkhalifa, S and Kosmidis, C and Callisti, G and Burroughs, LM and Chen, K and Carpenter, B and Fox, TA and Morris, EC and Uppuluri, R and Raj, R and Yanagimachi, M and Buddingh, EP and Oikonomopoulou, C and Gonzalez, CE and Dimitrova, D and Kanakry, JA and Arnold, DE and Pai, SY and Slatter, MA and Pearce, MS and Worth, AJ and Freeman, AF and Gennery, AR}, title = {Allogeneic haematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016158}, pmid = {40540800}, issn = {2473-9537}, abstract = {STAT3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatocoeles, and aspergillosis; lymphoma; and extra-immune manifestations including fractures and vasculopathy. Published data on immune and extra-immune HSCT outcomes focus on case reports or small cohorts. International multicentre retrospective study of HSCT in STAT3-HIES. Primary endpoints were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic GvHD). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 (4-45) years. Most patients had pre-HSCT respiratory disease (93%) including parenchymal lung disease (68%) and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cell (51%) or marrow (49%) from HLA 10/10-MUD (44%), MFD (44%), MMFD (10%), or one 9/10 MMUD (2%). Median CD34+ stem cell dose was 6.2 (0.05-22.0) cells x106/kg. Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 (0.8-28) years. 5-year OS was 93% and 5-year EFS 90%. Cumulative incidence of grade II-IV acute GvHD was 22%. Median whole blood donor chimerism at latest follow up was 100%. 87% of patients have reduced or no bacterial or fungal respiratory infection. Post-HSCT, 20% developed new skeletal fractures. This worldwide study expand data on HSCT for STAT3-HIES to 41 patients. Despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease, though the impact on extra-immune manifestations appears limited.}, }
@article {pmid40540276, year = {2025}, author = {Banerjee, R and Acob, YC}, title = {Telehealth and Time Burden in Patients With Advanced Cancer.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2516769}, doi = {10.1001/jamanetworkopen.2025.16769}, pmid = {40540276}, issn = {2574-3805}, }
@article {pmid40540274, year = {2025}, author = {Neupane, A and Petrykey, K and Li, K and French, J and Zhou, X and Wang, J and Im, C and Dixon, SB and Ehrhardt, MJ and Mulrooney, DA and Jefferies, JL and Gramatges, MM and Chow, EJ and Bhatia, S and Robison, LL and Ness, KK and Hudson, MM and Burridge, PW and Armstrong, GT and Yasui, Y and Sapkota, Y}, title = {TTN and BAG3 in Cancer Therapy-Related Cardiomyopathy Among Long-Term Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2515793}, pmid = {40540274}, issn = {2574-3805}, mesh = {Humans ; Male ; Female ; *Cancer Survivors/statistics & numerical data ; *Adaptor Proteins, Signal Transducing/genetics ; Retrospective Studies ; *Apoptosis Regulatory Proteins/genetics ; *Cardiomyopathies/genetics/etiology/epidemiology ; Adult ; Child ; *Neoplasms/therapy ; *Connectin/genetics ; Adolescent ; Anthracyclines/adverse effects ; Prospective Studies ; Young Adult ; }, abstract = {IMPORTANCE: Cancer therapy-related cardiomyopathy (CCM) is an important concern for childhood cancer survivors. In the general population, rare variants in TTN and BAG3 are associated with an increased risk of familial dilated cardiomyopathy, and common variants are associated with a decreased risk of sporadic dilated cardiomyopathy.
OBJECTIVES: To examine associations of common and rare protein-altering variants (PAVs) in TTN and BAG3 with late-onset CCM risk in childhood cancer survivors.
This retrospective cohort study with a prospective follow-up included childhood cancer survivors from the St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS) with prior exposure to anthracyclines and/or chest-directed radiation. Cancer therapy-related cardiomyopathy was clinically assessed in SJLIFE and self-reported in CCSS, with severity graded using Common Terminology Criteria for Adverse Events, version 4.03. The data analysis was conducted from January 4, 2023, to March 6, 2025.
EXPOSURE: Late-onset CCM.
MAIN OUTCOME AND MEASURES: Multivariable logistic regression was used to evaluate the association of common variants in TTN and BAG3 with late-onset CCM risk, adjusting for relevant demographic and cancer treatment exposures. In SJLIFE alone, 7 echocardiographic parameters were assessed. Rare PAVs were examined using Fisher exact test. Cohort-specific results were combined using meta-analytic approaches.
RESULTS: The cohort included 1843 childhood cancer survivors from SJLIFE (median [IQR] age at CCM diagnosis, 34.9 [28.0-42.3] years; 53.2% male) and 4577 from CCSS (median [IQR] age at CCM diagnosis, 32.0 [23.0-41.0] years; 51.6% female). In the combined sample of European ancestry survivors from SJLIFE (205 with CCM grade ≥2) and CCSS (248 with CCM grade ≥2), common variants rs3829746-C in TTN (odds ratio, 0.81; 95% CI, 0.68-0.97) and rs2234962-C in BAG3 (odds ratio, 0.79; 95% CI, 0.65-0.95) were associated with a decreased risk of late-onset CCM. In SJLIFE African ancestry survivors, no association was observed with either of the common variants. Rare PAVs were not associated with late-onset CCM in European or African ancestry survivors. In European ancestry survivors, both rs3829746-C and rs2234962-C were also associated with reduced left ventricular end-systolic volume (β [SE], -1.90 [0.65] and -2.68 [0.64], respectively) and global longitudinal peak strain (β [SE], -0.31 [0.13] and -0.30 [0.12]) and with increased left ventricular ejection fraction (β [SE], 0.62 [0.27] and 0.86 [0.27], respectively).
CONCLUSIONS AND RELEVANCE: The findings of this cohort study show that common variants in TTN and BAG3 are associated with a decreased risk of late-onset CCM among childhood cancer survivors, while rare PAVs showed no association.}, }
@article {pmid40539461, year = {2025}, author = {Pandrangi, VC and Liao, JJ and de Almeida, JR and El-Sayed, IH and Hanna, G and Su, SY and Tsang, R and Won, TB and Witterick, I and Choby, G and Kuan, EC and Geltzeiler, M}, title = {Current Trends in the Management of Recurrent Nasopharyngeal Carcinoma.}, journal = {Head & neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.28219}, pmid = {40539461}, issn = {1097-0347}, abstract = {BACKGROUND: Recurrent nasopharyngeal carcinoma (NPC) is associated with challenges in treatment due to the complex anatomic location and impact of prior treatment modalities such as radiation therapy. The purpose of this review is to discuss modern treatment strategies for recurrent NPC, potential challenges, and outcomes.
METHODS: A narrative review was performed, evaluating management strategies of recurrent NPC, survival measures, and advancements in treatment considerations.
RESULTS: Treatment options including radiation, surgery, and chemotherapy are discussed, including data on survival outcomes and treatment-related morbidity. We review additional considerations including advances in endoscopic surgery, operative management of the internal carotid artery (ICA), novel radiation and chemotherapy protocols, and the introduction of immune checkpoint inhibitors.
CONCLUSION: This review describes contemporary management strategies for recurrent NPC, highlighting evolving management strategies that may reduce treatment-associated morbidity and improve survival.}, }
@article {pmid40537477, year = {2025}, author = {Bentley, AR and Brown, MR and Musani, SK and Schwander, KL and Winkler, TW and Sims, M and Kilpeläinen, TO and Aschard, H and Bartz, TM and Bielak, LF and Chai, JF and Chitrala, KN and Franceschini, N and Graff, M and Guo, X and Hartwig, FP and Horimoto, ARVR and Lim, E and Liu, Y and Manning, AK and Nolte, IM and Noordam, R and Richard, MA and Smith, AV and Sung, YJ and Vojinovic, D and Wang, R and Wang, Y and Feitosa, MF and Harris, SE and Lyytikäinen, LP and Pistis, G and Rauramaa, R and van der Most, PJ and Ware, E and Weiss, S and Wen, W and Yanek, LR and Arking, DE and Arnett, DK and Ballantyne, C and Boerwinkle, E and Chen, YI and Daviglus, ML and de Las Fuentes, L and de Vries, PS and Delaney, JAC and Fretts, AM and Ekunwe, L and Faul, JD and Gallo, LC and Heikkinen, S and Homuth, G and Ikram, MA and Isasi, CR and Jonas, JB and Keltikangas-Järvinen, L and Komulainen, P and Kraja, AT and Krieger, JE and Launer, L and , and Liu, J and Lohman, K and Luik, AI and Manichaikul, AW and Marques-Vidal, P and Milaneschi, Y and Mwasongwe, SE and O'Connell, JR and Rice, K and Rich, SS and Schreiner, PJ and Schwettmann, L and Shikany, JM and Shu, XO and Smith, JA and Snieder, H and Sotoodehnia, N and Tai, ES and Taylor, KD and Tinker, L and Tsai, MY and Uitterlinden, AG and van Duijn, CM and van Heemst, D and Waldenberger, M and Wallace, RB and Wee, HL and Weir, DR and Wei, WB and Willems van Dijk, K and Wilson, G and Yao, J and Young, KL and Zhang, X and Zhao, W and Zhu, X and Zonderman, AB and Deary, IJ and Gieger, C and Grabe, HJ and Lakka, TA and Lehtimäki, T and Oldehinkel, AJ and Preisig, M and Wang, YX and Zheng, W and Evans, MK and Province, M and Gauderman, J and Gudnason, V and Hartman, CA and Horta, BL and Kardia, SLR and Kooperberg, C and Liu, CT and Mook-Kanamori, DO and Penninx, BW and Pereira, AC and Peyser, PA and Psaty, BM and Rotter, JI and Sim, X and North, KE and Rao, DC and Bierut, L and Miller, CL and Morrison, AC and Rotimi, CN and Fornage, M and Fox, ER}, title = {Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {207}, pmid = {40537477}, issn = {2158-3188}, support = {Z01HG200362//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; Z01 HG200362/ImNIH/Intramural NIH HHS/United States ; R01 HL118305/HL/NHLBI NIH HHS/United States ; R01 HL156991/HL/NHLBI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Male ; *Lipids/blood/genetics ; Female ; *Gene-Environment Interaction ; Adult ; Genetic Loci ; Middle Aged ; Social Support ; }, abstract = {Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10[-5]) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10[-8]) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.}, }
@article {pmid40537474, year = {2025}, author = {Bradshaw, CS and Plummer, EL and Muzny, CA and Mitchell, CM and Fredricks, DN and Herbst-Kralovetz, MM and Vodstrcil, LA}, title = {Bacterial vaginosis.}, journal = {Nature reviews. Disease primers}, volume = {11}, number = {1}, pages = {43}, pmid = {40537474}, issn = {2056-676X}, mesh = {Humans ; Female ; *Vaginosis, Bacterial/physiopathology/epidemiology/complications/diagnosis/microbiology/therapy ; Vagina/microbiology/physiopathology ; Anti-Bacterial Agents/therapeutic use/pharmacology ; Microbiota/physiology ; Quality of Life/psychology ; Prevalence ; }, abstract = {Bacterial vaginosis (BV) is a vaginal microbiome disorder that is associated with preterm birth and spontaneous abortion, increased risk of HIV infection and sexually transmitted infections, and has negative effects on quality of life. BV affects one in four women globally, with the highest burden in resource-limited settings. Marked alterations in vaginal microbiome composition, in pro-inflammatory cytokines and chemokines, and in the proteome and metabolome characterize BV and contribute to adverse sequelae. Despite its prevalence, the exact aetiologic agent of BV is unknown and its pathophysiology is poorly understood. These knowledge gaps impede diagnostic and management approaches, with recommended treatment strategies resulting in recurrence that exceeds 50% over 3-6 months. New data on the sexual transmission of BV, including evidence that male-partner treatment improves cure, have improved our understanding of its aetiology and pathogenesis, and provide opportunities for developing optimal diagnostic, treatment and prevention strategies. Other factors probably also contribute to the low efficacy of current treatments, including biofilm and/or antimicrobial resistance, and failure to recolonize a favourable vaginal microbiome after treatment. The complex pathophysiology of BV highlights that individualized and multifaceted management approaches will be required to manage the refractory and adverse sequelae of BV.}, }
@article {pmid40536977, year = {2025}, author = {Sinnott-Armstrong, N and Forsythe, D and Benoit, JM and Chappell, CR and Coe, LSY and de Oliveira, BFR and Evans, N and Fagre, AC and Gilligan, JM and Hamilton, M and Henneberry, CM and Ishaq, SL and Johnston, J and Krichilsky, E and Lopez, JA and McMonigal, K and Ortiz Alvarez de la Campa, M and Rahman, R and Schwartz, NE and Talluto, L and Taylor, EJ and Vargas-Muñiz, JM and Weissman, JL}, title = {Protect transgender scientists.}, journal = {Science (New York, N.Y.)}, volume = {388}, number = {6753}, pages = {1283-1284}, doi = {10.1126/science.ady0962}, pmid = {40536977}, issn = {1095-9203}, }
@article {pmid40535475, year = {2025}, author = {Raychaudhuri, S and Gooley, TA and Rasmussen, A and Quach, K and Gill, E and Halpern, AB and Appelbaum, JS and Ghiuzeli, CM and Hendrie, PC and Cassaday, RD and Walter, RB and Percival, MM}, title = {Phase 1 trial of venetoclax with cladribine, cytarabine, G-CSF, and mitoxantrone for AML and high-grade myeloid neoplasm.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100085}, pmid = {40535475}, issn = {2950-3280}, abstract = {Intensifying induction by combining venetoclax with a high-dose cytarabine regimen may improve outcomes for high-risk populations such as adult patients with adverse-risk newly diagnosed or relapsed acute myeloid leukemia. In a phase 1 trial testing the novel combination of venetoclax and CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor [G-CSF], and mitoxantrone), the maximum tolerated dose was venetoclax 400 mg on days 1 through 14, combined with cladribine 5 mg/m[2] on days 1 through 5, cytarabine 1.5 g/m[2] on days 1 through 5, G-CSF 5 μg/kg on days 0 through 5, and mitoxantrone 16 or 18 mg/m[2] on days 1 through 3 (for relapsed/refractory and newly diagnosed adverse-risk patients, respectively). The 28-day mortality rate was 5%. Composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery) was 65%. These findings support further phase 2 study of venetoclax in combination with CLAG-M. This trial was registered at www.ClinicalTrials.gov as #NCT04797767.}, }
@article {pmid40534994, year = {2025}, author = {Tratt, M and Bandhlish, A and Eaton, KD and Gooley, T and Giustini, N and Deng, L}, title = {Survival Outcomes of Lung Adenocarcinoma With Intestinal Differentiation in the Era of Immunotherapy.}, journal = {JTO clinical and research reports}, volume = {6}, number = {7}, pages = {100827}, pmid = {40534994}, issn = {2666-3643}, abstract = {INTRODUCTION: Lung adenocarcinoma (LUAD) with intestinal differentiation (LAID) comprises a rare and heterogeneous NSCLC of invasive mucinous, enteric, and colloid characteristics. In the era of chemotherapy, LAID was associated with a poorer prognosis compared with other LUADs. Leveraging the National Cancer Database, we assessed survival outcomes of LAID in the era of immunotherapy.
METHODS: The National Cancer Database was queried for stage IV adenocarcinoma cases diagnosed from 2016 to 2019. LAID was defined as invasive mucinous adenocarcinoma, colloid adenocarcinoma, or enteric adenocarcinoma. An unadjusted comparison of survival distributions was performed using a log-rank test and adjusted by Cox multivariable regression.
RESULTS: A total of 40,516 patients were identified, of whom 855 had LAID and 39,661 had other LUAD. Among the cases of LAID, 593 were classified as colloid, 253 as mucinous, and nine as enteric. Patients with LAID had a higher risk of death compared with other LUAD subtypes, with a hazard ratio (HR) of 1.31 (95% confidence interval: 1.21-1.43) and a median survival of 9.19 months and 11.81 months, respectively. This was relatively consistent across all treatment subgroups (HR = 1.40: immunotherapy alone, HR = 1.29: chemoimmunotherapy; HR = 1.25: chemotherapy alone). Patients with LAID treated with chemoimmunotherapy had a median overall survival of 11.16 months, 9.19 months when treated with immunotherapy alone, and 7.09 months when treated with chemotherapy alone.
CONCLUSIONS: Compared with other LUADs, LAID remains associated with poorer survival in the era of immunotherapy. Nevertheless, exposure to immunotherapy may be associated with improved survival compared with chemotherapy alone in this rare subgroup.}, }
@article {pmid40534492, year = {2025}, author = {Portuguese, AJ and Liang, EC and Huang, JJ and Jeon, Y and Dima, D and Banerjee, R and Kwok, M and Cicero, KI and Hirayama, AV and Basom, R and Khouderchah, C and Shadman, M and Fong, L and Cowan, AJ and Gauthier, J}, title = {Extramedullary disease is associated with severe toxicities following B-cell maturation antigen CAR T-cell therapy in multiple myeloma.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.287985}, pmid = {40534492}, issn = {1592-8721}, abstract = {Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor outcomes following B-cell maturation antigen (BCMA)-targeted CAR-T therapy, yet its impact on treatment-related toxicity remains unclear. This study evaluates the impact of active EMD on toxicity, efficacy, and survival in patients with MM treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel). We conducted a retrospective cohort study of all patients with MM who received ide-cel (n=32) or cilta-cel (n=76) as standard-of-care therapy at our institution from August 2021 to October 2024. EMD was defined as the presence of soft tissue masses in extraosseous locations, and outcomes were compared based on EMD status. Among 108 patients, 26 (24%) had EMD. Patients with EMD experienced higher rates of grade (G)1+ (38% vs. 17%, p=0.022) and G3+ ICANS (19% vs. 1.2%, p=0.003), as well as G1+ (96% vs. 78%, p=0.041) and G3+ eICAHT (31% vs. 0%, p.}, }
@article {pmid40533557, year = {2025}, author = {Li, Y and Zhang, H and Sun, C and Dong, XD and Xie, C and Liu, YT and Lin, RB and Kong, XW and Hu, ZL and Ma, XY and Dai, DL and Zhu, QY and Li, YC and Li, Y and Liu, SX and Yuan, L and Zhou, PH and Gao, S and Tang, YP and Yang, JY and Han, P and McGuire, AT and Zhao, B and Bei, JX and Robertson, E and Zeng, YX and Zhong, Q and Zeng, MS}, title = {R9AP is a common receptor for EBV infection in epithelial cells and B cells.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40533557}, issn = {1476-4687}, abstract = {Epstein-Barr virus (EBV) persistently infects more than 90% of the human population, causing infectious mononucleosis[1], susceptibility to autoimmune diseases[2] and multiple malignancies of epithelial or B cell-origin[3]. EBV infects epithelial cells and B cells through interaction between viral glycoproteins and different host receptors[4], but it has remained unknown whether a common receptor mediates infection of its two major host cell targets. Here, we establish R9AP as a crucial EBV receptor for entry into epithelial and B cells. R9AP silencing or knockout, R9AP-derived peptide and R9AP monoclonal antibody each significantly inhibit, whereas R9AP overexpression promotes, EBV uptake into both cell types. R9AP binds directly to the EBV glycoprotein gH/gL complex to initiate gH/gL-gB-mediated membrane fusion. Notably, the interaction of R9AP with gH/gL is inhibited by the highly competitive gH/gL-neutralizing antibody AMMO1, which blocks EBV epithelial and B cell entry. Moreover, R9AP mediates viral and cellular membrane fusion in cooperation with EBV gp42-human leukocyte antigen class II or gH/gL-EPHA2 complexes in B cells or epithelial cells, respectively. We propose R9AP as the crucial common receptor of B cells and epithelial cells and a potential prophylactic and vaccine target for EBV.}, }
@article {pmid40533069, year = {2025}, author = {Shatila, M and Devalaraju, S and Takigawa, K and Catinis, C and Lee, I and Baerman, E and Ngo, S and Mittal, N and Glombicki, S and Machado, AP and Lu, L and Aleem, AS and Thompson, J and Funchain, P and Grover, S and Zhang, HC and Thomas, AS and Wang, Y}, title = {Worse Survival and Gastrointestinal Toxicity Outcomes Among Patients Receiving Proton Pump Inhibitors During Checkpoint Inhibitor Therapy.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {}, number = {}, pages = {1-7}, doi = {10.6004/jnccn.2025.7023}, pmid = {40533069}, issn = {1540-1413}, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) for cancer carry a risk of immune-related adverse events (irAEs). Upper and lower gastrointestinal tract inflammation are common toxicities. Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal irAEs. Studies have suggested these agents may also worsen lower gastrointestinal irAEs. Our study evaluated the effect of PPI exposure on gastrointestinal irAE severity.
METHODS: This was a single-center retrospective chart review including all patients receiving ICIs between January 2010 and February 2024 who developed upper or lower gastrointestinal toxicity. Patients were grouped based on PPI use, defined as receiving a PPI any time from 3 months before ICI initiation until gastrointestinal toxicity diagnosis.
RESULTS: A total of 1,228 patients were included: 88 (7.2%) with upper gastrointestinal toxicity and 1,140 (92.8%) with lower toxicity. Upper gastrointestinal irAEs were more severe among PPI users (69.6% with grade 3 toxicity in the PPI group vs 29.6% in the non-PPI group; P<.05). Similarly, lower gastrointestinal irAEs were more severe among PPI users, with a higher need for multiple lines of biologic treatment, higher hospitalization rates, and longer hospital stays (P<.05 for all). PPI use was associated with significantly worse overall survival among patients receiving ICIs (P<.05).
CONCLUSIONS: Our study is the largest to date showing the impact of PPI use on immunotherapy toxicity. PPI use may predispose to more severe toxicities and worse outcomes. PPIs may also reduce immunotherapy efficacy, as reflected by worse overall survival. These findings support the judicious use of PPIs in patients receiving ICIs and call for prospective studies to validate our results.}, }
@article {pmid40532723, year = {2025}, author = {Jabbour, E and Lussana, F and Martínez-Sánchez, P and Torrent, A and Rifón, JJ and Agrawal, V and Tormo, M and Cassaday, RD and Cluzeau, T and Huguet, F and Papayannidis, C and Hernández-Rivas, JM and Rijneveld, A and Fleming, S and Vucinic, V and Böll, B and Ikezoe, T and Abdul-Hay, M and Savoie, ML and Schuh, AC and Berthon, C and Schwartz, S and Chiaretti, S and Yuda, J and Miyazaki, T and González-Campos, J and Chen, Y and Wong, H and Choudhry, J and Zugmaier, G and Guest, E and Gordon, P and Kantarjian, H}, title = {Subcutaneous blinatumomab in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: post-hoc safety and activity analysis from a multicentre, single-arm, phase 1/2 trial.}, journal = {The Lancet. Haematology}, volume = {12}, number = {7}, pages = {e529-e541}, doi = {10.1016/S2352-3026(25)00144-9}, pmid = {40532723}, issn = {2352-3026}, mesh = {Humans ; *Antibodies, Bispecific/therapeutic use/administration & dosage/adverse effects/pharmacokinetics ; Male ; Female ; Adult ; Middle Aged ; Injections, Subcutaneous ; Aged ; *Antineoplastic Agents/therapeutic use/administration & dosage/adverse effects/pharmacokinetics ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Recurrence ; Young Adult ; Treatment Outcome ; }, abstract = {BACKGROUND: Two doses of subcutaneous blinatumomab in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia were identified as preliminary recommended phase 2 doses, based on the dose-escalation phase of this multicentre single-arm, phase 1/2 trial. Here, we aim to further study the safety, activity, and pharmacokinetics of these doses in all participants who have received them, including those treated in the completed phase 1b expansion part of the study.
METHODS: We did a post-hoc analysis of data from patients enrolled in the dose-escalation and dose-expansion phases and in the pharmacokinetic evaluation cohort of this multicentre, single-arm, phase 1/2 study. Patients were recruited from 44 hospitals in 11 countries. Eligible participants were aged 18 years or older with relapsed or refractory B-cell acute lymphoblastic leukaemia, at least 5% of blasts in the bone marrow, and an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients received either 250 μg subcutaneous blinatumomab once daily in week 1 of cycle 1 and then 500 μg three times weekly thereafter (250 μg/500 μg group), or 500 μg and then 1000 μg subcutaneous blinatumomab on the same schedule (500 μg/1000 μg group), previously identified as the preliminary recommended phase 2 doses. Each treatment cycle included a 4-week treatment period and a 1-week treatment-free interval. Patients received between two and five cycles. The primary endpoint for the dose-expansion phase was complete remission or complete remission with partial haematological recovery within the first two cycles, which was used as the primary outcome for this study. Data were pooled from all cohorts of the same dose level to form two dose groups. The response rates, adverse event incidence, and pharmacokinetics were summarised in each dose group separately and compared descriptively. Response was calculated with two-sided exact 80% CIs (Clopper-Pearson method). This study is registered with ClinicalTrials.gov, NCT04521231; phase 1 is complete, and phase 2 is active but not recruiting.
FINDINGS: Participants were recruited from Oct 18, 2021, to Sept 23, 2024, and median follow-up for the analyses was 5 months (IQR 3-9). Of the 88 patients included in the analysis at the data cutoff of Nov 28, 2024, 36 (41%) were treated with the 250 μg/500 μg regimen and 52 (59%) with the 500 μg/1000 μg regimen. The enrolled population comprised 55 (63%) male and 33 (38%) female participants; 56 (64%) were White, six (7%) Asian, three (3%) Black or African American, two (2%) American Indian or Alaska Native, and 20 (23%) other. Hispanic or Latino ethnicity was reported for 33 (38%) patients. 27 (75%) of 36 patients in the 250 μg/500 μg group and 41 (79%) of 52 in the 500 μg/1000 μg group showed complete remission or complete remission with partial haematological recovery. The most common grade 3-4 adverse events were neutropenia (19 [22%] patients), cytokine release syndrome (CRS; 18 [20%] patients), and immune effector cell-associated neurotoxicity syndrome (ICANS; 15 [17%] patients). Serious adverse events occurred in 70 (80%) of 88 patients and included CRS (33 [38%] patients), ICANS (20 [23%] patients), and neurotoxicity (six [7%] patients). No treatment-related deaths were reported. Consistent pharmacokinetics with dose-proportional exposures was observed following subcutaneous administration. Based on the totality of data, including efficacy, safety, and pharmacokinetic data, the subcutaneous blinatumomab dose regimen of 250 μg/500 μg was selected as the recommended phase 2 dose.
INTERPRETATION: Treatment with subcutaneous blinatumomab at the two dose regimens of 250 μg/500 μg and 500 μg/1000 μg resulted in promising preliminary activity and a manageable safety profile in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. The phase 2 part of the trial is ongoing to further evaluate subcutaneous blinatumomab activity and duration of response.
FUNDING: Amgen.}, }
@article {pmid40532705, year = {2025}, author = {Ganesan, A and Moore, AR and Zheng, H and Toh, J and Freedman, M and Magis, AT and Heath, JR and Khatri, P}, title = {A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.05.020}, pmid = {40532705}, issn = {1097-4180}, abstract = {Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single-cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of the baseline immune state and response to chronic, subacute, and acute illnesses.}, }
@article {pmid40532592, year = {2025}, author = {Jeong, D and Richards, AR and Jean-Baptiste, E and Gomez, MF and Thomas, KL and Mo, Q and Gigic, B and Figueiredo, JC and Li, CI and Shibata, D and Toriola, AT and Byrd, DA and Ulrich, CM and Stewart, PA and Siegel, EM and Kresovich, JK}, title = {Comparison of volumetric and single-slice computed tomography body composition metrics for colorectal cancer survival.}, journal = {European journal of radiology}, volume = {190}, number = {}, pages = {112241}, doi = {10.1016/j.ejrad.2025.112241}, pmid = {40532592}, issn = {1872-7727}, abstract = {BACKGROUND: Body composition is associated with colorectal cancer (CRC) survival. However, body composition measurements have traditionally relied on single-slice, axial imaging. Fully automated volumetric body composition analysis is widely available, but associations with CRC survival have yet to be examined in detail.
METHODS: Among a nested case-control sample of CRC patients with existing CT scans, volumetric and single-slice body composition analysis was performed, including total area and proportional skeletal muscle (SM), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT). Body composition was measured from the T12 vertebra to the sacrum, with the mid-L3 level used for single-slice analysis. We used multivariable Cox regression models to estimate associations between height-indexed volumetric and single-slice body composition metrics with all-cause mortality.
RESULTS: The mean age of the 121 enrolled patients was 61, and 38 (31 %) died over a mean follow-up of 7.7 years. The T12-sacrum, T12-L3, and L3-sacrum volumetric measurements were correlated with each other and their corresponding mid-L3 metric (all ρ > 0.8). In adjusted models, the T12-sacrum VAT index proportion yielded the strongest association with CRC survival (per 1-SD increase, HR: 2.07, 95 % CI: 1.13, 3.80, P = 0.02). Mid-L3 and volumetric composition metrics showed similar associations with CRC survival.
CONCLUSIONS: Volumetric body composition metrics are associated with CRC survival but did not outperform single-slice metrics in predicting CRC survival. Proportional metrics, which account for total abdominal muscle and adipose tissue area, may be a novel computational technique for assessing body composition.}, }
@article {pmid40532178, year = {2025}, author = {Uppaluri, R and Haddad, RI and Tao, Y and Le Tourneau, C and Lee, NY and Westra, W and Chernock, R and Tahara, M and Harrington, KJ and Klochikhin, AL and Braña, I and Vasconcelos Alves, G and Hughes, BGM and Oliva, M and Pinto Figueiredo Lima, I and Ueda, T and Rutkowski, T and Schroeder, U and Mauz, PS and Fuereder, T and Laban, S and Oridate, N and Popovtzer, A and Mach, N and Korobko, Y and Costa, DA and Hooda-Nehra, A and Rodriguez, CP and Bell, RB and Manschot, C and Benjamin, K and Gumuscu, B and Adkins, D and , }, title = {Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer.}, journal = {The New England journal of medicine}, volume = {393}, number = {1}, pages = {37-50}, doi = {10.1056/NEJMoa2415434}, pmid = {40532178}, issn = {1533-4406}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; Antineoplastic Agents, Immunological/administration & dosage/adverse effects ; B7-H1 Antigen/analysis/metabolism/antagonists & inhibitors ; Chemotherapy, Adjuvant/adverse effects/methods ; *Head and Neck Neoplasms/drug therapy/mortality/pathology/surgery ; Intention to Treat Analysis ; *Neoadjuvant Therapy/adverse effects/methods ; Progression-Free Survival ; *Squamous Cell Carcinoma of Head and Neck/drug therapy/mortality/pathology/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear.
METHODS: In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1.
RESULTS: A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group.
CONCLUSIONS: The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.).}, }
@article {pmid40532127, year = {2025}, author = {Fay, M and Liao, RS and Lone, ZM and Reddy, CA and Muhammad, H and Xie, C and Jain, P and Huang, W and Basu, HS and Nair, SS and Chakravarty, D and Williamson, SR and Gupta, S and Weight, C and Roy, R and Wilding, G and Tewari, AK and Klein, EA and Mian, OY}, title = {Artificial Intelligence-Based Digital Histologic Classifier for Prostate Cancer Risk Stratification: Independent Blinded Validation in Patients Treated With Radical Prostatectomy.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400292}, pmid = {40532127}, issn = {2473-4276}, mesh = {Humans ; Male ; *Prostatic Neoplasms/surgery/pathology/diagnosis/mortality ; *Prostatectomy/methods ; *Artificial Intelligence ; Middle Aged ; Aged ; Retrospective Studies ; Prognosis ; Risk Assessment/methods ; Neoplasm Grading ; Follow-Up Studies ; }, abstract = {PURPOSE: Artificial intelligence (AI) tools that identify pathologic features from digitized whole-slide images (WSIs) of prostate cancer (CaP) generate data to predict outcomes. The objective of this study was to evaluate the clinical validity of an AI-enabled prognostic test, PATHOMIQ_PRAD, using a clinical cohort from the Cleveland Clinic.
METHODS: We conducted a retrospective analysis of PATHOMIQ_PRAD using CaP WSIs from patients who underwent radical prostatectomy (RP) between 2009 and 2022 and did not receive adjuvant therapy. Patients also had Decipher genomic testing available. WSIs were deidentified, anonymized, and outcomes were blinded. Patients were stratified into high-risk and low-risk categories on the basis of predetermined thresholds for PATHOMIQ_PRAD scores (0.45 for biochemical recurrence [BCR] and 0.55 for distant metastasis [DM]).
RESULTS: The study included 344 patients who underwent RP with a median follow-up of 4.3 years. Both PathomIQ and Decipher scores were associated with rates of biochemical recurrence-free survival (BCRFS; PathomIQ score >0.45 v ≤0.45, P <.001; Decipher score >0.6 v ≤0.6, P = .002). There were 16 patients who had DM, and 15 were in the high-risk PathomIQ group (Mets Score >0.55). Both PathomIQ and Decipher scores were associated with rates of metastasis-free survival (PathomIQ score >0.55 v ≤0.55, P <.001; Decipher score >0.6 v ≤0.6, P = .0052). Despite the low event rates for metastasis, multivariable regression demonstrated that high PathomIQ score was significantly associated with DM (>0.55 v ≤0.55, hazard ratio, 10.10 [95% CI, 1.28 to 76.92], P = .0284).
CONCLUSION: These findings independently validate PATHOMIQ_PRAD as a reliable predictor of clinical risk in the postprostatectomy setting. PATHOMIQ_PRAD therefore merits prospective evaluation as a risk stratification tool to select patients for adjuvant or early salvage interventions.}, }
@article {pmid40531856, year = {2025}, author = {McTiernan, A}, title = {In Motion: Experimental Evidence on Exercise and Breast Cancer in Women and Mice.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-1313}, pmid = {40531856}, issn = {1557-3265}, abstract = {Strong evidence from observational studies show that high levels of physical activity are associated with a reduced risk of breast cancer, with a dose-response effect. Human trials and animal models have identified mechanisms explaining these associations, which aid in designing prescriptions and guidelines for exercise in breast cancer prevention.}, }
@article {pmid40528125, year = {2025}, author = {Bilen, MA and Burbage, S and Rossi, C and Khilfeh, I and Diaz, L and Wang, Y and Pilon, D and Brown, G and Shore, N and Lowentritt, B and Lin, DW}, title = {Comparison of Real-World Outcomes between Patients with BRCA1/2-Positive and Homologous Recombination Repair-Negative Metastatic Castration-Sensitive Prostate Cancer.}, journal = {Advances in therapy}, volume = {}, number = {}, pages = {}, pmid = {40528125}, issn = {1865-8652}, abstract = {INTRODUCTION: This real-world study compared time-to-next-treatment (TTNT), time-to-castration resistance (TTCR), and overall survival between patients with BRCA1/2-positive (BRCA+) and homologous recombination repair-negative (HRR-) metastatic castration-sensitive prostate cancer (mCSPC).
METHODS: Patients who received a genetic test and initiated treatment for mCSPC (index date) after 1/1/2018 were selected from the Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (1/1/2017-12/31/2022). Outcomes were compared between patients with ≥ 1 positive BRCA test (BRCA+) and those without detected HRR mutations (HRR-) using weighted Kaplan-Meier analyses and Cox proportional hazards models after baseline characteristics (12 months pre-index) were balanced using inverse-probability of treatment weighting.
RESULTS: In total, 149 patients with BRCA+ and 1066 with HRR- mCSPC were included. Baseline characteristics were well-balanced after weighting. By 24 months after treatment initiation, a significantly higher proportion of the BRCA+ than the HRR- cohort progressed to next treatment [69.7% vs. 56.8%; hazard ratio (HR) = 1.45 (95% confidence interval (CI) 1.10, 1.92), p = 0.009]; median TTNT was shorter in the BRCA+ than the HRR- cohort (10.9 vs. 18.7 months). By 24 months, a significantly higher proportion of the BRCA+ than the HRR- cohort progressed to castration resistance [72.2% vs. 61.4%; HR = 1.46 (95% CI 1.16, 1.84), p = 0.001]; median TTCR was shorter in the BRCA+ than HRR- cohort (12.9 vs. 16.9 months). Numerically fewer patients in the BRCA+ than the HRR- cohort survived 24 months after PC diagnosis [80.6% vs. 85.4%; HR = 1.46 (95% CI 0.99, 2.14), p = 0.054].
CONCLUSION: Findings demonstrate worse outcomes for patients with BRCA+ mCSPC treated with available advanced therapies, supporting the need for effective genetically targeted therapies in this population.}, }
@article {pmid40527319, year = {2025}, author = {Purice, MD and Quitevis, EJA and Manning, RS and Severs, LJ and Tran, NT and Sorrentino, V and Finkbeiner, C and Wu, F and Zager, M and Setty, M and Singhvi, A}, title = {Molecular profiling of adult C. elegans glia across sexes by single-nuclear RNA-seq.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2025.05.013}, pmid = {40527319}, issn = {1878-1551}, abstract = {A comprehensive understanding of nervous system function requires molecular insight into the diversity and sex dimorphism of both its component cell types, glia and neurons. Here, we present a single-nuclear RNA sequencing (RNA-seq) census of all neuroectoderm-derived glia in the adult C. elegans nervous system, across sexes. By iteratively coupling computational modeling and custom analytics with in vivo validations, we uncovered molecular markers for all glia, as well as class-specific and pan-glial molecular signatures. These identified that each glia is functionally heterogeneous across the nervous system and variably sex dimorphic between sexes. Thus, this glial transcriptome (wormglia.org) offers deep mechanistic insights into glial biology brain wide. Complementing the existing C. elegans neuronal transcriptome and mapped connectome, it also enables single-cell and molecular resolution insight into the entire nervous system of an adult metazoan.}, }
@article {pmid40526835, year = {2025}, author = {Poh, C and Voutsinas, JM and Shadman, M and Lynch, RC and Warren, EH and Crimp, CA and Till, BG and Ujjani, CS and Di, M and Raghunathan, V and Smith, SD and Wu, QV and Shinohara, MM and Gopal, AK}, title = {Pralatrexate Is Effective in Cytotoxic Cutaneous T-cell Lymphomas.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016680}, pmid = {40526835}, issn = {2473-9537}, abstract = {Cytotoxic cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell lymphomas with variable prognoses and no standard of care. We identified patients with primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAETL), primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) who were treated with at least one dose of pralatrexate between 2015 and 2024 at the University of Washington/Fred Hutchinson Cancer Center. Eighteen patients met criteria, 3 with CD8+ PCAETL, 6 with PCGDTL, and 9 with SPTCL. The median number of prior systemic therapies was 1 (range 0-4), and the median pralatrexate treatment duration was 14 weeks (range 8-43). The overall response rate was 100%, with 12 (67%) achieving complete response. Median progression-free and overall survival was 5.6 months and not reached, respectively. Among CR patients, the median response duration was 22 months. At a median follow-up of 45 months, 6 (33%) patients remain in sustained remission. This retrospective analysis is the first to evaluate pralatrexate's efficacy in this aggressive disease population, demonstrating its effectiveness and association with durable responses in cytotoxic CTCL.}, }
@article {pmid40523534, year = {2025}, author = {Dominitz, JA and Ladabaum, U and Holub, JL and Issaka, RB and Ko, CW and Robertson, DJ}, title = {Association Between Adenoma Detection Rate and Prevalent Colorectal Cancer Detection Rate in a National Colonoscopy Registry Subtitle: Association Between Adenoma and Colorectal Cancer Detection.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2025.06.009}, pmid = {40523534}, issn = {1528-0012}, abstract = {BACKGROUND: While the adenoma detection rate (ADR) is associated with post-colonoscopy colorectal cancer (PCCRC) risk, it is unknown to what extent this reflects missed colorectal cancer (CRC) versus missed pre-cancerous lesions. We evaluated the association between physician ADR and prevalent CRC detection during colonoscopy.
METHODS: We used cross-sectional 2019-2022 GI Quality Improvement Consortium (GIQuIC) data for >1.73 million colonoscopies performed by 3567 endoscopists for screening or abnormal fecal test (AFT) follow-up from 683 US endoscopy units. Endoscopist ADR and sessile serrated lesion detection rate (SSLDR) were determined based on screening exams.
RESULTS: CRC was detected in 0.3% of screening and 1.5% of follow-up colonoscopies. From lowest to highest endoscopist ADR quintile, CRC detection increased from 26.6 (95% confidence interval (CI) 24.4-27.9) to 33.1 (95%CI 29.7-33.7), and from 107.8 (95%CI 96.2-129.4) to 164.7 (95% CI 140.8-188.6) per 10,000 screening and AFT follow-up colonoscopies, respectively. In multivariable models with lowest ADR quintile as reference, the odds ratios (ORs) of CRC detection in the highest ADR quintile were 1.27 (95% CI 1.14-1.41) for screening and 1.50 (95% CI 1.16-1.93) for AFT follow-up colonoscopies. Compared to high-ADR/high-SSLDR endoscopists, the ORs of CRC detection were lower for low-ADR endoscopists irrespective of SSLDR (high-SSLDR, 0.87, 95% CI 0.80-0.96; low-SSLDR 0.92, 95% CI 0.85-0.98), but similar for high-ADR/low-SSLDR endoscopists.
CONCLUSIONS: ADR reflects prevalent CRC detection as well as detection and removal of CRC precursors. Our findings suggest that PCCRC is not uncommonly due to missed CRC, especially among endoscopists with low ADR.}, }
@article {pmid40523203, year = {2025}, author = {Rutherford, SC and Li, H and Herrera, AF and LeBlanc, M and Ahmed, S and Davison, K and Parsons, SK and Unger, JM and Perry, AM and Casulo, C and Bartlett, NL and Tuscano, JM and Hess, BT and Torka, P and Kumar, P and Jacobs, R and Song, JY and Castellino, SM and Kahl, B and Leonard, JP and Smith, SM and Friedberg, JW and Evens, AM}, title = {Nivolumab-AVD Versus Brentuximab Vedotin-AVD in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma Enrolled on S1826.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500204}, doi = {10.1200/JCO-25-00204}, pmid = {40523203}, issn = {1527-7755}, abstract = {Older patients with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients. We report a subset analysis of older patients (60 years and older) enrolled in the phase three S1826 trial conducted by SWOG that randomly assigned patients with newly diagnosed advanced-stage (III-IV) cHL to six cycles of nivolumab (N)-AVD or brentuximab vedotin (BV)-AVD. Of 103 enrolled patients 60 years and older, 99 were eligible. At a median follow-up of 2.1 years, the 2-year progression-free survival was 89% after N-AVD (n = 50) and 64% after BV-AVD (n = 49, HR 0.24, 95%CI 0.09-0.63, 1-sided stratified log-rank P = .001). The 2-year OS was 96% with N-AVD versus 85% with BV-AVD (HR 0.16, 95%CI 0.03-0.75 stratified 1-sided log-rank P = .005). Six cycles were delivered without dose reduction in 69% on N-AVD and 26% on BV-AVD; 55% discontinued BV, and 14% discontinued nivolumab. The nonrelapse mortality was 16% with BV-AVD and 6% with N-AVD. Despite more neutropenia with N-AVD, febrile neutropenia, sepsis, and infections were higher with BV-AVD, as was peripheral neuropathy. Patient-reported outcomes of key adverse events confirmed the improved toxicity profile of N-AVD over BV-AVD. N-AVD was better tolerated and more effective than BV-AVD and is therefore a new standard of care for older patients with advanced-stage cHL fit for anthracycline-based combination therapy.}, }
@article {pmid40522834, year = {2025}, author = {Kulsuptrakul, J and Emerman, M and Mitchell, PS}, title = {CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40522834}, issn = {2050-084X}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; DP2 AI154432/AI/NIAID NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; DP1 DA051110/NH/NIH HHS/United States ; T32 GM007270/NH/NIH HHS/United States ; DP2 AI 154432-01/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV-1/physiology ; *CARD Signaling Adaptor Proteins/metabolism/genetics ; *Inflammasomes/metabolism ; *HIV Infections/virology/transmission/immunology ; Macrophages/virology/immunology ; HIV Protease/metabolism/genetics ; T-Lymphocytes/virology ; Neoplasm Proteins ; }, abstract = {Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.}, }
@article {pmid40522215, year = {2025}, author = {Lin, N and Vitonis, AF and Mongiovi, JM and Farland, LV and Huang, T and Terry, KL and Eliassen, AH and Townsend, MK and Zhang, C and Hu, FB and Sasamoto, N}, title = {History of breastfeeding in relation to circulating inflammatory and metabolic biomarkers.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-0034}, pmid = {40522215}, issn = {1538-7755}, abstract = {BACKGROUND: Breastfeeding history has been associated with reduced risk of chronic diseases, although the underlying biological link is unclear.
METHODS: The study included 16,165 parous women in the Nurses' Health Studies who reported lactation history and biomarkers measured using plasma samples collected at mid-life. We calculated multivariable-adjusted geometric means of ten inflammatory biomarkers [high sensitivity C-reactive protein(hsCRP), interleukin-6 (IL6), IL8, IL10, insulin-like growth factor-1 (IGF1), soluble tumor necrosis factor α receptor 2 (sTNFR2), B-cell activating factor, C-X-C motif chemokine ligand 13 (CXCL13), sIL2-receptor-α (Rα), sIL6Rα] and eight metabolic biomarkers[triglyceride, total cholesterol, high- and low-density lipoprotein (HDL and LDL), leptin, soluble leptin receptor, adiponectin, retinol-binding protein 4] by self-reported history of breastfeeding prior to blood collection. False discovery rate (FDR) was used for multiple testing corrections.
RESULTS: Average age at blood collection was 52.6 years. Ever breastfeeding was associated with higher IGF1 (149.22 vs. 143.76 ng/mL, p-value=0.0002/FDR=0.004) compared with never breastfeeding. Longer breastfeeding duration was associated with lower IL10 (p-trend=0.001/FDR=0.01) and higher IGF1 (p-trend=0.0005/FDR=0.01). No significant associations were observed for other biomarkers. Longer breastfeeding duration was associated with higher IGF1 among premenopausal women but not among postmenopausal women (p-interaction=0.02). Longer breastfeeding duration was associated with lower soluble leptin receptor levels among those with BMI≥25kg/m2 (p-trend=0.01/FDR=0.09) but not among those with BMI<25 kg/m2 (p-interaction=0.0002).
CONCLUSION: Ever breastfeeding and longer breastfeeding duration was associated with higher IGF1 levels measured in mid-life.
IMPACT: Our results support the potential long-term systemic impact of breastfeeding on circulating IGF1 levels, which may influence future chronic disease risk.}, }
@article {pmid40521388, year = {2024}, author = {Puleo, J and Buchanan, A and Katenka, N and Halloran, ME and Friedman, SR and Nikolopoulos, G}, title = {Assessing Spillover Effects of Medications for Opioid Use Disorder on HIV Risk Behaviors among a Network of People Who Inject Drugs.}, journal = {Stats}, volume = {7}, number = {2}, pages = {549-575}, pmid = {40521388}, issn = {2571-905X}, support = {DP1 DA034989/DA/NIDA NIH HHS/United States ; DP2 DA046856/DA/NIDA NIH HHS/United States ; P30 DA011041/DA/NIDA NIH HHS/United States ; R01 AI085073/AI/NIAID NIH HHS/United States ; }, abstract = {People who inject drugs (PWID) have an increased risk of HIV infection partly due to injection behaviors often related to opioid use. Medications for opioid use disorder (MOUD) have been shown to reduce HIV infection risk, possibly by reducing injection risk behaviors. MOUD may benefit individuals who do not receive it themselves but are connected through social, sexual, or drug use networks with individuals who are treated. This is known as spillover. Valid estimation of spillover in network studies requires considering the network's community structure. Communities are groups of densely connected individuals with sparse connections to other groups. We analyzed a network of 277 PWID and their contacts from the Transmission Reduction Intervention Project. We assessed the effect of MOUD on reductions in injection risk behaviors and the possible benefit for network contacts of participants treated with MOUD. We identified communities using modularity-based methods and employed inverse probability weighting with community-level propensity scores to adjust for measured confounding. We found that MOUD may have beneficial spillover effects on reducing injection risk behaviors. The magnitudes of estimated effects were sensitive to the community detection method. Careful consideration should be paid to the significance of community structure in network studies evaluating spillover.}, }
@article {pmid40519326, year = {2025}, author = {Mittal, A and Jones, T and Karkar, R and Suh, J and Williams, S and Zheng, Y and Andris, LM and Bates, N and Bauer, AM and Lostutter, TW and Fann, JR and Fogarty, J and Hsieh, G}, title = {SCOPE: Examining Technology-Enhanced Collaborative Care Management of Depression in the Cancer Setting.}, journal = {Proceedings of the ACM on human-computer interaction}, volume = {9}, number = {2}, pages = {}, pmid = {40519326}, issn = {2573-0142}, support = {R01 CA244171/CA/NCI NIH HHS/United States ; P50 MH115837/MH/NIMH NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R01 LM012810/LM/NLM NIH HHS/United States ; }, abstract = {Collaborative care management is an evidence-based approach to integrated psychosocial care for patients with comorbid cancer and depression. Prior work highlights challenges in patient-provider collaboration in navigating parallel cancer care and psychosocial care journeys of these patients. We design and deploy SCOPE, a platform for technology-enhanced collaborative care combining a patient-facing mobile app with a provider-facing registry. We examine SCOPE through a total of 45 interviews with patients and providers conducted in SCOPE's 15 months of design and development and 24 months of SCOPE's deployment for actual care in 6 cancer clinics. We find that: (1) SCOPE supported patient engagement in its underlying collaborative care and behavioral activation interventions, (2) patient-generated data in SCOPE improved patient-provider collaboration between and within in-person sessions, (3) SCOPE supported providers in delivering care and improved care team collaboration, (4) experience with SCOPE created evolving expectations for collaboration around data, and (5) SCOPE's deployment in actual care surfaced important implementation barriers. We discuss the implications of our findings in terms of designing for engagement with behavioral health interventions, negotiating patient data sharing and provider responsiveness, supporting personalized self-tracking goals in evidence-based interventions, exploring the role of digital health navigators in technology-enhanced care, and the need for flexibility in aligning technology-supported interventions to patient needs.}, }
@article {pmid40518799, year = {2025}, author = {Grzelak, CA and Ghajar, CM}, title = {Incorporating Centrally Tolerized Mice as a Design Principle to Circumvent Reporter Immunogenicity in Cancer Research Models.}, journal = {Cancer research}, volume = {85}, number = {12}, pages = {2143-2145}, doi = {10.1158/0008-5472.CAN-25-1055}, pmid = {40518799}, issn = {1538-7445}, mesh = {Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; *Neoplasms/immunology/pathology ; *Immune Tolerance ; Humans ; Genes, Reporter/immunology ; Luminescent Proteins/immunology/genetics ; }, abstract = {The study of tumor progression and metastasis in a physiologic setting commonly involves implantation of tumor cells into immunocompetent mice. For this purpose, tumor cells are labeled routinely with bioluminescent and/or fluorescent proteins prior to transplantation, despite the fact that these foreign proteins generate adaptive immune responses. We have described previously how incorporating centrally tolerized mouse strains into tumor and metastasis modeling can be used as a study design principle to properly control for artifactual immune responses against such reporters. In this issue of Cancer Research, Khan and colleagues applied a tolerized mouse strain-the Tol mouse-to overcome limitations associated with the use of xenoantigenic fluorescent and bioluminescent reporters in immunocompetent settings. The authors showed how antigenic responses against such proteins can confound interpretation of study results when measuring the efficacy of immunotherapy regimens. This study readily demonstrates the utility of employing centrally tolerized transgenic models to improve preclinical investigations of cancer metastasis and therapeutic resistance. See related article by Khan et al., p. 2165.}, }
@article {pmid40516922, year = {2025}, author = {Batista, MV and Chaer, FE and Englund, JA and Boeckh, M and Carpenter, PA and Dadwal, SS and Waghmare, A and Navarro, D and Hirsch, HH and Piñana, JL and Papanicolaou, GA and Chemaly, RF}, title = {American Society for Transplantation and Cellular Therapy Series #10: Management of Parainfluenza and Human Metapneumovirus Infections in Hematopoietic Cell Transplantation and Cellular Therapy Recipients.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.016}, pmid = {40516922}, issn = {2666-6367}, abstract = {In 2019, The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Diseases Special Interest Group to update the 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). The new format is now structured around frequently asked questions (FAQs), concise tables, and figures to better support clinical providers. Here, a panel of experts in HCT and infectious diseases identified relevant FAQs, which they graded based on the strength of clinical practice recommendations and the level of supporting evidence, as described herein. In the ninth set of guidelines in the series, the focus is on parainfluenza virus and human metapneumovirus, with FAQs addressing epidemiology, incidence, clinical manifestations, risk factors, diagnosis, prevention (including vaccines), and therapeutic management in recipients of HCT and chimeric antigen receptor T cells (cellular therapy). Special considerations for pediatric patients, unmet needs, and future research directions are conveyed in the guidelines.}, }
@article {pmid40516446, year = {2025}, author = {Dasari, AKR and Bhatt, N and Haque, MA and Irving, R and Kayed, R and Lim, KH}, title = {Cryo-EM structural analyses reveal diverse porous structures in brain-derived tau oligomers.}, journal = {Biochemical and biophysical research communications}, volume = {776}, number = {}, pages = {152189}, doi = {10.1016/j.bbrc.2025.152189}, pmid = {40516446}, issn = {1090-2104}, abstract = {Misfolding and aggregation of tau into oligomers and neurofibrillary tangles are associated with Alzheimer's disease and related dementia (ADRD). Misfolded oligomeric species are widely believed to play a critical role in both disrupting cellular functions and propagating protein misfolding between cells. Characterization of the misfolded oligomers is crucial for understanding the mechanisms underlying protein aggregation and its role in disease pathogenesis. However, structural characterization of these misfolded oligomers has proven challenging due to their transient and heterogeneous nature. Here we report structural features of brain-derived tau oligomers extracted from Alzheimer's brains. Initial screening using negative staining transmission electron microscopy (TEM) and atomic force microscopy (AFM) reveal that tau (2N4R) forms a diverse array of pore-like oligomers with a diameter of 5-20 nm and a height of ∼2-8 nm. Higher-resolution structural analyses using cryo-EM on oligomers with diameters of 10-20 nm revealed the presence of two distinct layers within the pore-like structures, resolved at 2.5-4 Å. Our structural studies support the hypothesis that misfolded proteins may function as pore-forming toxins, potentially disrupting cellular membranes.}, }
@article {pmid40516378, year = {2025}, author = {Huang, Y and Zhang, L and Gelderblom, H and Seaton, KE and Yates, NL and Paez, CA and Karuna, ST and Andrew, P and Gamble, T and Robinson, ST and Ledgerwood, JE and Hyrien, O and Walsh, SR and Gay, CL and Gwira, JA and Spiegel, HML and Sobieszczyk, ME and Mannheimer, SB and Edupuganti, S and Hurt, CB and Stephenson, KE and Yu, C and Kelley, CF and Mahomed, S and Siegel, M and Yacovone, M and Pensiero, MN and Donnell, D and Cohen, MS and Corey, L and Gilbert, PB and Koup, RA and Tomaras, GD and , }, title = {Fixed dosing versus weight-based dosing of HIV-1 prophylactic monoclonal antibodies in adults: a post-hoc, cross-protocol pharmacokinetics modelling study.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105804}, pmid = {40516378}, issn = {2352-3964}, abstract = {BACKGROUND: Pharmacokinetic (PK) modelling and simulations have been used to support label changes of dosing levels or strategies for multiple marketed therapeutic monoclonal antibodies (mAbs). Using data from early-phase clinical trials in adults without HIV-1, we compared fixed and weight-based dosing strategies for three HIV-1 broadly neutralising mAbs planned for prevention efficacy evaluation: PGDM1400LS, PGT121.414.LS, and VRC07-523LS.
METHODS: We used a two-compartment population PK model to describe overall trends and inter-individual variability in post-administration serum concentrations over time from individuals administered PGDM1400LS (n = 95), PGT121.414.LS (n = 113), or VRC07-523LS (n = 251) subcutaneously or intravenously. We evaluated the effect of body weight on various PK parameters, including clearance rate, and simulated mAb concentrations after fixed and weight-based dosing administrations using sex-specific weights observed in participants from two recent HIV-1 mAb efficacy trials. We compared magnitudes and inter-individual variabilities of concentrations at specific post-administration timepoints, areas under the time-concentration curves (AUC), and predicted neutralisation titres against representative HIV-1 virus strains.
FINDINGS: For all three mAbs, we observed a modest effect of body weight on clearance rate and volumes of the central and peripheral compartments. The population-level magnitude and variability in time-specific concentrations, AUC, and predicted neutralisation titres were comparable between the two dosing strategies for both sexes. The relationship between body weight and concentrations differed between the two dosing strategies with a positive correlation for weight-based dosing and a negative correlation for fixed dosing. For individuals with body weight below the 15th or above the 85th percentiles, fixed dosing resulted in <3% difference in median AUC compared to the overall population. For lower weight individuals, fixed dosing improved AUC, potentially correcting the underdosing seen in the previous weight-based mAb efficacy trials. For higher weight individuals (e.g., >100 kg), body weight-based dosing or a higher fixed dose may be preferred.
INTERPRETATION: For HIV-1 prophylactic mAbs, a fixed-dose approach, possibly banded by weight categories may be advantageous over weight-based dosing, as it offers increased operational efficiency while maintaining comparable pharmacokinetics and inter-individual consistency.
FUNDING: NIAID.}, }
@article {pmid40514012, year = {2025}, author = {Schoettler, ML and Gavriilaki, E and Carreras, E and Cho, BK and Dandoy, CE and Ho, VT and Jodele, S and Moiseev, I and Sánchez-Ortega, I and Srivastava, A and Atsuta, Y and Carpenter, PA and Koreth, J and Kröger, N and Ljungman, P and Page, K and Popat, U and Shaw, BE and Sureda, AM and Soiffer, R and Vasu, S}, title = {An ASTCT, CIBMTR, EBMT, and APBMT Consensus Statement Defining Response Criteria for Hematopoietic Cell Transplantation Associated Thrombotic Microangiopathy (TA-TMA) Directed Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.028}, pmid = {40514012}, issn = {2666-6367}, abstract = {BACKGROUND: Transplant associated thrombotic microangiopathy (TA-TMA) confers significant morbidity and mortality in hematopoietic cell transplant recipients. The safety and efficacy of multiple TA-TMA directed therapeutic agents are being tested in ongoing clinical trials. In the absence of approved drugs, several treatments are used off-label. Response definitions to TA-TMA directed therapy from retrospective studies and ongoing interventional clinical trials vary widely, limiting cross study comparisons. An expert panel from multiple international blood and marrow transplant societies (ASTCT, CIBMTR, EBMT, APBMT) who initially convened to harmonize diagnostic and risk stratification criteria for TA-TMA extended its mandate to review response criteria.
OBJECTIVE: Our objective was to propose clinically meaningful response criteria for TA-TMA directed therapy to enhance consistent evaluation of therapeutic agents in clinical practice, interventional trials, and registry studies.
METHODS: After a relevant literature review, the Delphi method was used to achieve consensus on proposed response criteria.
RESULTS: The panel focused on the 3 key concepts. First, due to ongoing concurrent co-morbidities and severity of illness, the complete resolution of TA-TMA manifestations may be difficult to achieve immediately after initiating treatment, making the definition of clinically meaningful partial responses essential to assess early efficacy of TA-TMA-directed therapies. Second, because hematologic manifestations may resolve faster than organ damage, we suggest assessing hematologic/biochemical and organ manifestations independently, in addition to having an overall response assessment. Finally, using the previously established diagnostic criteria as a framework, we propose objective response definitions for each TA-TMA criterion and organ manifestation. While consensus was achieved on response definitions, due to the lack of evidence, there was no agreement on standardized time points for assessing response or when to consider alternative therapies for patients unresponsive to initial treatments. Hematologic and biochemical response assessments include anemia and thrombocytopenia, with criteria accounting for transfusion dependence or independence at the time of treatment, schistocytes, lactate dehydrogenase, and soluble C5b-9. Patients with other established etiologies of cytopenias (i.e. poor graft function or relapsed hematologic malignancy) should be considered unevaluable for hematologic response. Responses for involved organ manifestations were also proposed. In an overall assessment, the best overall response is limited by the lowest hematologic/biochemical or organ response. NR of either hematologic/biochemical or organ is considered an overall NR.
CONCLUSION: The consensus response criteria proposed by this expert panel are a step towards standardizing the assessment of treatment responses of TA-TMA directed agents for future studies and interventional clinical trials. Adoption of these criteria will enhance consistency of response assessment and facilitate the comparison of TA-TMA treatments. Since achieving an early overall CR may be challenging/protracted in patients with organ injury; establishment of criteria for clinically meaningful PR is important and may be a more useful early endpoint in studies. Given the complexity of these patients and assessment of response, these definitions may need be revised in the future after application in large cohorts diverse in age, HCT approaches, and interventional agents.}, }
@article {pmid40514010, year = {2025}, author = {Kharfan-Dabaja, MA and Kumar, A and Pinilla-Ibarz, J and Brown, JR and Shadman, M and Awan, FT and Kenderian, SS and Siddiqi, T and Abramson, JS and Al-Juhaishi, T and Brander, DM and Coombs, CC and Furman, RR and Jain, N and Khan, N and Saba, NS and Collins, JM and Beitinjaneh, A and Stephens, DM and Woyach, J and Hamadani, M}, title = {Clinical Practice Recommendations on the Role Of Allogeneic Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy in Patients With Chronic Lymphocytic Leukemia on Behalf of the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.06.002}, pmid = {40514010}, issn = {2666-6367}, abstract = {Chimeric antigen receptor T-cell therapy (CAR T-cell) is a new treatment option for relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). Novel therapies including Bruton's tyrosine kinase inhibitors (BTK), covalent or noncovalent, and an inhibitor of the B-cell leukemia/lymphoma 2 protein (BCL-2), venetoclax, have replaced chemoimmunotherapy (CIT) regimens in the front-line and the R/R setting, and have relegated allogeneic hematopoietic cell transplantation (allo-HCT) to later treatment stages. Updating the 2016 clinical practice recommendations on allo-HCT in CLL is necessary to help guide contemporary clinical practice. A panel of 18 physicians with diverse expertise across different CLL treatment modalities and one methodologist participated in this effort. Any recommendation receiving ≥ 70% votes was considered a consensus. CAR T-cell therapy is recommended for patients not responding or relapsing after at least 2 lines of therapy consisting of a covalent BTK inhibitor and a BCL-2 inhibitor. In addition, CAR T-cell therapy is recommended for patients who subsequently received a noncovalent BTK inhibitor in the third-line or later setting, regardless of response. CAR T-cell therapy is also recommended in CLL relapsing after an allo-HCT, assuming that patients are fit for the procedure. In those CLL patients who are candidates, allo-HCT is recommended if disease is R/R to CAR T-cell therapy provided that an objective response is demonstrated prior to the allograft. Allo-HCT is also recommended in patients with clonally-related Richter transformation (RT) after demonstrating an objective response to front-line CIT or other treatments. CAR T-cell therapy is recommended in R/R RT. We emphasize the importance of enrolling patients in clinical trials whenever available to continue to advance the field and improve prognosis of R/R CLL. We acknowledge that there are unique clinical scenarios not covered herein which may require a case-by-case approach.}, }
@article {pmid40513563, year = {2025}, author = {Khan, AT and Adebamowo, C and Fullerton, SM and Hirbo, J and Konigsberg, IR and Kraft, P and Martin, I and Nelson, SC and Ramsay, M and Wojcik, GL and Adebamowo, SN and Conomos, MP and Darst, BF and Hysong, MR and Li, Y and Martin, AR and Mathias, RA and Rich, SS and Sakoda, LC and Schrider, DR and Sharma, J and Smith, JL and Sun, Q and Zhang, Y and , and Gogarten, SM}, title = {A data model for population descriptors in genomic research.}, journal = {American journal of human genetics}, volume = {112}, number = {7}, pages = {1504-1514}, doi = {10.1016/j.ajhg.2025.05.011}, pmid = {40513563}, issn = {1537-6605}, mesh = {Humans ; *Genomics/methods ; *Genetics, Population ; Multifactorial Inheritance/genetics ; }, abstract = {Population descriptors used in genetic studies have broad social and translational implications. There are no globally agreed-upon definitions or usages of common population descriptors (e.g., race, ethnicity, nationality, and tribe), many of which are applied ad hoc and/or derived from political or bureaucratic conventions. Recent recommendations have encouraged the retention of as much granularity in population descriptors as possible during data preparation, analysis, and interpretation of research results. However, genomic research infrastructures (i.e., current practices, resources, and workflows in genomic research) often lack systematic and flexible organization, structure, and harmonization of multifaceted and detailed population descriptor data. This can lead to loss of information, barriers to international collaboration, and potential issues in clinical translation. Here, we describe a data model, developed by the NIH-funded Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium, that organizes and retains detailed population descriptor data for future research use. The model supports a versatile, traceable, and reproducible harmonization system that offers multiple benefits over existing data structures. This data model affords researchers the flexibility to thoughtfully choose and scientifically justify their choice of population descriptors. It avoids the conflation of social identities with biological categories and guards against harmful typological inferences. Genomic research tools of this kind will be crucial for producing scientifically robust findings that minimize potential harms of descriptor misuse while maximizing benefits for diverse communities.}, }
@article {pmid40513032, year = {2025}, author = {Curtis, DJ and Patil, SS and Reynolds, J and Purtill, D and Lewis, C and Ritchie, DS and Gottlieb, DJ and Yeung, DT and Wong, E and Tey, SK and Perera, T and Moore, J and Koldej, RM and De Abreu Lourenco, R and Stubbs, J and Morrissey, CO and Munsef, N and Arenas, A and Hill, GR and , }, title = {Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2503189}, pmid = {40513032}, issn = {1533-4406}, abstract = {BACKGROUND: Allogeneic peripheral-blood stem-cell transplantation (SCT) from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers. The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease (GVHD) prophylaxis in these patients. Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite. However, the effects of post-transplantation cyclophosphamide specifically after SCT from a matched related donor remain uncertain, and effects in the context of myeloablative conditioning are unclear.
METHODS: We randomly assigned adults who were undergoing SCT from a matched related donor after myeloablative or reduced-intensity conditioning to receive either post-transplantation cyclophosphamide-cyclosporin (experimental prophylaxis) or cyclosporin-methotrexate (standard prophylaxis). The primary end point was GVHD-free, relapse-free survival.
RESULTS: Among 134 patients who underwent randomization, 66 were assigned to receive experimental prophylaxis and 68 to receive standard prophylaxis. GVHD-free, relapse-free survival was significantly longer with experimental prophylaxis (median, 26.2 months; 95% confidence interval [CI], 9.1 to not reached) than with standard prophylaxis (median, 6.4 months; 95% CI, 5.6 to 8.3; P<0.001 by a log-rank test). GVHD-free, relapse-free survival at 3 years was 49% (95% CI, 36 to 61) with experimental prophylaxis and 14% (95% CI, 6 to 25) with standard prophylaxis (hazard ratio for GVHD, relapse, or death, 0.42; 95% CI, 0.27 to 0.66). The cumulative incidence of grade III to IV acute GVHD at 3 months was 3% (95% CI, 1 to 10) in the experimental-prophylaxis group and 10% (95% CI, 4 to 19) in the standard-prophylaxis group. At 2 years, overall survival was 83% and 71%, respectively (hazard ratio for death, 0.59; 95% CI, 0.29 to 1.19). The incidence of serious adverse events was similar in the two groups in the first 100 days after SCT.
CONCLUSIONS: The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis after transplantation from a matched related donor with either reduced-intensity or myeloablative conditioning in patients with blood cancers. (Funded by the Australian Government Medical Research Future Fund and others; ALLG BM12 CAST Australian-New Zealand Clinical Trials Registry number, ACTRN12618000505202.).}, }
@article {pmid40510739, year = {2025}, author = {Goodman, K and Cook, C and Weatherbee, D and Yadav, S and Mudaranthakam, DP and Sexton, R and Mahaffey, N and Garcia, L and Ta, T and Cebula, E and Smart, J and Goudeau, T and Annis, S and Gilmore, A and Chugina, D and Ahmadzai, P and Hoering, A and LeBlanc, M}, title = {Automating Data Entry from Electronic Health Record to Electronic Data Capture Using a Trusted Cloud-Based Application in Multisite Cancer Clinical Trials.}, journal = {Journal of the Society for Clinical Data Management}, volume = {5}, number = {1}, pages = {1-16}, pmid = {40510739}, issn = {2694-1473}, support = {P30 CA168524/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: For more than two decades, researchers have sought to develop and to improve technologies to seamlessly move data from electronic health record (EHR) systems to study forms in electronic data capture (EDC) systems. The goal is to utilize advancing technology to improve study data accuracy and quality while decreasing the burden of data collection on busy clinical research professionals.
OBJECTIVES: This report discusses findings from the SWOG Cancer Research Network's use of a secure and trusted third-party cloud-based application as a technology link between EHR databases and the clinical trial EDC application. The objectives are to ease the burden on site staff and improve data accuracy and completeness.
METHODS: Three SWOG sites used a cloud-based EHR-to-EDC application to enter study data for two follow-up tumor assessment case report forms for six patients each. This software-assisted method was compared to manual medical record abstraction. Time savings, error rate, and interrater reliability were measured.
RESULTS: A comparison of the two methods demonstrated substantial time savings and improvements in data quality. This is especially true for data fields that can be automatically captured using the application for clinical trials using the software-assisted approach.
CONCLUSIONS: Using a secure and trusted cloud-based application to access the EHR to assist in data collection for clinical trials resulted in welcome time savings for clinical research professionals and higher data accuracy.}, }
@article {pmid40509873, year = {2025}, author = {Hazelton, WD and Prest, M and Chen, L and Rouse, K and Elkin, EB and Ferris, JS and Xu, X and Bickell, NB and Kong, CY and Blank, S and Feuer, EJ and Samimi, G and Heckman-Stoddard, BM and Layne, TM and Wright, JD and Myers, ER and Havrilesky, LJ}, title = {Trends in uterine cancer incidence and mortality: insights from a natural history model.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf135}, pmid = {40509873}, issn = {1460-2105}, abstract = {BACKGROUND: Uterine cancer incidence and mortality are increasing, with concomitant disparities in outcomes between racial groups. Natural history modeling can evaluate risk factors, predict future trends, and simulate approaches to reducing mortality and disparities.
METHODS: We designed a natural history model of uterine cancer using a multistage clonal expansion design. The model is informed by National Health and Nutrition Examination Surveys (NHANES), National Health Examination Surveys (NHES), age, period, birth cohort, and birth certificate data on reproductive histories (RH) and body mass index (BMI), and is fit and calibrated to Surveillance, Epidemiology, and End Results (SEER) data by race/ethnicity and histologic subgroup. We projected future incidence and estimated the degree of contribution of BMI, RH, and competing hysterectomy to excess uterine cancer incidence.
RESULTS: The model accurately replicated SEER incidence for endometrioid (EM), non-endometrioid (non-EM), and sarcoma subgroups for non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients. For EM, non-EM, and Sarcomas, BMI-attributable risks are greater for NHW than NHB; RH-attributable risks are greater for NHB. Between 2018 and 2050, EM incidence is projected to rise by 64.9% in NHB and17.5% in NHW; non-EM projected rise is 41.4% in NHB and 22.5% in NHW; sarcoma incidence projected increase is 36% in NHB and 29.2% in NHW.
CONCLUSIONS: Uterine cancer risk is substantially explained by RH and BMI, with differences observed between NHB and NHW and future projections indicating perpetuation of disparities. Lower rates of hysterectomy and rising obesity rates will likely contribute to continued increases in uterine cancer incidence.}, }
@article {pmid40507311, year = {2025}, author = {King, GG and Baker, KK and Coveler, AL and Harris, WP and Cohen, SA and Shankaran, V and Zhen, DB and Safyan, RA and Lee, HH and Alidina, A and Hensel, J and Hibbert, R and Durm, GA and LaFary, YC and Younger, A and Kugel, S and Collisson, E and Konnick, EQ and Redman, MW and Schneider, BP and Pritchard, CC and Shahda, S and Chiorean, EG}, title = {Phase Ia/Ib Study of Afatinib with Capecitabine in Patients with Refractory Solid Tumors and Pancreaticobiliary Cancers.}, journal = {Cancers}, volume = {17}, number = {11}, pages = {}, pmid = {40507311}, issn = {2072-6694}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; TBD//Boehringer-Ingelheim Pharmaceuticals, Inc./ ; }, abstract = {BACKGROUND: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors.
PATIENTS AND METHODS: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m[2] twice daily on days 1-14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD).
RESULTS: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRAS[WT] PDA, and 5.0 months (95% CI 1.6, 6.1) for KRAS[WT] BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRAS[MUT] PDA and 3.1 months (95% CI 1.0, 22.8) for KRAS[MUT] BTC, respectively.
CONCLUSIONS: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRAS[WT] cancers further selected with a comprehensive molecular profile.}, }
@article {pmid40506647, year = {2025}, author = {Elbur, AI and Donnell, D and Hosek, S and Dye, BJ and Velloza, J and Delany-Moretlwe, S and Celum, C}, title = {Correction: The Association between Use of Adherence Support Interventions and Adherence To HIV Preexposure Prophylaxis among Young South African and Zimbabwean Women in HPTN 082.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10461-025-04807-7}, pmid = {40506647}, issn = {1573-3254}, }
@article {pmid40505814, year = {2025}, author = {Gao, L and Nelson, A and Barata, A and Horick, N and Wekwerth, B and Wood, A and Fernandes, A and Lee, SJ and LeBlanc, TW and Amonoo, HL and El-Jawahri, A and Newcomb, R}, title = {Prolonged Hospitalization for Hematopoietic Cell Transplantation: Characteristics, Risk Factors and Associations with Patient-Reported and Clinical Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.026}, pmid = {40505814}, issn = {2666-6367}, abstract = {Patients hospitalized for hematopoietic cell transplantation (HCT) may experience prolonged length of stay (PLOS). However, the associations between PLOS and patient-reported outcomes (PROs) during and after HCT hospitalization is unknown. We aimed to evaluate the associations of pre-HCT demographic and disease characteristics and PROs with PLOS, as well as the associations between PLOS and trajectory of PROs and risk of rehospitalization in the first year post-HCT. We conducted a secondary analysis of data from adult patients with hematologic malignancies undergoing HCT who were enrolled in a prospective observational study or one of two randomized clinical trials evaluating integrated specialty palliative care during HCT hospitalization. PLOS was defined as ≥30 continuous days for allogeneic HCT and ≥21 continuous days for autologous HCT. Quality of life (QOL; Functional Assessment of Cancer Therapy Bone Marrow Transplant), symptom burden (Edmonton Symptom Assessment Scale), anxiety and depression symptoms (Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9), and posttraumatic stress symptoms (PCL) were measured at time of admission (ie, prior to HCT), 2 weeks, and 3 and 6 months post-HCT. Multivariate logistic regression was used to assess the association between pre-HCT PROs and PLOS adjusting for relevant covariates. Linear mixed-effects models were used to characterize the trajectory of PROs by PLOS during and after HCT. Cox proportional hazards regression was used to evaluate differences between LOS groups in time to readmission or death in the first year post-HCT. A total of 606 patients (mean age = 55.7 years [18.3 to 78.0 years]; 56.6% male; 81.5% White; 53.1% allogeneic HCT) were included. Patients with PLOS were younger (mean 53.3 versus 56.6 years, P = .004), in complete remission prior to HCT (52.8% versus 46.3%, P = .02), diagnosed with acute leukemia (34.2% versus 26.1%, P < .001), and underwent allogeneic HCT (62.1% versus 49.9%, P < .0001). In multivariate analyses, worse pre-HCT QOL (OR 0.99, P = .003), symptom burden (OR 1.02, P = .01), and depressive symptoms (OR 1.07, P = .01) were associated with higher risk of PLOS. Patients with PLOS reported worse QOL at 2 weeks (∆ = -12.3, P < .0001), 3 months (∆ = -6.9, P = .002), and 6 months post-HCT (∆ =-4.8, P = .02) compared to those without PLOS. Patients with PLOS reported greater symptom burden at 2 weeks (∆ = 10.2, P < .0001) and 3 months (∆ = 3.9, P = .04), but not 6 months post-HCT (∆ = 0.5, P = .79). Patients with PLOS reported higher depression burden at 2 weeks (∆ = 2.5, P < .0001) and 3 months (∆ = 1.1, P = .03), but not 6 months post-HCT (∆ = 0.6, P = .19). Patients with PLOS experienced shorter time to death or re-admission in the first year post-HCT (median 221 days versus not reached, HR 1.7; CI 1.3 to 2.2, P < .001). Pre-HCT PROs including QOL, symptom burden, and depressive symptoms were associated with PLOS. Moreover, patients with PLOS go on to experience worse QOL, symptom burden, and depressive symptoms up to 6 months post-HCT and are at an increased risk of mortality and greater healthcare utilization. Patients with PLOS may have unique needs compared to the usual HCT population and may benefit from augmented supportive care during and after HCT.}, }
@article {pmid40505527, year = {2025}, author = {Snyder, LB and Newton, KM and Ng, HX and Reed, SD and Guthrie, KA and Zambrano, V and LaCroix, AZ}, title = {Positive impact of a menopause website - MyMenoplan.org - on treatment intentions, knowledge, and decision making: A randomized controlled trial.}, journal = {Maturitas}, volume = {199}, number = {}, pages = {108630}, doi = {10.1016/j.maturitas.2025.108630}, pmid = {40505527}, issn = {1873-4111}, abstract = {OBJECTIVE: Assess the impact of a new website, MyMenoplan.org, on menopause knowledge, decision-making progress, treatment and coping intentions among people experiencing perimenopause and menopause. The website was designed to provide women and their clinicians with comprehensive, evidence-based information and decision-making tools about a broad range of symptoms and treatments, address common questions and facilitate conversations with clinicians when desired.
STUDY DESIGN: Women were recruited online and randomized to interact with the MyMenoplan.org website created by MsFLASH investigators (n = 200) or control websites (n = 210) for at least 20 min before completing an online survey. Women in the control arm could choose any website(s), including three suggested high-quality websites from governmental or non-profit organizations. Fraud-detection protocols were followed. Outcome differences by arm were estimated via adjusted linear regression models.
PRIMARY OUTCOMES: Behavioral change intentions, menopause knowledge, decision-making progress, and user website experience.
RESULTS: 99 % of controls visited at least one recommended website. Compared with the control arm, the MyMenoplan.org arm reported significantly higher levels of intent to change treatment (3.87 vs. 3.61), knowledge of menopause symptoms and treatments (4.17 vs. 3.85), treatment decision-making progress (3.94 vs. 3.71), clarity about benefits and risks of treatments (4.04 vs. 3.81), perceived website quality (4.05 vs. 3.70), intentions to return to the website (4.40 vs. 3.97), and likelihood of recommending it to others (4.35 vs. 4.04; each p < 0.001).
CONCLUSION: MyMenoplan.org is the first NIH-funded website shown to be effective in helping women learn and make decisions about management of the menopause transition. The website serves as a model for providing much-needed, evidence-based information for health-care providers and women nearing or in perimenopause and menopause.
ClinicalTrials.gov ID NCT05299983.}, }
@article {pmid40505068, year = {2025}, author = {DeWolf, S and Kuttiyara, J and Vinci, P and Fei, T and Slingerland, J and Katsamakis, ZA and Fein, JA and Gipson, B and Lorenc, R and Zinsmeyer, V and Marcello, L and Giardina, P and Donohoe, W and Shah, GL and Lin, RJ and Papadopoulos, EB and Gyurkocza, B and Shaffer, BC and Tallman, MS and Politikos, I and Giralt, SA and Barker, J and Perales, MA and Tamari, R and Abdel-Wahab, O and Cho, C and Hsu, K and Peled, JU and van den Brink, MRM and Hanash, AM}, title = {Bone marrow and blood demonstrate distinct immune reconstitution patterns and correlations with relapse post-transplant.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015626}, pmid = {40505068}, issn = {2473-9537}, abstract = {The bone marrow represents the tumor microenvironment for many hematologic malignancies and a potentially critical site for alloimmunity following hematopoietic transplantation. Despite the importance of immune reconstitution (IR) post-transplant, marrow IR data are limited, and insights are largely derived from studies of peripheral blood (PB). We investigated lymphocyte IR longitudinally in marrow (n=110) and PB (n=115) samples from adults undergoing allogeneic transplantation for hematologic malignancies (n=33). This transplant cohort included a diverse representation of graft sources (mobilized peripheral blood, CD34-selected grafts, and umbilical cord blood) and degrees of HLA mismatch. Natural killer (NK) cells quickly expanded within the first 30 days post-transplant in both marrow and PB, but were then outnumbered by T cells in PB after day 100. In contrast, NK cells remained dominant in the marrow at day 100 (p<0.01, paired Wilcoxon signed-rank test), and thereafter marrow T and NK cell frequencies were similar throughout year-one. Tissue-specific features post-transplant included fewer regulatory T cells, more innate lymphoid cells, and increased CD69 expression on lymphocytes in marrow compared to PB. Furthermore, day 100 PD1 expression on marrow T cells was greater in non-relapsing patients than those who subsequently relapsed. These findings reveal persistent NK dominance of the marrow early post-transplant and suggest correlations between marrow immunity and clinical transplant outcomes.}, }
@article {pmid40504533, year = {2025}, author = {Unger, JM}, title = {Inclusive Cancer Clinical Trial Participation-A Recipe for New Treatment Advances.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2515210}, doi = {10.1001/jamanetworkopen.2025.15210}, pmid = {40504533}, issn = {2574-3805}, }
@article {pmid40503682, year = {2025}, author = {Haddox, HK and Angehrn, G and Sesta, L and Jennings-Shaffer, C and Temple, SD and Galloway, JG and Hinrichs, AS and DeWitt, WS and Bloom, JD and Iv, FAM and Neher, RA}, title = {The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure.}, journal = {Nucleic acids research}, volume = {53}, number = {11}, pages = {}, pmid = {40503682}, issn = {1362-4962}, support = {BAA 200-2021-11554/CC/CDC HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; 2919.02//National Science Foundation/ ; //Schmidt Sciences/ ; 310030_188547/SNSF_/Swiss National Science Foundation/Switzerland ; //National Defense Science and Engineering/ ; 75D30124C20302/CC/CDC HHS/United States ; //James S. McDonnell Foundation/ ; S10OD028685/RI/ORIP NIH HHS/United States ; NSF PHY-2309135/GF/NIH HHS/United States ; //LLC/ ; //Gordon and Betty Moore Foundation/ ; //Kavli Institute for Theoretical Physics/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 AI146028/SNSF_/Swiss National Science Foundation/Switzerland ; }, mesh = {*SARS-CoV-2/genetics ; *Genome, Viral ; *RNA, Viral/genetics/chemistry ; *Mutation Rate ; Nucleic Acid Conformation ; COVID-19/virology ; Humans ; Evolution, Molecular ; Mutation ; Silent Mutation ; }, abstract = {RNA viruses like SARS-CoV-2 have high mutation rates, which contribute to their rapid evolution. Mutation rates depend on mutation type and can vary between sites in a virus's genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using millions of SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for each mutation type and examine how much these rates vary between sites. We find a surprisingly high level of variability. A substantial fraction of this variability can be explained by local sequence context, genomic region, and RNA secondary structure. We estimate fitness effects of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on a model of the above features. We identify small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.}, }
@article {pmid40502162, year = {2025}, author = {Bernard, MJ and Ruiz, A and Diaz, JA and Nunley, NM and Dove, RN and Heering, KY and Bopardikar, S and Gallardo, A and Hashimoto, T and Agrawal, R and Smith, CM and Wilde, BR and Matulionis, N and Richards, HM and Sharifi, MN and Lang, JM and Zhao, SG and Haffner, MC and Boutros, PC and Christofk, HR and Goldstein, AS}, title = {OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40502162}, issn = {2692-8205}, support = {T32 GM152342/GM/NIGMS NIH HHS/United States ; TL1 DK132768/DK/NIDDK NIH HHS/United States ; U2C CA271894/CA/NCI NIH HHS/United States ; U2C DK119889/DK/NIDDK NIH HHS/United States ; R01 CA270108/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; U2C DK119886/DK/NIDDK NIH HHS/United States ; P50 CA092131/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; T32 GM007185/GM/NIGMS NIH HHS/United States ; OT2 OD030544/OD/NIH HHS/United States ; }, abstract = {Cells regularly adapt their metabolism in response to changes in their microenvironment or biosynthetic needs. Prostate cancer cells leverage this metabolic plasticity to evade therapies targeting the androgen receptor (AR) signaling pathway. For example, nucleotide metabolism plays a critical role in treatment-resistant prostate cancer by supporting DNA replication, DNA damage response and cell fate decisions. Identifying novel regulators of nucleotide metabolism in treatment-resistant cancer that are dispensable for the health of normal cells may lead to new therapeutic approaches less toxic than commonly used chemotherapies targeting nucleotide metabolism. We identify the metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as a regulator of nucleotide metabolism, tumor growth, and treatment-induced plasticity in prostate cancer. While OGDHL is a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation while having minimal impact on TCA cycle activity. Loss of OGDHL profoundly decreases nucleotide metabolite pools, induces the DNA damage response marker Ɣ2AX, and alters androgen receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6. Finally, OGDHL is highly expressed in neuroendocrine prostate cancer (NEPC). These findings support an unexpected role of OGDHL in prostate cancer, where it functions to sustain nucleotide pools for proliferation, DNA repair, and AR inhibition-induced plasticity.}, }
@article {pmid40501932, year = {2025}, author = {Otto, DJ and Arriaga-Gomez, E and Thieme, E and Yang, R and Lee, SC and Setty, M}, title = {Comparing phenotypic manifolds with Kompot: Detecting differential abundance and gene expression at single-cell resolution.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501932}, issn = {2692-8205}, support = {R01 CA292932/CA/NCI NIH HHS/United States ; R35 GM147125/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; }, abstract = {Kompot is a statistical framework for holistic comparison of multi-condition single-cell datasets, supporting both differential abundance and differential expression. Differential abundance captures changes in how cells populate the phenotypic manifold across conditions, while differential expression identifies condition-specific changes in gene regulation that may be localized to particular regions of that manifold. Kompot models the distribution of cells and gene expression as continuous functions over a low-dimensional representation of cell states, enabling single-cell resolution inference with calibrated uncertainty estimates. Applying Kompot to aging murine bone marrow, we identified a continuum of shifts in hematopoietic stem cell and mature cell states, transcriptional remodeling of monocytes independent of compositional changes, and divergent regulation of oxidative stress response genes across cell types. By capturing both global and cell-state-specific effects of perturbation, Kompot reveals how aging reshapes cellular identity and regulatory programs across the hematopoietic landscape. This framework is broadly applicable to dissecting condition-specific effects in complex single-cell landscapes.}, }
@article {pmid40501893, year = {2025}, author = {Robertson, AJ and Kerr, B and Feder, AF}, title = {Social interactions shape antiviral resistance outcomes in poliovirus via eco-evolutionary feedback.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501893}, issn = {2692-8205}, support = {T32 GM136534/GM/NIGMS NIH HHS/United States ; }, abstract = {Antiviral resistance evolution poses a major obstacle for controlling viral infections. A promising strategy is to target shared viral proteins that allow drug susceptible viruses to sensitize resistant ones during cellular coinfection, muting selection for resistance. Pocapavir, a poliovirus capsid inhibitor, employs this sociovirological strategy. While susceptible viruses significantly suppressed resistance in the presence of pocapavir in cell culture, a pocapavir clinical trial observed widespread resistance evolution and limited improvements to clearance times. To reconcile these findings, we present an intra-host eco-evolutionary model of poliovirus in the presence of pocapavir, which reproduces both the potent interference observed in vitro and the resistance emergence seen in patients. In the short term, our model predicts that a high density of susceptible viruses sensitizes resistant ones to pocapavir, mirroring cell culture results. However, over multiple replication cycles, pocapavir's high potency collapses viral density, which reduces coinfection and allows resistance to evolve as observed in the clinical trial. Since coinfection is essential to suppress resistance, enabling greater survival of susceptible viruses could offer therapeutic advantages. Counterintuitively, we demonstrate that this can be achieved by lessening antiviral potency, which can limit resistance evolution while also maintaining a low viral load. These findings suggest that antivirals that rely on viral social interaction must balance immediate neutralization with the preservation of future coinfection, yielding more sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, social phenotypes and absolute fitness not only provides new insights into designing effective therapies but also illuminates viral evolutionary dynamics more broadly.}, }
@article {pmid40501795, year = {2025}, author = {McKellar, SA and Pineda, JMB and Lattupally, R and Codd, AS and Newell, EW and Lu, SX and Bradley, RK}, title = {Chorionic Gonadotropin Beta 7 is a marker of immune evasion in cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501795}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA251138/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; }, abstract = {Human chorionic gonadotropin beta (beta-hCG) is an oncofetal antigen expressed by trophoblast cells of the placenta, with minimal expression in adult somatic tissues. Numerous studies have demonstrated that beta-hCG-encoding genes are expressed in various cancers, but expression of these genes (CGB3, CGB5, CGB7, and CGB8) across diverse cancers has not been systematically evaluated. Here, we report that CGB genes are more widely expressed across diverse cancer types than previously appreciated and that secreted beta-hCG is readily detected. In particular, CGB genes are expressed in the majority of urothelial bladder cancers, where CGB7 is most frequently expressed and significantly associated with an immunosuppressed tumor microenvironment, including decreased CD8[+] T cell infiltration. Multiple CGB genes are associated with failure to respond to immune checkpoint inhibitor (ICI) therapy, and CGB7 is particularly strongly predictive of poor prognosis. Overall, our findings indicate that beta-hCG is a clinically accessible, predictive biomarker of immunotherapeutic response.}, }
@article {pmid40501778, year = {2025}, author = {Schattgen, S and Vegesana, K and Hazelton, WD and Minervina, A and Valkiers, S and Slowikowski, K and Smith, N and , and Villani, AC and Thomas, PG and Bradley, P}, title = {Diverse modes of T cell receptor sequence convergence define unique functional and cellular phenotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501778}, issn = {2692-8205}, support = {U01 AI150747/AI/NIAID NIH HHS/United States ; T32 AR007258/AR/NIAMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R21 AI169085/AI/NIAID NIH HHS/United States ; DP2 CA247831/CA/NCI NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {Single-cell techniques allow concurrent study of gene activity and T cell receptor (TCR) sequences, identifying connections between TCR structure and cell traits. Expanding on our CoNGA software, we present a "metaCoNGA" analysis of 6 million T cells from 91 diverse studies, mapping TCR sequence similarity across tissues and diseases. This approach exposes shared TCR features within specific T cell subsets, including those associated with infection, cancer, and autoimmunity. We introduce a method to identify T cell groups with similar gene expression and biased TCR amino acid composition, providing a systematic framework for classifying diverse unconventional T cells, including KIR+ CD8+ T cells, CD4+ regulatory T cells, and subsets of NKT and MAIT cells. A new TCR clustering approach identifies thousands of convergent TCR sequence clusters hypothesized to target shared antigens. These clusters show coherent gene expression, highlighting the role of antigen exposure in shaping T cell behavior. Finally, we provide a tool for users to merge new data with this resource and rapidly identify T cell features in their data sets. This resource empowers investigations into the complex relationship between TCR sequence and T cell function in human health.}, }
@article {pmid40501614, year = {2025}, author = {Singh, P and Wright, JH and Smythe, KS and Fukuda, B and Hung, LH and Yeung, CC and Yeung, KY}, title = {Graphical and Interactive Spatial Proteomics Image Analysis Workflow.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501614}, issn = {2692-8205}, support = {R21 CA280520/CA/NCI NIH HHS/United States ; U24 HG012674/HG/NHGRI NIH HHS/United States ; }, abstract = {Spatial proteomics provides a spatially resolved view of protein expression and localization within cells and tissues by mapping the location and abundance of proteins. There is a need for containerized end-to-end imaging workflows for spatial proteomic analysis that are flexible, high-throughput, and support graphical and interactive visualizations. We present a modular and interactive spatial proteomics imaging workflow that empowers biomedical researchers to reproducibly execute and customize complex analyses. Our workflow consists of cell segmentation, unsupervised clustering, validation of clusters on the image, and cell type clustering results visualization. Users can utilize a form-based graphical interface to execute and customize multi-step workflows with a single click or interactively adjust image processing steps within the workflow, apply workflows to various datasets, and modify input parameters as needed. We illustrated the functionality of our workflow using a cancer imaging dataset consisting of a tissue microarray (TMA) stained by high-plex immunohistochemistry. This TMA contained a variety of cancer and tissue cell types to assess the broad applicability of this workflow to different biopsy types.}, }
@article {pmid40500115, year = {2025}, author = {Fogel, JM and Salih, MA and Haddaway, K and Marzinke, MA and Marshall, C and Wang, Z and Cummings, V and Piwowar-Manning, E and Rooney, JF and McCauley, M and Grinsztejn, B and Landovitz, RJ and Eshleman, SH}, title = {Use of DNA profiling to resolve HIV status in a person using injectable cabotegravir for HIV pre-exposure prophylaxis.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210202}, pmid = {40500115}, issn = {1472-4146}, }
@article {pmid40499654, year = {2025}, author = {Baillie, HT and Tinker, LF and An, P and Brasky, TM and Liu, S and Manson, JE and Snetselaar, L and Tabung, FK and Lampe, JW and Neuhouser, ML}, title = {Dietary Supplement Use Is Associated with Select Serum Nutrient Biomarkers among Postmenopausal Women: Results from a Controlled Feeding Study.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2025.06.003}, pmid = {40499654}, issn = {1541-6100}, abstract = {BACKGROUND: Dietary supplement use is common among older adults; however, the association between supplement use and corresponding nutrient biomarkers in this population is less well understood.
OBJECTIVES: This study aimed to determine whether older women using dietary supplements had higher serum concentrations of corresponding biomarkers and whether those using multiple supplement sources of the nutrient had incrementally higher serum nutrient concentrations.
METHODS: Participants from the Women's Health Initiative enrolled in a 2-wk feeding study (n = 153). Women consumed an individualized menu and maintained intake of usual dietary supplements. Serum vitamin B12, lutein + zeaxanthin, and phospholipid fatty acids were measured at the end of the feeding period. Multiple linear regression of dietary supplement use, and participant characteristics on log-transformed serum biomarker concentrations was used to evaluate the association. One-way analysis of variance determined whether there were significant differences in mean serum biomarkers among participants based on the number of sources of a nutrient consumed via dietary supplement.
RESULTS: In multiple linear regression models (n = 152), users of vitamin B12 supplements had 58% higher geometric mean serum concentrations of vitamin B12 than nonusers (P < 0.001). Users of omega-3 fatty acid dietary supplements had geometric mean serum phospholipid docosahexaenoic acid + eicosapentaenoic acid that were 38%-46% higher than nonusers (P < 0.0001). In contrast, use of lutein + zeaxanthin-containing supplements was not associated with serum lutein + zeaxanthin (P = 0.72). Users of 2 sources of vitamin B12 and lutein + zeaxanthin-containing dietary supplements had higher corresponding serum biomarkers than users of only a multivitamin and users of neither (P < 0.0001).
CONCLUSIONS: The use of vitamin B12 and omega-3 fatty acid supplements were associated with higher serum biomarkers, respectively. Dietary supplements containing lutein + zeaxanthin may not increase serum biomarkers among postmenopausal women.
TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00000611.}, }
@article {pmid40499589, year = {2025}, author = {Aelvoet, AS and Dekker, E and Cruise, MW and Grady, WM and Idos, GE and Kelly, K and Kieber-Emmons, A and Kupfer, SS and Markowitz, AJ and Samadder, NJ and Weiss, JM and Yurgelun, MB and Burke, CA}, title = {Gastric Polyposis and Cancer in Western Patients With Familial Adenomatous Polyposis: Epidemiology, Detection, and Management.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {6}, pages = {}, doi = {10.6004/jnccn.2025.7027}, pmid = {40499589}, issn = {1540-1413}, mesh = {Humans ; *Adenomatous Polyposis Coli/epidemiology/complications/diagnosis/therapy ; *Stomach Neoplasms/epidemiology/diagnosis/therapy/etiology ; Risk Factors ; Disease Management ; Adenomatous Polyps ; }, abstract = {Patients with familial adenomatous polyposis (FAP) are at increased risk of developing cancer, with the most common sites being colorectal, duodenal/ampullary and thyroid. In the last decade, an alarming increase in gastric cancer has been reported in the Western FAP population. These cancers are often diagnosed at an advanced stage with poor prognosis, even in patients undergoing regular upper endoscopic surveillance. Most gastric cancers in Western patients with FAP occur in the proximal stomach, where a carpeting of fundic gland polyposis hampers visualization of gastric cancer and its precursor lesions during endoscopic surveillance. Although fundic gland polyps are the most prevalent proximal polyp, several different dysplastic lesions can be found in the stomachs of patients with FAP. including fundic gland polyps with dysplasia, foveolar-type adenomas, pyloric gland adenomas, and intestinal-type adenomas. Although adenomas are the most likely precursors to gastric cancer, the exact lesions responsible for gastric cancer in FAP are not yet fully understood. This review focuses on gastric polyposis and the characteristics of gastric cancer in Western patients with FAP, including risk factors, lesion detection, surveillance and management of gastric polyposis, and areas for future research.}, }
@article {pmid40499462, year = {2025}, author = {Robinson, HR and Lakritz, S and Pavlick, DC and Davis, SL and Lieu, CH and Eule, CJ and Graham, LS and Spiess, PE and Li, R and Kamat, AM and Grivas, P and Jacob, JM and Bratslavsky, G and Basnet, A and Wong, KA and Lin, DI and Necchi, A and Ross, JS and Lam, ET}, title = {Squamous cell carcinoma of unknown primary (SCCUP): a genomic landscape study.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105312}, pmid = {40499462}, issn = {2059-7029}, mesh = {Humans ; *Neoplasms, Unknown Primary/genetics/pathology ; *Carcinoma, Squamous Cell/genetics/pathology ; Female ; Male ; Middle Aged ; Aged ; Genomics/methods ; Biomarkers, Tumor/genetics ; Microsatellite Instability ; Mutation ; Aged, 80 and over ; Adult ; B7-H1 Antigen ; }, abstract = {BACKGROUND: Squamous cell carcinoma (SCC) of unknown primary (SCCUP) refers to any SCC for which the primary tumor origin cannot be identified despite guideline-directed evaluation. Although strategies employing comprehensive genomic profiling (CGP) to identify targets for non-SCC carcinomas of unknown primary (CUPs) have shown benefit, the genomic landscape in SCCUP remains poorly defined. Here we describe results of CGP in patients with SCCUP to identify potential therapy targets and characteristic biomarkers.
PATIENTS AND METHODS: Cases of advanced SCCUP were identified in the FoundationCORE® database by review of clinical history and pathology records. Samples underwent DNA extraction and sequencing to identify genomic alterations (GAs), microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic mutational signatures, and viral reads. Programmed death-ligand 1 (PD-L1) expression was determined by immunohistochemistry.
RESULTS: 443 SCCUP cases were identified. Common presentation sites included lymph nodes (41.1%), liver (15.6%), and soft tissue (15.1%). A mean of 6.5 GAs were observed per case. The most frequent non-targetable GAs involved TP53 (62.5%), CDKN2A (37.0%), CDKN2B (19.6%), KMT2D (18.3%), and TERT (16.0%); the most frequent GAs potentially targetable in biomarker-driven trials included PIK3CA (27.3%), PTEN (15.1%), MTAP (13.1%), KRAS (10.4%), and NOTCH1 (8.4%). Among all SCCUP cases, 2.0% had MSI-high (MSI-H) status and 33.9% had TMB ≥10 mutations/megabase. Among 204 cases with available PD-L1 testing, 39.2% were low-positive [tumor proportion score (TPS) 1%-49%] and 29.9% were high-positive (TPS ≥50%). SCCUP cases presenting with liver involvement had fewer GAs per tumor and lower TMB compared with other SCCUP cases. In contrast, cases presenting with inguinal, pelvic, or retroperitoneal involvement were more likely to demonstrate evidence of human papilloma virus (HPV) infection and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) genomic signatures.
CONCLUSIONS: CGP of this SCCUP cohort identified GAs that may guide consideration of molecularly targeted therapy via tumor-agnostic indications and/or treatment in biomarker-driven trials. SCCUPs frequently exhibit biomarkers associated with response to immune checkpoint inhibitors.}, }
@article {pmid40499013, year = {2025}, author = {Pershad, Y and Uddin, MM and Xue, L and Haessler, J and Collins, JM and Mack, T and Glick, E and Glaser, V and Zhao, K and Jaiswal, S and Manson, JE and Pandey, U and Desai, P and Natarajan, P and Honigberg, MC and Kooperberg, C and Whitsel, EA and Kitzman, J and Bick, AG and Reiner, AP}, title = {Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 16-Year Longitudinal Study of 6976 Women.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025028417}, pmid = {40499013}, issn = {1528-0020}, abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,976 postmenopausal women from the Women's Health Initiative at two timepoints: the WHI baseline exam and approximately 16 years later at the Long Life Study (LLS) visit. Among 3,685 CH mutations detected at baseline (VAF ≥ 0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germline variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the Clonal Hematopoiesis Risk Score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.}, }
@article {pmid40498998, year = {2025}, author = {Marcos-Kovandzic, L and Avagliano, M and Ben Khelil, M and Srikanthan, J and Abdallah, R and Petrocelli, V and Rengassamy, J and Alfaro, A and Bied, M and Fidelle, M and Ferrere, G and Daillere, R and Arbab, A and Amine-Hneineh, R and Pages, A and Dartigues, P and Ly, P and Simon, S and Durand, S and Gottschlich, A and Ginhoux, F and Bleriot, C and Liu, P and Zhao, L and Creusot, L and Rolhion, N and Derosa, L and Kroemer, G and Menger, L and Kobold, S and Castilla-Llorente, C and Sokol, H and Casola, S and Pasolli, E and Zitvogel, L and Bigenwald, C}, title = {Gut microbiota modulation through Akkermansia spp. supplementation increases CAR-T cell potency.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-1230}, pmid = {40498998}, issn = {2159-8290}, abstract = {This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 CAR-T cell therapy, both in patients and in a preclinical syngeneic tumor model. B cell lymphoma patients treated with CD19-CAR-T cells exhibited profound intestinal dysbiosis, exacerbated after CAR-T infusion. This dysbiosis was characterized by low bacterial richness, low sMAdCAM-1 and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR-T cell infiltration into bone marrow, inverted the CD4/CD8 CAR-T ratio, favored Tc1 CD8+ T cell polarization and promoted release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of Akkermansia spp. supplementation was abolished when CAR-T cells were genetically deficient for the indole receptor, aryl hydrocarbon receptor (Ahr). Ahr-agonistic indoles alone failed to replicate the bacterium's anticancer effects. These findings suggest Akkermansia supplementation could improve CAR-T cell potency in patients with intestinal Akkermansia deficiency.}, }
@article {pmid40497723, year = {2025}, author = {Schleiss, MR and Fernández-Alarcón, C and Bierle, CJ and Geballe, AP and Badillo-Guzman, A and Tanna, CE and Tsriwong, K and Blackstad, M and Wang, JB and McVoy, MA}, title = {Replication-deficient whole-virus vaccines against cytomegalovirus induce protective immunity in a guinea pig congenital infection model.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0020725}, doi = {10.1128/jvi.00207-25}, pmid = {40497723}, issn = {1098-5514}, abstract = {Vaccines are needed to prevent congenital human cytomegalovirus (HCMV) infections. This study used the guinea pig cytomegalovirus (GPCMV) model to examine replication-deficient whole-virus vaccines for protection against maternal viremia and congenital CMV infection. Two recombinant GPCMVs, GP51-DD and GP52-DD, were engineered with destabilization domains fused to the essential viral late proteins GP51 and GP52. These viruses, predicted to replicate in the presence of the synthetic ligand Shield-1 but not in its absence, were evaluated for Shield-1 dependence in vitro and for safety, immunogenicity, and efficacy in the GPCMV model. GP52-DD was profoundly Shield-1-dependent, producing no detectable infectious progeny in its absence. In contrast, the replication of GP51-DD was delayed in the absence of Shield-1 but reached similar peak titers with or without the compound. GPCMV-seronegative guinea pigs received two subcutaneous injections of phosphate-buffered saline, GP51-DD, GP52-DD, or wild-type GPCMV (WT-GPCMV). DNAemia attributable to vaccination was noted in 10/10 (100%) of WT-GPCMV-immunized animals but in only 10/28 animals (36%) immunized with DD vaccines (P < 0.001). GPCMV-specific ELISA and interferon-gamma ELISpot responses were similar in all vaccinated groups. When immunized animals were bred and challenged during pregnancy with virulent GPCMV, DNAemia was detected in all sham-immunized controls and in 44% of GP52-DD-immunized dams (at significantly reduced levels) but was absent in dams immunized with GP51-DD or WT-GPCMV. Immunization with GP52-DD, GP51-DD, or WT-GPCMV significantly reduced congenital GPCMV transmission compared to placebo (protective efficacies of 89, 94, and 100%, respectively). Thus, replication-impaired GP51-DD and replication-deficient GP52-DD vaccines were comparable to WT-GPCMV in immunogenicity and protective efficacy.IMPORTANCECongenital HCMV infections could potentially be prevented by a vaccine, but most vaccines that have advanced in clinical trials have been modestly effective, at best. Subunit HCMV vaccines chiefly target envelope glycoproteins, but none has proven effective at engendering durable protective immunity. A vaccine that confers immune responses to a broader repertoire of immunogens than a subunit vaccine, such as a whole-virus, live-attenuated vaccine, could confer improved protection. However, there are safety concerns for live-attenuated HCMV vaccines. Using the GPCMV model of congenital infection, this study demonstrates that two replication-impaired whole virus vaccines, though attenuated in animals, are highly immunogenic and induce preconception immunity that protects against maternal viremia and fetal infection after wild-type GPCMV challenge during pregnancy.}, }
@article {pmid40493417, year = {2025}, author = {Roudier, MP and Gulati, R and Sayar, E and Patel, RA and Tratt, M and Richards, HM and Cejas, P and Munoz Gomez, M and Qiu, X and Xie, Y and Hanratty, B and Zaidi, S and Zhao, JL and Adil, M and Mittal, C and Zhao, Y and Dumpit, R and Coleman, I and Low, JY and Persse, T and Galipeau, PC and Lee, JK and Tretiakova, M and Chambers, M and Vakar-Lopez, F and True, LD and Perrone, M and Lam, HM and Kollath, LA and Ding, CC and Harmon, S and Cheng, HH and Yu, EY and Montgomery, RB and Hawley, JE and Lin, DW and Corey, E and Schweizer, MT and Setty, M and Ha, G and Sawyers, CL and Morrissey, C and Long, HW and Nelson, PS and Haffner, MC}, title = {Patterns of intra- and inter-tumor phenotypic heterogeneity in lethal prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI186599}, pmid = {40493417}, issn = {1558-8238}, abstract = {Metastatic prostate cancer (mPC) is a clinically and molecularly heterogeneous disease. While there is increasing recognition of diverse tumor phenotypes across patients, less is known about the molecular and phenotypic heterogeneity present within an individual. In this study, we aimed to define the patterns, extent, and consequences of inter- and intra-tumoral heterogeneity in lethal prostate cancer. By combining and integrating in situ tissue-based and sequencing approaches, we analyzed over 630 tumor samples from 52 mPC patients. Our efforts revealed phenotypic heterogeneity at the patient, metastasis, and cellular levels. We observed that intra-patient, inter-tumoral molecular subtype heterogeneity was common in mPC and showed associations with genomic and clinical features. Additionally, cellular proliferation rates varied within a given patient across molecular subtypes and anatomic sites. Single-cell sequencing studies revealed features of morphologically and molecularly divergent tumor cell populations within a single metastatic site. These data provide a deeper insight into the complex patterns of tumoral heterogeneity in mPC with implications for clinical management and the future development of diagnostic and therapeutic approaches.}, }
@article {pmid40493363, year = {2025}, author = {Appelbaum, JS and Percival, ME and Scott, BL}, title = {A cure for the kiss of death?.}, journal = {Blood advances}, volume = {9}, number = {11}, pages = {2855-2856}, pmid = {40493363}, issn = {2473-9537}, }
@article {pmid40492914, year = {2025}, author = {Kim, HJ and Partridge, SC and Lee, J and Yoen, H and Moon, WK and Ha, SM}, title = {Preoperative Diagnosis of Ipsilateral and Contralateral Breast Cancer: Role of Diffusion-weighted MRI.}, journal = {Radiology}, volume = {315}, number = {3}, pages = {e242423}, pmid = {40492914}, issn = {1527-1315}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; Retrospective Studies ; *Diffusion Magnetic Resonance Imaging/methods ; *Breast Neoplasms/diagnostic imaging/surgery/pathology ; Adult ; Breast/diagnostic imaging ; Contrast Media ; Aged ; *Preoperative Care/methods ; Sensitivity and Specificity ; }, abstract = {Background The interpretation of the multiparametric MRI, which combines dynamic contrast-enhanced (DCE) MRI with diffusion-weighted imaging (DWI), has the potential to increase MRI diagnostic accuracy. Purpose To investigate and validate the potential of DWI with an apparent diffusion coefficient (ADC) cutoff in evaluating additional lesions detected at preoperative MRI in patients with breast cancer. Materials and Methods In this retrospective review, data from patients with additional lesions (Breast Imaging Reporting and Data System [BI-RADS] category 3 or higher) who underwent MRI between June 2019 and June 2021 were evaluated. Two breast radiologists independently evaluated additional enhanced lesions and measured the ADC values. The optimal ADC cutoff for downgrading lesions was determined according to the Youden index and was applied to a separate validation cohort. The efficacy of prespecified ADC values (1.53 × 10[-3] mm[2]/sec and 1.3 × 10[-3] mm[2]/sec) was investigated. Diagnostic performance was evaluated and compared using generalized estimating equations. Results Data from 219 patients (mean age, 50.8 years ± 10.2 [SD]) with 292 additional lesions were evaluated. The optimal ADC cutoff was 1.0 × 10[-3] mm[2]/sec, which, compared with that for DCE MRI alone, increased specificity (from 28.7% to 73.1%; P < .001) but decreased sensitivity (from 99.2% to 89.6%; P < .001) of MRI. In the validation cohort (104 patients, 133 additional lesions), 48 of 133 (36.1%) lesions were diagnosed as cancer, and applying the ADC cutoff derived from the development cohort increased specificity (from 21.2% to 68.2%; P < .001) but decreased sensitivity (from 97.9% to 83.3%; P = .01). For ipsilateral lesions, specificity increased (from 8.7% to 65.2%; P < .001), but the sensitivity did not decrease significantly (from 97.1% to 85.3%; P = .052). For contralateral lesions, similar performance improvements were observed for specificity (from 35.9% to 71.8%; P < .001), but a greater decrease in sensitivity was observed (from 100% to 78.6%; P < .001). Application of the prespecified ADC cutoffs achieved higher sensitivity values but smaller improvements in specificity. Conclusion The ADC cutoff based on MRI with DWI improved the performance of preoperative MRI in diagnosing additional lesions in patients with breast cancer. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.}, }
@article {pmid40492758, year = {2025}, author = {Ashby, E and Zhang, B and Fouda, GG and Fong, Y and Janes, H}, title = {Negative Control Outcome Adjustment in Early-Phase Randomized Trials: Estimating Vaccine Effects on Immune Responses in HIV Exposed Uninfected Infants.}, journal = {Statistics in medicine}, volume = {44}, number = {13-14}, pages = {e70142}, doi = {10.1002/sim.70142}, pmid = {40492758}, issn = {1097-0258}, support = {UM1AI068616//National Institute of Allergy and Infectious Diseases/ ; UM1AI068632//National Institute of Allergy and Infectious Diseases/ ; UM1AI068635//National Institute of Allergy and Infectious Diseases/ ; UM1AI106716//National Institute of Allergy and Infectious Diseases/ ; DGE-2140004//National Science Foundation/ ; U01AI068632//International Maternal Pediatric Adolescent AIDS Clinical Trials Network/ ; }, mesh = {Humans ; *HIV Infections/immunology/prevention & control ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Infant ; Models, Statistical ; Computer Simulation ; Infant, Newborn ; Female ; }, abstract = {Adjustment for prognostic baseline variables can reduce bias due to covariate imbalance and increase efficiency in randomized trials. While the use of covariate adjustment in late-phase trials is justified by favorable large-sample properties, it is seldom used in small, early-phase studies, due to uncertainty in which variables are prognostic and the potential for precision loss, type I error rate inflation, and undercoverage of confidence intervals. To address this problem, we consider adjustment for a valid negative control outcome (NCO), or an auxiliary post-randomization outcome believed to be completely unaffected by treatment but more highly correlated with the primary outcome than baseline covariates. We articulate the assumptions that permit adjustment for NCOs without producing post-randomization selection bias, and describe plausible data-generating models where NCO adjustment can improve upon adjustment for baseline covariates alone. In numerical experiments, we illustrate performance and provide practical recommendations regarding model selection and finite-sample variance corrections. We apply our methods to the reanalysis of two early-phase vaccine trials in HIV exposed uninfected (HEU) infants, where we demonstrate that adjustment for auxiliary post-baseline immunological parameters can enhance the precision of vaccine effect estimates relative to standard approaches that avoid adjustment or adjust for baseline covariates alone.}, }
@article {pmid40491924, year = {2025}, author = {Shen, Q and Wang, S and Wu, K and Wang, L and Gong, W and Lu, G and Chen, W and Yuan, C and Tu, B and Li, W and Wang, Y and Yang, W}, title = {Identification of Grb2 protein as a potential mediator of macrophage activation in acute pancreatitis based on bioinformatics and experimental verification.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1575880}, pmid = {40491924}, issn = {1664-3224}, mesh = {*GRB2 Adaptor Protein/genetics/metabolism/immunology ; *Pancreatitis/immunology/metabolism/genetics/pathology ; Animals ; *Macrophage Activation/immunology/genetics ; Mice ; Computational Biology/methods ; *Macrophages/immunology/metabolism ; Male ; Humans ; Signal Transduction ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Acute Disease ; }, abstract = {INTRODUCTION: Macrophage activation is closely associated with Acute pancreatitis (AP). We screened and found that Growth factor receptor bound protein 2 (Grb2) is highly expressed in macrophages during AP. However, the relationship between Grb2 and AP is still poorly understood. In this study, we explored the role of Grb2 in AP.
METHODS: We screened for gene affecting macrophage activation in AP by combining transcriptomics with Single-cell RNA-sequence analysis. Next, the expression of Grb2 in M1/M2 macrophage activation was detected by Single-cell RNA-sequence analysis and western blot. Furthermore, the effect of Grb2 on M1/M2 macrophage activation was detected by flow cytometry. The severity of AP was assessed by histological analysis, serum amylase, serum lipase and serum inflammatory factors in vivo. NOD-like receptor thermal protein domain associated protein 3 (Nlrp3) and Nuclear factor kappa-B (NF-kB) signaling pathways were also evaluated.
RESULTS: Grb2 is mainly expressed in macrophages of pancreas in AP and up-regulated in M1 macrophage activation. Inhibiting Grb2 could alleviate AP by preventing M1 macrophage activation through down-regulating Nlrp3 and NF-κB.
DISCUSSION: Inhibition of Grb2 can effectively prevent M1 macrophage activation and alleviate AP. Grb2 may potentially be an effective target of macrophage activation for the treatment of AP.}, }
@article {pmid40491440, year = {2025}, author = {Li, X and Johnston, JM and Homan, C and Marsh, TL and Kim, NJ and Liu, Y and VoPham, T and Grady, WM and Mera, J and McMahon, BJ and Ioannou, GN and Feng, Z and He, Q}, title = {Modeling 5-Year Hepatocellular Carcinoma Risk in Alaska Native Peoples With Hepatitis B Virus Infection.}, journal = {Gastro hep advances}, volume = {4}, number = {7}, pages = {100661}, pmid = {40491440}, issn = {2772-5723}, support = {P20 CA252732/CA/NCI NIH HHS/United States ; R01 CA223498/CA/NCI NIH HHS/United States ; R01 GM105785/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Modeling hepatocellular carcinoma (HCC) risk in Alaska Native (AN) peoples with chronic hepatitis B virus (HBV) infection is important for risk stratification and surveillance. Existing HCC risk prediction models use baseline characteristics ascertained at the time of HBV diagnosis, rather than predicting HCC risk within 5 years of a relevant time point (such as a clinic visit), and do not include the HBV genotype (GT). We aimed to develop an HCC risk prediction model that addresses these limitations.
METHODS: We used longitudinal data from a cohort of 1163 AN peoples with HBV. We considered age, sex, GT, serum alpha fetoprotein (AFP), along with serum alanine transaminase, albumin, aspartate aminotransferase, bilirubin, hepatitis B-e-antigen, platelet count, and fibrosis 4 score. To build a 5-year risk model, we structured the longitudinal data into multiple 5-year segments, using AFP as the landmark biomarker. We used the generalized estimation equation approach as well as the Random Forest approach to build risk prediction models.
RESULTS: Among the 11 predictors included in our final models, AFP was the most important followed by platelet count and GT. Based on cross-validation, the generalized estimation equation model had an area under the receiver operating characteristic curve of 0.81, with 46.5% sensitivity at 90% specificity for 5-year HCC risk prediction. The Random Forest model was superior with an area under the receiver operating characteristic curve of 0.88 and 70% sensitivity at 90% specificity, outperforming the PAGE-B, mPAGE-B, REACH-B and REAL-B models.
CONCLUSION: We developed an HCC risk prediction model using rich information from different time points in a patient's disease trajectory. Our model can accurately estimate HCC risk at different time points during follow-up for risk stratification and risk-based surveillance.}, }
@article {pmid40490100, year = {2025}, author = {Kim, DY and Huhmann, L and Hippe, DS and Wheless, L and Pavlis, M and Hwang, JC and Brophy, MT and Do, NV and Nghiem, P and Fillmore, N and Hartman, RI}, title = {Treatment and disease-specific survival differences among veterans with Merkel cell carcinoma.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.06.007}, pmid = {40490100}, issn = {1097-6787}, }
@article {pmid40489013, year = {2025}, author = {Wang, X and Guillem-Marti, J and Kumar, S and Lee, DS and Cabrerizo-Aguado, D and Werther, R and Alamo, KAE and Zhao, YT and Nguyen, A and Kopyeva, I and Huang, B and Li, J and Hao, Y and Li, X and Brizuela-Velasco, A and Murray, A and Gerben, S and Roy, A and DeForest, CA and Springer, T and Ruohola-Baker, H and Cooper, JA and Campbell, MG and Manero, JM and Ginebra, MP and Baker, D}, title = {De Novo Design of Integrin α5β1 Modulating Proteins to Enhance Biomaterial Properties.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e2500872}, doi = {10.1002/adma.202500872}, pmid = {40489013}, issn = {1521-4095}, support = {R01-HL-131729/HL/NHLBI NIH HHS/United States ; 1F31HL174166/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; RYC2022-038006-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; 2021UPC-MZ-67143//Universitat Politècnica de Catalunya/ ; PID2021-125150OB-I00//European Regional Development Fund/ ; HR0011-21-2-0012//Defense Sciences Office, DARPA/ ; T32CA080416/NH/NIH HHS/United States ; R01-HL-131729/NH/NIH HHS/United States ; R35GM147414/NH/NIH HHS/United States ; R01GM109463/NH/NIH HHS/United States ; T90DE021984/NH/NIH HHS/United States ; R35GM138036/NH/NIH HHS/United States ; R01DE033016/NH/NIH HHS/United States ; R35GM138036/GM/NIGMS NIH HHS/United States ; HDTRA1-21-1-0007//Department of the Defense, Defense Threat Reduction Agency/ ; DTRAJ5B_ML-MACROCYCLES-62-5503-2021//Department of the Defense, Defense Threat Reduction Agency/ ; PG117866//The Audacious Project/ ; PG117878//The Audacious Project/ ; GF124659//The Nordstrom Barrier Institute for Protein Design Directors Fund/ ; GF151772//Wu Tsai Protein Innovation Fund/ ; 63-8301-2021//BMGF Prometheus/ ; HR0011-21-2-0012//DARPA program Harnessing Enzymatic Activity for Lifesaving Remedies (HEALR)/ ; 2024FI-100198//Fred Hutchinson Cancer Center/ ; RRID//Fred Hutchinson Cancer Center/ ; SCR_022611//Fred Hutchinson Cancer Center/ ; DGE1762114//National Science Foundation/ ; //ICREA Academia Award/ ; //Pew Biomedical Scholars/ ; OFD/BTREC/CTRECFacultyCareerDevelopmentFellowship//Boston Children's Hospital/ ; }, abstract = {Integrin α5β1 is crucial for cell attachment and migration in development and tissue regeneration, and α5β1 binding proteins can have considerable utility in regenerative medicine and next-generation therapeutics. We use computational protein design to create de novo α5β1-specific modulating miniprotein binders, called NeoNectins, that bind to and stabilize the open state of α5β1. When immobilized onto titanium surfaces and throughout 3D hydrogels, the NeoNectins outperform native fibronectin (FN) and RGD peptides in enhancing cell attachment and spreading, and NeoNectin-grafted titanium implants outperformed FN- and RGD-grafted implants in animal models in promoting tissue integration and bone growth. NeoNectins should be broadly applicable for tissue engineering and biomedicine.}, }
@article {pmid40488832, year = {2025}, author = {Bhatt, NS and Richards, A and Beebe, KL and Khera, N}, title = {Challenges and Opportunities in the Care of Hematopoietic Cell Transplant Survivors in the Modern Era.}, journal = {Advances in experimental medicine and biology}, volume = {1475}, number = {}, pages = {209-226}, pmid = {40488832}, issn = {0065-2598}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Survivors ; *Graft vs Host Disease/etiology/prevention & control/therapy ; }, abstract = {With the constantly changing field of hematopoietic cell transplant (HCT) and cellular therapy and a growing number of survivors, there is an ongoing need for work to understand the changing landscape of late effects and develop interventions to optimize the long-term outcomes of survivors. In this chapter, we summarize the studies published in last 5 years describing late effects after HCT. We specifically discuss the available literature or the lack thereof for the late effects as it relates to the changes in transplant practices such as increased use of post-transplant cyclophosphamide, newer drugs to treat chronic graft vs. host disease, and chimeric antigen receptor T-cell therapy as a bridge to HCT or for a post-HCT relapse. We also summarize the recently updated recommendations for screening and management of late effects and a monitoring plan to cater to late effects specific to patients undergoing transplants for non-malignant diseases. We discuss the specific considerations such as challenges for adolescent and young adult HCT survivors, especially as they transition from pediatric to adult care. With the information discussed here, we outline challenges and opportunities for research and clinical practice highlighting the role of health care delivery models in addressing some of these issues.}, }
@article {pmid40488826, year = {2025}, author = {Lee, CJ and Carpenter, PA}, title = {Modern-Era Challenges in the Clinical Management of Graft-Versus-Host Disease.}, journal = {Advances in experimental medicine and biology}, volume = {1475}, number = {}, pages = {103-128}, pmid = {40488826}, issn = {0065-2598}, mesh = {*Graft vs Host Disease/therapy/diagnosis/immunology/etiology ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Animals ; Disease Management ; }, abstract = {For several decades, graft-versus-host disease (GVHD) has been a long-standing barrier to successful allogenic hematopoietic cell transplantation and a significant cause of post-transplant morbidity and mortality. Initially described as secondary disease or wasting syndrome in transplanted mice, the pathobiology of GVHD is increasingly understood as a dynamic interplay between innate and adaptive immunity in response to initial tissue damage, leading to inflammation and end-organ damage. In parallel, more uniform symptom capture, diagnosis, and response criteria have facilitated rigorous clinical trial design and conduct; together, these advancements have facilitated the development of novel GVHD prevention and treatment strategies. While these advancements have improved the GVHD treatment paradigm, new questions arise within this complex patient population. This chapter discusses several of the most pertinent current clinical practice challenges in GVHD, including its earlier diagnosis, risk stratification, initial and more advanced stage management, as well as a renewed focus on supportive care, given our increased understanding of key roles played by the human microbiome.}, }
@article {pmid40488365, year = {2025}, author = {Bloom, JD}, title = {The Data are Insufficient to Confidently Root the SARS-CoV-2 Phylogenetic Tree.}, journal = {Molecular biology and evolution}, volume = {42}, number = {6}, pages = {}, pmid = {40488365}, issn = {1537-1719}, support = {S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {*Phylogeny ; *SARS-CoV-2/genetics/classification ; COVID-19/virology ; Humans ; Genome, Viral ; }, abstract = {Several years ago, I published a paper that described the discrepancy between outgroup and date-based methods for rooting the SARS-CoV-2 phylogenetic tree, and proposed the discrepancy could arise from biases among the available early viral sequences. Here, I explain why the root remains uncertain, including via an interactive narrative at https://nextstrain.org/groups/jbloomlab/narratives/SARS2-rooting/early-SARS2-trees-v1 that enables the reader to examine the underlying data and understand discrepancies that lead different methods to reach different inferences about the root. I also demonstrate clear evidence of bias among the earliest available sequences, and explain why the root of the SARS-CoV-2 tree cannot be conclusively resolved with the current data.}, }
@article {pmid40487589, year = {2025}, author = {Ronsley, R and Bradford, MC and Crotty, EE and Vitanza, NA and Runco, DV and Stevens, J and Hoeppner, C and Holtzclaw, SL and Wein, AR and Lee, A and Cole, BL and Ermoian, R and Leary, SES}, title = {Children with medulloblastoma treated with modified ACNS0821 temozolomide, irinotecan, and bevacizumab: The Seattle Children's Hospital experience.}, journal = {Neuro-oncology practice}, volume = {12}, number = {3}, pages = {489-497}, pmid = {40487589}, issn = {2054-2577}, abstract = {BACKGROUND: Effective therapy for medulloblastoma at the time of relapse is limited. The objective of this study is to review outcomes from the Seattle Children's Hospital (SCH) institutional standard therapy for relapsed medulloblastoma, modified from the published ACNS0821 regimen.
METHODS: Retrospective review of patients treated for relapsed medulloblastoma from 2012-2024 treated with modified ACNS0821 therapy, including combination bevacizumab, irinotecan, and temozolomide, referred to as "TIB." Each TIB cycle includes oral temozolomide (200 mg/m[2]/day) for the first 5 days, intravenous (IV) bevacizumab (10 mg/kg/dose), and IV irinotecan (125 mg/m[2]/dose or 340 mg/m[2]) on days 1 and 15 of each cycle. Patient medical history, prior treatment, therapy toxicity, response, and outcome were collected. The analysis included Kaplan-Meier estimates of 3-year overall survival (OS) and 3-year progression-free survival.
RESULTS: Fifteen patients were treated with TIB for relapsed medulloblastoma at SCH (median age 5.81 (0.21-23.6) years, 60% male). Twelve patients completed planned therapy. Therapy was discontinued for toxicity (n = 1) and family preference (n = 1). The most common toxicities were thrombocytopenia (n = 7), neutropenia (n = 4), nausea (n = 5), vomiting (n = 5), and diarrhea (n = 3). Five patients required dose modification of one agent for toxicity. Median follow-up from TIB therapy start was 1.61 (0.47-7.66) years. Three-year OS was 48% (95% CI: 18%-74%) and 3-year event-free survival was 16% (95% CI: 1%-49%).
CONCLUSIONS: TIB was well-tolerated in pediatric patients with relapsed medulloblastoma, and outcomes were similar to those published in clinical trials. TIB therapy should be considered for patients with relapsed medulloblastoma, especially patients with limited access to care due to travel barriers.}, }
@article {pmid40487272, year = {2025}, author = {Phipps, AI and Hill, CM and Lin, G and Malen, RC and Reedy, AM and Kahsai, O and Ammar, H and Curtis, K and Ma, N and Randolph, TW and Ma, J and Ogino, S and Newcomb, PA and Hullar, MA}, title = {Fusobacterium nucleatum Enrichment in Colorectal Tumor Tissue: Associations With Tumor Characteristics and Survival Outcomes.}, journal = {Gastro hep advances}, volume = {4}, number = {6}, pages = {100644}, pmid = {40487272}, issn = {2772-5723}, abstract = {BACKGROUND AND AIMS: Fusobacterium nucleatum (Fn) is linked to colorectal cancer (CRC) etiology and survival. We hypothesized that CRC tumor attributes and survival are associated with the amount and presence of Fn in tumors.
METHODS: Fn abundance was measured via droplet digital polymerase chain reaction in patient-matched CRC tumor and normal tissue samples from 859 Puget Sound CRC Cohort participants. Fn enrichment was defined as the continuous difference in normalized abundance between patient-matched tumor and normal tissue samples. Fn presence in tumor was classified categorically as not present, low, or high, regardless of Fn status in matched normal tissue. Associations of Fn enrichment and presence with tumor site, stage, DNA mismatch repair (MMR) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutation status, and molecular subtypes based on combinations of tumor markers were assessed using logistic regression. Associations of Fn enrichment and presence with CRC survival was estimate with Cox regression.
RESULTS: Fn was present in 20% of tumor tissues and 10% of normal tissues, with higher average abundance in tumors. High Fn presence was independently associated with deficient MMR (dMMR) status and in the context of molecular subtypes for type 1 tumors (dMMR, CIMP-high, BRAF-mutated) and type 5 tumors (dMMR, CIMP-low or negative, BRAF-wildtype). Fn enrichment was associated with type 5 and type 2 tumors (proficient MMR, CIMP-high, BRAF-mutated). Fn enrichment and presence were associated with poorer CRC survival, with some suggestion that associations differed by MMR status.
CONCLUSION: Detectable Fn in CRC tissue is associated with certain CRC tumor attributes and survival; however, associations may vary based on Fn definition.}, }
@article {pmid40485091, year = {2025}, author = {Huang, Y and Zhang, L and Lemos, MP and Astronomo, RD and Narpala, S and Prabhakaran, M and Garcia, NMG and Lu, Y and Mize, GJ and Glantz, H and Colegrove, H and Mann, P and Paez, CA and Andersen-Nissen, E and Hutter, J and Dumond, J and McDermott, AB and Mascola, JR and Koup, RA and Bekker, LG and McElrath, MJ}, title = {Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of a Pair of Anti-HIV Monoclonal Antibodies, VRC01 and VRC01LS, in Adults without HIV.}, journal = {Journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcph.70060}, pmid = {40485091}, issn = {1552-4604}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {VRC01 and VRC01LS are a pair of parental and LS-modified anti-HIV IgG1-backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose. Using nonlinear mixed-effects models, we conducted the first population pharmacokinetics analysis of VRC01/LS concentrations in serum and rectal tissue, a primary site of HIV transmission. Serum concentration was described as a one-compartment model in equilibrium with one tissue compartment, with first-order elimination in both compartments. The model was parameterized with micro-constants to estimate volumes of distribution for serum and tissue, serum-tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half-life estimates were derived from the governing differential equations. To account for rectal biopsy heterogenicity between individuals, three normalization approaches were used: tissue weight adjusted, IgG concentration adjusted, and protein concentration adjusted. All three approaches rendered consistent estimates. Based on protein-concentration-normalized data, VRC01LS (vs VRC01) exhibited ∼10-fold higher concentrations over time in blood and rectal tissues, and faster blood-to-tissue distribution (K12 = 0.61 vs 0.13/day). Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum.}, }
@article {pmid40483257, year = {2025}, author = {Stephens, DM and Stewart, C and Avruch, L and Coombs, CC and Danilov, A and Hill, B and Shadman, M and Gerrie, A and Jensen, CE and Hoffmann, M and Winter, A and Ermann, DA and Barr, PM and O'Brien, S and Koffman, B and Byrd, JC}, title = {Feasibility of Bruton's Tyrosine Kinase Inhibitor Discontinuation in Chronic Lymphocytic Leukemia: The Patient Perspective.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.05.011}, pmid = {40483257}, issn = {2152-2669}, abstract = {BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) have prolonged survival in chronic lymphocytic leukemia (CLL), however continuous administration increases toxicity. Little is known about clinical outcomes of patients who discontinue BTKi for reasons other than CLL progression. We aimed to report these outcomes.
PATIENTS/METHODS: With the CLL Society, we solicited volunteers with CLL who self-reported BTKi discontinuation for reasons other than CLL progression to participate in a web-based survey.
RESULTS: In 170 patients, BTKi was discontinued for toxicity, because CLL was in remission, or personal choice in 62%, 14% and 8%, respectively. When asked how they felt about stopping the BTKi, most were relieved that they may eliminate toxicity (45%), could focus less on CLL (11%), and would not have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived quality of life (QOL) was observed from prior- versus post-BTKi discontinuation. Of patients who reported that they experienced clinical CLL progression (n = 80), 46% reported that these events did not happen for ≥ 1 year after BTKi discontinuation. Those that were on a BTKi for ≥ 2 years before discontinuation had more time without CLL relapse.
CONCLUSIONS: These data provide a unique report of patient experiences. The data suggest that BTKi may be feasible and result in a period of treatment-free remission. The data also indicate that patients are generally relieved when they anticipate BTKi discontinuation and observe significant QOL improvements after BTKi discontinuation. As such, these data should prompt prospective study of time-limited BTKi therapy for CLL.}, }
@article {pmid40481728, year = {2025}, author = {Fladeboe, KM and O'Daffer, A and Engelberg, RA and Salsman, JM and Merluzzi, T and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Developing a skill-based intervention to address social health needs of adolescents and young adults with cancer: an ORBIT Phase 1 Study.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {59}, number = {1}, pages = {}, pmid = {40481728}, issn = {1532-4796}, support = {K99CA267481/CA/NCI NIH HHS/United States ; R00CA267481/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *Neoplasms/psychology ; Young Adult ; Female ; Male ; *Behavior Therapy/methods ; *Adaptation, Psychological ; Child ; Pilot Projects ; *Social Support ; Adult ; *Stress, Psychological/therapy ; }, abstract = {BACKGROUND: Few interventions have improved social health of adolescents and young adults (AYAs) with cancer. Following the obesity-related behavioral intervention trials model, we developed a skill-based social needs module for integration within the Promoting Resilience in Stress Management (PRISM) behavioral intervention.
METHODS: The social needs module targeting social relationship coping efficacy included behavioral skills adapted to AYAs. The module was refined through 2 separate pilot studies. For Study 1, AYAs 12-24 years old completed the module and a feedback interview. Rapid assessment process methods assessed acceptability, appropriateness, understandability, and informed content revisions. For Study 2, AYAs completed PRISM plus the social needs module (PRISM + Social Needs) and a feedback interview. Rapid assessment process methods assessed acceptability of program and session length, timing, and format.
RESULTS: For Study 1, 6 AYAs completed the initial module focused on identifying and seeking support (mean age = 16 years); most found content acceptable and appropriate (4/6) but suggested adding skills for maintaining social connections and managing cancer-related conversations. Seven AYAs completed the revised module and interview (M = 16 years old); most found content acceptable (6/7) and appropriate (7/7) and suggestions were minimal. For Study 2, 7 AYAs completed the revised full program (M = 16 years old). Most were satisfied with program length (4/7) and duration (7/7); preferred in-person over virtual delivery (6/7); and wanted PRISM + Social Needs early in treatment (5/7).
CONCLUSIONS: A skill-based social needs module may be acceptable, appropriate, and promising for AYAs. The PRISM + Social Needs intervention may be best delivered in-person and early in treatment, suggesting AYAs value face-to-face connection. Findings inform subsequent proof-of-concept studies.}, }
@article {pmid40481491, year = {2025}, author = {Wood, KA and Jin, Y and Krafty, RT and James, JH and Iyer, SK and Badhwar, N}, title = {Concurrent validity testing of the patient perspective of arrhythmia questionnaire.}, journal = {Health and quality of life outcomes}, volume = {23}, number = {1}, pages = {59}, pmid = {40481491}, issn = {1477-7525}, mesh = {Humans ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Arrhythmias, Cardiac/psychology ; *Quality of Life/psychology ; Reproducibility of Results ; Surveys and Questionnaires/standards ; *Patient Reported Outcome Measures ; Aged ; Psychometrics ; Adult ; }, abstract = {BACKGROUND: Disease-specific patient reported outcome measures (PROMs) are widely used to evaluate not only a patient's view of their symptoms, functional status, and health related quality of life, but also clinical benefit of treatments. The Patient Perspective of Arrhythmia Questionnaire (PPAQ) was initially developed as a self-administered, disease-specific PROM for patients with supraventricular tachycardia (SVT) assessing the impact of the arrhythmia and symptoms on patients' daily activities and physical, emotional, and social functioning. Preliminary evidence of content and construct validity has been previously demonstrated, but only in SVT patients in the U.S. and Poland. The aim of this study was to further evaluate the concurrent validity of the PPAQ in patients having a variety of arrhythmias and to explore whether differences in symptoms existed by gender.
METHODOLOGY: In this cross-sectional study, adult cardiac arrhythmia outpatients from a tertiary care, academic medical center completed the 6-item PPAQ, the SF-12, a Fatigue Visual Analog Scale (VAS), the Brief Symptom Inventory (BSI), and the Patient Health Questionnaire (PHQ-9). Included were patients with atrial fibrillation (82.4%), ventricular tachycardia (15.7%), and atrial tachycardia (2%). Descriptive statistics and independent t-tests, pairwise comparisons with Pearson correlations, Goodman Kruskal gamma statistic for ordinal associations, Cronbach's alpha, and Kuder-Richardson-20 (KR-20) were used to determine concurrent construct validity and internal consistency reliability.
RESULTS: Participants (n=51) had a mean age of 59.4 years (± 12.6), were majority male (66.7%) and Caucasian (75%). Preliminary evidence of concurrent construct validity was found based on moderate to strong correlations (range from 0.4 to 0.7) between the PPAQ and other validated measures, as well as strong internal reliability (KR-20 of 0.80 and Cronbach's alpha of 0.91). The most common symptoms reported were fatigue (60.8%) and heart fluttering (52.9%). Blurred vision (p<0.04), dizziness (p<0.01), and fatigue (p<0.04) were seen significantly more frequently in men compared to women.
CONCLUSIONS: Results present additional evidence of the validity and reliability of the PPAQ. The PPAQ comprehensively measures the burden of the disease from cardiac arrhythmia patients' perspective. Validated, reliable, disease-specific PROMs are needed to direct personalized clinical decision-making.}, }
@article {pmid40480929, year = {2025}, author = {Rajan, A and Keene, AC}, title = {The ABCs of lipid exposure in maintaining neural health.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2025.05.011}, pmid = {40480929}, issn = {1878-108X}, abstract = {ABC transporters modulate lipid homeostasis and are implicated in neurodegenerative diseases. In a recent study, Chen et al. uncovered unexpected dual roles for the Drosophila ABCA protein eater of debris (Eato), which suppresses phospholipid exposure in both neurons and phagocytes, conferring opposite functional outcomes in each cell type. This challenges classical models of ATP-binding cassette (ABC) transporter function and reveals new mechanisms by which lipid signaling regulates neuron-glia interactions in neurodegenerative contexts.}, }
@article {pmid40480832, year = {2025}, author = {Wang, L and Taylor, T and Rathnakumar, K and Khyzha, N and Liang, M and Alizada, A and Campitelli, LF and Pour, SE and Patel, ZM and Antounians, L and Tobias, IC and Hou, H and Hughes, TR and Roy, S and Mitchell, JA and Fish, JE and Wilson, MD}, title = {Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding.}, journal = {Genome research}, volume = {35}, number = {7}, pages = {1544-1559}, pmid = {40480832}, issn = {1549-5469}, support = {R01 HG010045/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *DNA Transposable Elements/genetics ; Mice ; Cattle ; *Transcription Factor RelA/metabolism/genetics ; Evolution, Molecular ; *NF-kappa B/metabolism/genetics ; Species Specificity ; *Inflammation/genetics ; Binding Sites ; *Response Elements ; Protein Binding ; Tumor Necrosis Factor-alpha/pharmacology ; Endothelial Cells/metabolism ; }, abstract = {Transposable elements (TEs) provide a source of transcription factor (TF) binding sites that can rewire gene regulatory networks. NF-kB is an evolutionarily conserved TF complex primarily involved in innate immunity and inflammation. The extent to which TEs have contributed to NF-kB responses during mammalian evolution is not well established. Here, we perform a multi-species analysis of TEs bound by the NF-kB subunit RELA in response to the proinflammatory cytokine TNF. By comparing RELA ChIP-seq data from TNF-stimulated primary aortic endothelial cells isolated from human, mouse, and cow, we find that 55 TE subfamilies are associated with RELA-bound regions, many of which reside near TNF-responsive genes. A prominent example of lineage-specific contribution of transposons comes from the bovine SINE subfamilies Bov-tA1/2/3 which collectively contributed over 14,000 RELA-bound regions in cow. By comparing RELA binding data across species, we also find several examples of RELA motif-bearing TEs that colonized the genome prior to the divergence of the three species and contributed to species-specific RELA binding. For example, we find human RELA-bound MER81 instances are enriched for the interferon gamma pathway and demonstrate that one RELA-bound MER81 element can control the TNF-induced expression of interferon gamma receptor 2 (IFNGR2). Using ancestral reconstructions, we find that RELA containing MER81 instances rapidly decayed during early primate evolution (>50 million years ago [MYA]) before stabilizing since the separation of Old World monkeys (<50 MYA). Taken together, our results suggest ancient and lineage-specific transposon subfamilies contributed to mammalian NF-kB regulatory networks.}, }
@article {pmid40480658, year = {2025}, author = {Cabanski, CR and Yang, E and Stewart, MD and Allen, JD and Connolly, JE and Dugan, U and Greenberg, PD and Mackall, CL and June, CH and Marson, A and Maus, MV and Ribas, A}, title = {Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {6}, pages = {}, pmid = {40480658}, issn = {2051-1426}, mesh = {Humans ; *Genetic Therapy/methods ; Clinical Trials as Topic ; *Neoplasms/therapy/immunology/genetics ; *Cell- and Tissue-Based Therapy/methods ; Gene Editing ; *Immunotherapy, Adoptive/methods ; }, abstract = {Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the "Unlocking Complex Cell-based Gene Therapies" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.}, }
@article {pmid40480553, year = {2025}, author = {Petrykey, K and Chen, Y and Neupane, A and French, JN and Wang, H and Xiang, H and Dixon, SB and Vukadinovich, C and Im, C and Ehrhardt, MJ and Mulrooney, DA and Sharafeldin, N and Wang, X and Howell, RM and Jefferies, JL and Burridge, PW and Oeffinger, KC and Gramatges, MM and Bhatia, S and Robison, LL and Ness, KK and Hudson, MM and Chow, EJ and Armstrong, GT and Yasui, Y and Sapkota, Y}, title = {Predicting the 10-year risk of cardiomyopathy in long-term survivors of childhood cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.05.539}, pmid = {40480553}, issn = {1569-8041}, abstract = {BACKGROUND: Considering the heightened risk of cancer treatment-related cardiomyopathy and cardiac death in long-term survivors of childhood cancer, we aimed to develop and validate a clinically applicable risk prediction model for cardiomyopathy.
PATIENTS AND METHODS: Childhood cancer survivors from the St. Jude Lifetime Cohort, [SJLIFE, model-development; n = 3479; median age 32.3 years, interquartile range (IQR) 24.4-40.9 years] and the Childhood Cancer Survivor Study (CCSS, model-validation; n = 6875; median age 33.2 years, IQR 27.9-38.9 years) were assessed for demographic and cardiovascular risk factors, treatment exposures, and polygenic risk scores (PRSs) for cardiomyopathy, heart failure, cardiac structure and function, and anthracycline-related cardiomyopathy risk. Multivariable Poisson regression predicted the 10-year risk of cardiomyopathy (Common Terminology Criteria for Adverse Events grade ≥3: requiring heart failure medications or heart transplantation or leading to death) following baseline visit/survey. Model performance was assessed by area under the receiver operating characteristic curve (AUC).
RESULTS: Cardiomyopathy was clinically identified in 75 (2.2%, SJLIFE) and self-reported in 87 (1.3%, CCSS) survivors within 10 years of the baseline assessment. AUC of the clinical model with sex, age at cancer diagnosis, cumulative anthracycline, and mean heart radiation doses was 0.833 (SJLIFE) and 0.812 (CCSS). Age at baseline, hypertension, and genetic ancestry showed associations with higher cardiomyopathy rates in SJLIFE but did not increase AUC in CCSS (0.812). Adding PRSs for hypertrophic cardiomyopathy and left ventricular end-systolic volume improved AUC in CCSS (0.822; P = 0.016). Compared with existing survivorship-care guidelines, the PRS model classified fewer survivors as high-risk or moderate-risk, while identifying survivors in those categories as having 1.5-times greater risk.
CONCLUSIONS: We developed and validated models with highest-to-date performance for estimating the 10-year risk of cardiomyopathy in survivors of childhood cancer. Results could enhance identification of at-risk survivors beyond current guidelines.}, }
@article {pmid40480199, year = {2025}, author = {Park, MS and Kumar, RD and Ovadiuc, C and Folta, A and McEwen, AE and Snyder, A and Villani, RM and Spurdle, AB and Fowler, DM and Rubin, AF and Shirts, BH and Starita, LM and Stergachis, AB}, title = {Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.}, journal = {American journal of human genetics}, volume = {112}, number = {6}, pages = {1468-1478}, doi = {10.1016/j.ajhg.2025.04.009}, pmid = {40480199}, issn = {1537-6605}, mesh = {Humans ; *Genetic Variation/genetics ; Surveys and Questionnaires ; Male ; Female ; Genetic Testing ; Adult ; }, abstract = {Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.}, }
@article {pmid40480020, year = {2025}, author = {Lundin, JI and Peters, U and Hu, Y and Ammous, F and Benjamin, EJ and Bis, JC and Brody, JA and Cushman, M and Fuller, H and Gignoux, C and Guo, X and Haessler, J and Haiman, C and Joehanes, R and Kasela, S and Kenny, E and Lappalainen, T and Levy, D and Liu, C and Liu, Y and Loos, RJF and Matise, T and North, KE and Park, SL and Ratliff, SM and Reiner, A and Rich, SS and Rotter, JI and Smith, JA and Sotoodehnia, N and Tracy, R and Van den Berg, D and Ye, T and Zhao, W and Raffield, LM and Kooperberg, C and , }, title = {Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.}, journal = {Atherosclerosis}, volume = {407}, number = {}, pages = {120219}, doi = {10.1016/j.atherosclerosis.2025.120219}, pmid = {40480020}, issn = {1879-1484}, abstract = {BACKGROUND AND AIMS: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects.
METHODS: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across ∼4,400 ancestrally diverse individuals (81 % self-reported White; 9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American).
RESULTS: We identified 178 CpG sites associated with IL-6 (p<0.05/∼395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis.
CONCLUSIONS: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.}, }
@article {pmid40475854, year = {2025}, author = {Shriver, MC and Milletich, PL and Moreno, A and Larsen, SE and Posavad, CM and Berube, BJ and Wali, B and Ellis, M and Manning, K and Moore, KM and Zhu, Z and Grewal, N and Cadena, IA and Cardemil, CV and Munoz, FM and Neuzil, KM and Coler, RN and Suthar, MS and Pasetti, MF and , }, title = {Development and Concordance of Binding and Neutralizing Assays to Determine SARS-CoV-2 Antibody Activity in Human Milk.}, journal = {Pathogens & immunity}, volume = {10}, number = {2}, pages = {97-121}, pmid = {40475854}, issn = {2469-2964}, support = {U19 AI145825/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Maternal immunization provides vaccine-specific immunity to the infant via breast milk. Multiple studies have reported the presence of SARS-CoV-2 antibodies in human breast milk (HBM) from infected and/or vaccinated women. However, there is limited information on the analytical performance, consistency, and quality of the methods used. Standardized and rigorous assays are needed to meet clinical study endpoints and for comparisons across studies.
METHODS: We optimized high-throughput multiplex immunoassays for quantification of SARS-CoV-2 immunoglobulin (Ig)G and IgA in HBM and determined antibody levels in HBM samples from 236 SARS-CoV-2 vaccinated (infected and non-infected) and 50 pre-pandemic (unexposed) lactating women. Additionally, SARS-CoV-2 neutralizing activity was examined in a subset of 75 SARS-CoV-2 HBM from vaccinated (infected and non-infected) women using live virus focus reduction neutralization and pseudovirus assays. Concordance between SARS-CoV-2 binding and live virus neutralization outcomes was examined.
RESULTS: The multiplex SARS-CoV-2 assays had adequate analytical sensitivity, repeatability, precision, and assay linearity and were reliable for quantification of IgG and IgA in HBM. Positivity thresholds for Spike- and Nucleocapsid-specific IgG and IgA were established; IgG discriminated positive/negative SARS-CoV-2-immune HBM with high sensitivity and specificity, while IgA reactivity overlapped. A strong correlation was observed between live SARS-CoV-2 and pseudovirus neutralization activity. HBM Spike IgA and neutralization titers were highly correlated.
CONCLUSIONS: SARS-CoV-2 binding and neutralizing antibody activity in HBM was determined using standardized and rigorous assays. HBM positivity cutoff values for SARS-CoV-2 vaccination and infection were established. The methods and approach described here could be applied to other pathogens and mucosal secretions.}, }
@article {pmid40475658, year = {2025}, author = {Yu, TC and Kikawa, C and Dadonaite, B and Loes, AN and Englund, JA and Bloom, JD}, title = {Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475658}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {The evolution of human influenza virus hemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here, we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability, and neutralization by human serum antibodies. We find that epistasis has enabled emergence of antigenic mutations that were detrimental to HA's cell entry function in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair HA's stability, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.}, }
@article {pmid40475599, year = {2025}, author = {Mage, PL and Konecny, AJ and Mair, F}, title = {Measurement and prediction of unmixing-dependent spreading in spectral flow cytometry panels.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475599}, issn = {2692-8205}, support = {R01 AI123323/AI/NIAID NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; }, abstract = {Advances in spectral cytometry instrumentation and fluorescent reagents have led to the possibility of ultra-high-parameter panels exceeding 50 colors. However, panel size is limited in practice by unmixing-dependent spreading (UDS), a mathematical phenomenon which leads to a progressive deterioration of unmixed signal-to-noise ratios in panels that contain fluorochrome combinations with significant spectral overlap. Choosing spectrally compatible sets of fluorochromes that avoid UDS is a complex and labor-intensive task involving substantial trial-and-error experimentation. Here, we provide a detailed explanation of UDS and practical strategies for handling UDS in large spectral panels. We describe the empirical hallmarks of UDS, demonstrate how to quantify its impact, and dissect its underlying mathematical cause in terms of spectral collinearity. We present novel computational metrics that can be used to select optimal combinations of fluorochromes in a platform-agnostic fashion based on publicly available reference data, providing a general tool for spectral panel design.}, }
@article {pmid40475489, year = {2025}, author = {Hart, SFM and Alcala, N and Feder, AF and Harris, K}, title = {A signature-agnostic test for differences between tumor mutation spectra reveals carcinogen and ancestry effects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475489}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; }, abstract = {Mutational signatures contain valuable information about the mutational processes shaping cancer genomes. However, despite dozens of tools to identify signatures in cancer samples, there is not an established metric for statistically comparing mutational signature results and quantifying the overall significance of differences among complex mixtures of signatures. To close this methodological gap, we demonstrate that a signature-agnostic metric for measuring differences in mutation spectra - the aggregate mutation spectrum distance permutation method (AMSD) - can discover differences overlooked by signature analysis. First, we reanalyzed a study of carcinogen exposure in mice, identifying statistically significant shifts in mutation spectra caused by eleven of twenty tested carcinogens. Only three carcinogens were previously reported to induce distinct mutation signatures, suggesting that many carcinogens perturb mutagenesis by altering the composition of endogenous signatures rather than introducing unique signatures. Next, we used human tumor data to determine whether patient ancestry has a measurable impact on tumor mutation spectra, finding significant ancestry-associated differences across ten cancer types: for example, Africans have elevated SBS4 in lung adenocarcinomas, East Asians have elevated SBS16 in esophageal and liver cancers plus elevated SBS10a/b in uterine and colorectal cancers, and Europeans have elevated SBS17b in esophageal cancers plus elevated SBS2/13 in bladder cancers. These examples suggest that AMSD is a robust tool for detecting differences among tumor mutation spectra, complementing signature-based approaches and enabling the discovery of environmental and genetic influences on mutagenesis in large datasets.}, }
@article {pmid40475394, year = {2025}, author = {Ebadi, M and Gem, H and Sebastian, G and Abasaeed, R and Lloid, M and Tseng, YD and Mian, OY and Minot, S and Dean, DR and Rashidi, A}, title = {Different Patterns of Oral Mucositis and Microbiota Injury After Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Allogeneic Hematopoietic Cell Transplantation.}, journal = {Advances in radiation oncology}, volume = {10}, number = {6}, pages = {101787}, pmid = {40475394}, issn = {2452-1094}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Oral mucositis (OM) is a common complication of allogeneic hematopoietic cell transplantation, causing pain, infections, swallowing/speech impairment, and poor quality of life. We hypothesized that patterns (severity and dynamics) of OM and oral microbiota disruptions may be different after high-dose total body irradiation (TBI)- versus chemotherapy-based myeloablative conditioning.
METHODS AND MATERIALS: We conducted an exploratory study including comprehensive, longitudinal mucositis assessment, paired with supragingival plaque and saliva collection. OM was assessed at baseline and days +7, +14, +21, +28, and +84. Total mucositis score at each timepoint was calculated from objective findings in 2 domains and 9 oral sites using a validated scoring system. Plaque and saliva samples (baseline and days +14, +28, and +84) were profiled using shotgun metagenomic sequencing.
RESULTS: A total of 249 OM assessments were performed and 342 samples were collected from 47 patients (27 chemotherapy-based, 20 TBI-based). Salivary flow rate remained stable in the chemotherapy-based cohort, but steadily declined in the TBI-based cohort, reaching a significantly lower level in the TBI-based cohort at day +84 both compared to baseline and the chemotherapy-based cohort. OM severity peaked at day +7 in the TBI-based cohort versus day +14 in the chemotherapy-based cohort. Day +14 OM was significantly more severe in the chemotherapy-based cohort; other timepoints were not different. Although the cohorts were similar in plaque microbiota composition at baseline, they became significantly different at all post- hematopoietic cell transplantation timepoints. Salivary microbiota composition was not significantly different between the 2 cohorts. Day +84 plaque microbiota diversity was significantly higher in the TBI-based cohort.
CONCLUSIONS: We demonstrated different patterns of OM, microbiota injury, and salivary flow rate after TBI- versus chemotherapy-based conditioning. If validated in future studies, our findings could enhance evidence-based pretransplant counseling on oral toxicity and have implications for short- and long-term oral health in transplant survivors.}, }
@article {pmid40475393, year = {2025}, author = {Quaye, ANM and Addison, ECDK and Osei, E and Yorke, AA}, title = {A Feasibility Study for Clinical Implementation of hypo fractionated SBRT Program at a Clinic in an LMIC Using Locally Designed Lung Phantom.}, journal = {Advances in radiation oncology}, volume = {10}, number = {6}, pages = {101752}, pmid = {40475393}, issn = {2452-1094}, abstract = {PURPOSE: This study aims to assess the feasibility of implementing a hypofractionated radiation therapy (HFRT) program at the Oncology Directorate of Komfo Anokye Teaching Hospital in Ghana, addressing specific infrastructure limitations that hinder patient care and treatment efficiency. Hence, we conducted a feasibility study to start a HFRT lung stereotactic body radiation therapy (SBRT) program using currently available resources. The goal is to alleviate the burden on patients and health care providers, particularly in the context of limited resources.
METHODS AND MATERIALS: A lung phantom was designed from locally sourced materials consisting of wood slabs to mimic the lung, a perspex tank filled with water for tissue equivalence, and a 3-cm diameter acrylic ball to simulate the tumor. A motion platform was also designed for the phantom to simulate patients breathing in the superior-inferior direction. We acquired 3 computed tomography (CT) scan data sets using a slow CT scan technique for target motions of 0 cm (no_target_motion), 0.5 cm (0.5-cm_target_motion), and 1 cm (1-cm_target_motion) displacements. Treatment plans were generated for each phantom CT image data set using 9-field 6-Mega-Voltage (MV) photon beams in the eclipse treatment planning system. We also generated a treatment plan using an actual patient CT data set to assess the doses to target in the lung and critical organs at risk during a typical lung SBRT treatment. The quality of each treatment plan was evaluated using the near maximum (D2%), near minimum (D98%), mean (Dmean), V100, V95, V90, heterogeneity index (HI), conformity index (CI), the ratio of 50% prescription isodose volume to the PTV volume, (R50%), maximum dose (in % of dose prescribed) at 2 cm from PTV in any direction (D2cm, Gy) and dose-volume-histograms for the planning target volume (PTV). The near maximum (D2%), mean, V5, V10, V15, and V20 values were used as the dose metrics to evaluate the dose to the lung. Maximum dose was used to evaluate the dose to the spinal cord, and the maximum and mean doses were used to evaluate doses to the esophagus, heart, trachea, and ribs.
RESULTS: We quantitatively assessed the quality of the phantom treatment plans by calculating the CI, HI, R50%, and D2cm for each plan. The CI values for the PTV for the no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 1.07, 1.08, and 1.06, respectively. The HIs for the PTV for no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 1.20, 1.10, and 1.20 respectively. The R50% for the no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 3.98, 3.86, and 3.82, respectively, and the corresponding D2cm values are 27.30, 31.64, and 30.47, respectively. The CI, HI, R50%, and D2cm values for the PTV using the actual patient CT data set are 1.08, 1.22, 7.1, and 58.7 respectively. Therefore, our data demonstrate good dose conformity and heterogeneity within the PTV, with a sharp dose fall-off for all cases. The point dose measurements made in the phantom also show good agreement with treatment planning data.
CONCLUSIONS: Our results demonstrate that implementing HFRT using 3-dimensional conformal radiation therapy for lung SBRT is feasible with the current infrastructure of our institution. Although the proposed treatment plan is effective, future research on motion management and image guidance technologies is necessary to optimize treatment fidelity. These findings suggest that HFRT could be a viable option for addressing resource constraints in radiation therapy delivery in similar settings.}, }
@article {pmid40473829, year = {2025}, author = {Cheung, KJ and Horne-Badovinac, S}, title = {Collective migration modes in development, tissue repair and cancer.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, pmid = {40473829}, issn = {1471-0080}, abstract = {Migrating cells have key functions in shaping tissues during development, repairing tissues after development and supporting cancer invasion and metastasis. In all these contexts, cells often maintain contact with their neighbours and move as a group, in a process termed collective migration. In this Review, we describe the elegant mechanisms used by collectively migrating cells in vivo to coordinate their movements and obtain directional information. We start by highlighting the diverse physiological roles that migrating collectives have within the body and then focus on dominant paradigms for the organization of migrating collectives including the roles of leader and follower cells, local cell-cell adhesion and signalling, and external guidance cues. By comparing collective migrations occurring during development and cancer, we bring into focus shared principles for collective cell movement and distinct strategies used by cancer cells for their own dispersal. Throughout, we pay particular attention to how migrating collectives display emergent properties not exhibited by individually migrating cells and how these properties provide the robustness needed for efficient cell movement.}, }
@article {pmid40473660, year = {2025}, author = {Bottomly, D and Mathieson, C and Vigoda, M and Jeng, S and Evans, N and Anderson, A and Blucher, A and Lesch, A and Zheng, C and Laderas, T and Jacobs, J and Kulesz-Martin, M and McWeeney, S}, title = {Assessing individual head and neck squamous cell carcinoma patient response to therapy through integration of functional and genomic data.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {19742}, pmid = {40473660}, issn = {2045-2322}, support = {T32 CA106195/CA/NCI NIH HHS/United States ; S10 OD034224/OD/NIH HHS/United States ; P30 CA069533/CA/NCI NIH HHS/United States ; R01 CA192405/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Squamous Cell Carcinoma of Head and Neck/genetics/drug therapy/pathology ; *Head and Neck Neoplasms/genetics/drug therapy ; *Genomics/methods ; Mutation ; DNA Copy Number Variations ; Precision Medicine ; }, abstract = {Even though head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, there are only two PD-1 targeted immunotherapies (pembrolizumab and nivolumab) and one tumor intrinsic EGFR targeted therapy (cetuximab) that are FDA approved for treatment of HNSCC. Taking advantage of a high throughput inhibitor assay and computational tools originally showing success in leukemia, we designed and employed HNSCC-specific inhibitor panels that capture the diversity of aberrational pathways in HNSCC to test viable cells derived from patients' HNSCC tumors. This provides a functional context to the multi-omic readouts conducted on these samples (mutations, protein expression and copy number alterations). In addition to generating these deeply characterized functional genomics datasets, we also developed additional visual analytics that have the potential to provide greater insight into HNSCC drug response patterns and potentially aid precision oncology tumor boards in evaluation and assessment of effective targeted therapeutic agents.}, }
@article {pmid40473616, year = {2025}, author = {Mazziotta, F and Martin, LE and Egan, DN and Bar, M and Kinsella, S and Paulson, KG and Voillet, V and Lahman, MC and Hunter, D and Schmitt, TM and Duerkopp, N and Yeung, CCS and Tang, TH and Gottardo, R and Asano, Y and Wilcox, EC and Lee, B and Zhang, T and Lopedote, P and Penter, L and Wu, CJ and Milano, F and Greenberg, PD and Chapuis, AG}, title = {A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5214}, pmid = {40473616}, issn = {2041-1723}, support = {n/a//Fred Hutchinson Cancer Research Center (Hutchinson Center)/ ; P01 CA018029/CA/NCI NIH HHS/United States ; 5K08CA169485//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; K08 CA169485/CA/NCI NIH HHS/United States ; n/a//Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)/ ; T32 CA080416/CA/NCI NIH HHS/United States ; n/a//V Foundation for Cancer Research (V Foundation)/ ; n/a//Gabrielle's Angel Foundation for Cancer Research (Gabrielle's Angel Foundation)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/immunology/genetics ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *WT1 Proteins/immunology/genetics ; Female ; Middle Aged ; Male ; Adult ; *Receptors, Antigen, T-Cell/genetics/immunology ; *Genetic Therapy/methods/adverse effects ; *Killer Cells, Natural/immunology ; Transplantation, Homologous ; CD8-Positive T-Lymphocytes/immunology ; Herpesvirus 4, Human/immunology ; Cytomegalovirus/immunology ; Aged ; T-Lymphocytes/immunology ; Young Adult ; Treatment Outcome ; }, abstract = {Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8[+] T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.}, }
@article {pmid40473107, year = {2025}, author = {Mascaux, C and Sen, T and Sanchez-Cespedes, M and Ortiz-Cuaran, S and Bossé, Y and Dammeijer, F and Cavic, M and Barr, MP and Arulananda, S and Armisen, R and Berger, AH and Bianchi, F and Carbone, DP and Cerciello, F and Lockwood, WW and Mitsudomi, T and Ohara, S and Politi, K and Qin, S and Roisman, LC and Samstein, R and Skoulidis, F and Tan, AC and Thomas, A and Zhang, J and Wynes, MW and John, T and Tsao, MS and , }, title = {Advances in Lung Cancer Basic and Translational Research in 2025 - Overview and Perspectives Focusing on NSCLC.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, pmid = {40473107}, issn = {1556-1380}, support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; ZIA BC011793/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Basic and translational research in lung cancer is a rapidly evolving field with a transformational impact on early detection, diagnosis, therapeutic development, and personalization of care. Recent advances have greatly increased our understanding of the molecular genomics, proteomics, pathogenesis, and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprogramming, immunobiology, the immune microenvironment, and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.}, }
@article {pmid40472801, year = {2025}, author = {Kurniansyah, N and Strausz, SJ and Chittoor, G and Gupta, S and Justice, AE and Hrytsenko, Y and Keenan, BT and Cade, BE and Spitzer, BW and Wang, H and Huffman, J and Moll, MR and Haring, B and Jung, SY and Raffield, LM and Kaplan, R and Rotter, JI and Rich, SS and Gharib, SA and Bartz, TM and Liu, PY and Chen, H and Fornage, M and Hou, L and Levy, D and Morrison, AC and Ochs-Balcom, HM and Psaty, BM and Wilson, PWF and Cho, K and Pack, AI and Ollila, HM and Redline, S and Gottlieb, DJ and Sofer, T and , and , and , }, title = {Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105790}, pmid = {40472801}, issn = {2352-3964}, abstract = {BACKGROUND: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.
METHODS: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS).
FINDINGS: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations.
INTERPRETATION: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes.
FUNDING: R01AG080598.}, }
@article {pmid40471097, year = {2025}, author = {Jadvar, H and Rahbar, K and Ahmadzadehfar, H and Heidari, P and Esfahani, SA and Afshar-Oromieh, A and Iravani, A}, title = {Combination prostate-specific membrane antigen-targeted radiopharmaceutical therapy in metastatic prostate cancer.}, journal = {The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...}, volume = {69}, number = {2}, pages = {174-179}, doi = {10.23736/S1824-4785.25.03641-6}, pmid = {40471097}, issn = {1827-1936}, mesh = {Humans ; Male ; *Radiopharmaceuticals/therapeutic use ; *Prostatic Neoplasms/pathology/radiotherapy ; Neoplasm Metastasis ; *Antigens, Surface/metabolism ; *Glutamate Carboxypeptidase II/metabolism ; *Molecular Targeted Therapy/methods ; Combined Modality Therapy ; }, abstract = {Radiopharmaceutical therapy is emerging rapidly as an effective and safe pillar in cancer management. The regulatory approvals for [177]Lu-PSMA-617 radiopharmaceutical therapy in both the pre- and post-chemotherapy metastatic castration resistant prostate cancer clinical space have paved the way for the implementation of this life-prolonging therapy in clinical practice. However, the emergence of resistance to radiopharmaceutical therapy is inevitable, and therefore, combination therapies will be needed to synergize treatment efficacy without untoward collective toxicity. Biologically rational combination therapies across various phases of prostate cancer will lead to more optimal patient outcomes than what can be achieved with monotherapy. This article summarizes select clinical trials on prostate-specific membrane antigen-targeted radiopharmaceutical therapy in combination with other treatments that are either actively accruing or have provided preliminary results.}, }
@article {pmid40469905, year = {2025}, author = {Fang, H and Eacker, SM and Wu, Y and Neufeld-Kaiser, W and Laurino, M and Keel, S and Horwitz, MS and Liu, YJ}, title = {Genetic and functional characterization of inherited complex chromosomal rearrangements in a family with multisystem anomalies.}, journal = {Genetics in medicine open}, volume = {3}, number = {}, pages = {103423}, pmid = {40469905}, issn = {2949-7744}, abstract = {PURPOSE: Complex chromosomal rearrangements (CCRs) are rare structural variants involving 3 or more chromosomal breakpoints. Most de novo-reported CCRs pose challenges for diagnosis and management. They often require karyotyping, fluorescence in situ hybridization, and chromosomal microarray analysis (CMA) for clinical diagnosis because of the limitations of each method. Here, we report an inherited, exceptionally complex CCR involving 4 chromosomes and 13 breakpoints in a family with multisystem anomalies.
METHODS: We evaluated the CCRs using karyotyping, fluorescence in situ hybridization, CMA, and 2 emerging genomic technologies: high-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping. We also performed functional studies using transcriptome and methylome analyses.
RESULTS: The proband, who had intellectual disability and immune deficiency, shared CCRs with her unaffected mother involving chromosomes 1, 7, and 11 by karyotyping. However, CMA revealed a duplication and 3 deletions in the proband, in contrast to her mother's balanced genome. High-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping detected the CCRs and copy-number alterations but also uncovered additional breakpoints at high resolution, including an insertion in 4p and 2 cryptic rearrangements at 7p. Transcriptome and methylome analyses identified likely biological pathways associated with the proband's phenotypes.
CONCLUSION: Combining cytogenetic and genomic methods provided comprehensive characterization and defined the breakpoints at high resolution in both proband and mother. This underscores the value of novel cytogenetic and genomic techniques in deciphering complex genome rearrangements and the significance of integrative genomic analysis and functional characterization in understanding clinical phenotypes.}, }
@article {pmid40469752, year = {2025}, author = {Stone, D and Mietzsch, M and Ronzitti, G}, title = {Advancing AAV technology: From capsid design to scalable manufacturing.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {2}, pages = {101477}, pmid = {40469752}, issn = {2329-0501}, }
@article {pmid40469175, year = {2025}, author = {Mugisha, NM and Pinder, LF and Menon, MP}, title = {Editorial: Cervical screening awareness week 2023: integrating cervical cancer screening and precancer treatments.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1614832}, pmid = {40469175}, issn = {2234-943X}, }
@article {pmid40469020, year = {2025}, author = {Hamilton, EL and Guo, X and Dadabhai, S and Panchia, R and Ogendo, A and Reynolds, D and Chen, Y and Sandfort, TGM and , }, title = {Stigma and other correlates of self-esteem and depression in cisgender men and transfeminine persons with HIV who have sex with men in Kenya, Malawi, and South Africa (HPTN 075).}, journal = {AIDS care}, volume = {37}, number = {7}, pages = {1181-1193}, doi = {10.1080/09540121.2025.2488874}, pmid = {40469020}, issn = {1360-0451}, mesh = {Humans ; Male ; *Social Stigma ; *Self Concept ; South Africa/epidemiology ; *HIV Infections/psychology/epidemiology ; Adult ; *Homosexuality, Male/psychology/statistics & numerical data ; *Depression/psychology/epidemiology ; Kenya/epidemiology ; Malawi/epidemiology ; *Transgender Persons/psychology/statistics & numerical data ; *Sexual and Gender Minorities/psychology ; Middle Aged ; Young Adult ; }, abstract = {ABSTRACTHIV-related stigma profoundly impacts individuals living with HIV, hindering self-esteem and access to treatment. Few studies, if any, have assessed the effects of stigma on depression and self-esteem among men who have sex with men (MSM) and transfeminine persons (TFP) with HIV in African settings. We explored factors, including various forms of stigma, contributing to low self-esteem and poor mental health among 71 MSM and TFP in Kenya, Malawi, and South Africa, using data from the HPTN (HIV Prevention Trials Network) 075 study. Lower self-esteem was associated with moderate to severe depression and was significantly lower among those who experienced HIV as a stigma. Moreover, participants who had encountered MSM-related stigma in healthcare settings were more likely to exhibit moderate to severe depression. Being employed was a protective factor against depression. These results suggest that interventions aimed at reducing MSM-related stigma in healthcare settings and enhancing self-esteem through employment opportunities for MSM and TFP living with HIV might contribute toward ending the HIV epidemic.}, }
@article {pmid40467920, year = {2025}, author = {Mooney, SJ and Smith, CM and Spalt, EW and Piepmeier, L and Gassett, AJ and Gunning, G and Carlson, JA and Evenson, KR and Chambers, EC and Daviglus, M and Lovasi, GS and Gullón, PT and Hirsch, JA and Plascak, JJ and Rundle, AG and Fry, D and Bader, MDM and Kaufman, JD and Kaplan, R}, title = {Built Environment Change over Time Using Google Street View Assessments of Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cities.}, journal = {Journal of urban health : bulletin of the New York Academy of Medicine}, volume = {}, number = {}, pages = {}, pmid = {40467920}, issn = {1468-2869}, support = {R01ES030994/ES/NIEHS NIH HHS/United States ; }, abstract = {Google Street View's historical imagery is a promising data source for measuring neighborhood conditions over time. However, images are not available for all years. To assess bias that may arise due to a mismatch between the year imagery is available and the year of researcher interest, we assessed prevalence of change in 20 commonly assessed built environment features between the oldest and newest available high-quality images (median difference 10.5 years, range from 2007 to 2023) on Street View at 2118 total locations in four US cities representing the Hispanic Community Health Study/Study of Latinos (New York City, Chicago, Miami, and San Diego). Seventeen (85%) of the features were the same in more than 90% of images; only litter differed in more than 20%. Patterns of change were consistent across all four cities and not notably different in tracts with higher or lower median household incomes. For built environment features reflecting sidewalk conditions and disinvestment in neighborhoods not selected for their known rapid change, auditing an image that does not temporally match the time of etiological interest is unlikely to be a major source of bias.}, }
@article {pmid40467365, year = {2025}, author = {Bellmunt, J and Powles, T and Park, SH and Voog, E and Valderrama, BP and Gurney, H and Ullén, A and Loriot, Y and Sridhar, SS and Tsuchiya, N and Sternberg, CN and Aragon-Ching, JB and Petrylak, DP and Climent Duran, MA and Tyroller, K and Hoffman, J and Jacob, N and Grivas, P and Gupta, S}, title = {Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Long-term Outcomes from the JAVELIN Bladder 100 Trial in Patients with Nonvisceral or Lymph Node-only Disease.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.05.017}, pmid = {40467365}, issn = {1873-7560}, abstract = {In the JAVELIN Bladder 100 randomized phase 3 trial (N = 700), avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without progression after first-line platinum-based chemotherapy (PBC). Here, we report exploratory analyses of subgroups with nonvisceral metastases at the start of PBC (including bone metastases) or lymph node-only disease at randomization. The median OS with avelumab versus control in patients with nonvisceral metastases (n = 318) was 31.4 versus 17.1 mo (hazard ratio [HR], 0.60 [95% confidence interval {CI}, 0.45-0.79]), and in patients with lymph node-only disease (n = 102), it was 31.9 versus 22.7 mo (HR, 0.86 [95% CI, 0.51-1.47]). In patients with nonvisceral metastases, prolonged OS was observed with avelumab irrespective of the response to PBC or PBC regimen received. PFS analyses favored avelumab over control in all the subgroups. Incidences of avelumab-related adverse events were similar across the subgroups. Limitations include small sample sizes and the exploratory nature of analyses. Overall, exploratory analyses suggest that in first-line PBC-treated patients without progression, avelumab maintenance is effective and has a manageable toxicity profile in patients with aUC who have nonvisceral metastases or lymph node-only disease.}, }
@article {pmid40466030, year = {2025}, author = {Liao, N and Li, C and Gradishar, WJ and Klimberg, VS and Roshal, JA and Yuan, T and Agarwala, SS and Valero, VK and Swain, SM and Margenthaler, JA and Rubio, IT and Hurvitz, SA and Geyer, CE and Lin, NU and Rugo, HS and Zhang, G and Liu, N and Balch, CM}, title = {Accuracy and Reproducibility of ChatGPT Responses to Breast Cancer Tumor Board Patients.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500001}, doi = {10.1200/CCI-25-00001}, pmid = {40466030}, issn = {2473-4276}, mesh = {Humans ; *Breast Neoplasms/therapy/diagnosis ; Female ; Reproducibility of Results ; Middle Aged ; Generative Artificial Intelligence ; }, abstract = {PURPOSE: We assessed the accuracy and reproducibility of Chat Generative Pre-Trained Transformer's (ChatGPT) recommendations in response to breast cancer patients by comparing generated outputs with consensus expert opinions.
METHODS: 362 consecutive breast cancer patients sourced from a weekly international breast cancer webinar series were submitted to a tumor board of renowned experts. The same 362 clinical patients were also prompted to ChatGPT-4.0 three separate times to examine reproducibility.
RESULTS: Only 46% of ChatGPT-generated content was entirely concordant with the recommendations of breast cancer experts, and only 39% of ChatGPT's responses demonstrated inter-response similarity. ChatGPT's responses demonstrated higher concordance with CEN experts in earlier stages of breast cancer (0, I, II, III) compared to advanced (IV) patients (P = .019). There were less accurate responses from ChatGPT when responding to patients involving molecular markers and genetic testing (P = .025), and in patients involving antibody drug conjugates (P = .006). ChatGPT's responses were not necessarily incorrect but often omitted specific details about clinical management. When the same prompt was independently sent to CEN into the model on three occasions, each time by difference users, ChatGPT's responses exhibited variable content and formatting in 68% (246 out of 362) of patients and were entirely consistent with one another in only 32% of responses.
CONCLUSION: Since this promising clinical decision-making support tool is widely used currently by physicians worldwide, it is important for the user to understand its limitations as currently constructed when responding to multidisciplinary breast cancer patients, and for researchers in the field to continue improving its ability with contemporary, accurate and complete breast cancer information. As currently constructed, ChatGPT is not engineered to generate identical outputs to the same input and was less likely to correctly interpret and recommend treatments for complex breast cancer patients.}, }
@article {pmid40465842, year = {2025}, author = {Mack, PC and Redman, MW and Tukachinsky, H and Kozono, DE and Minichiello, K and Dragnev, KH and Tolba, KA and Neal, JW and Madison, RW and Waqar, SN and Aggarwal, C and Hirsch, FR and Patel, JD and Herbst, RS and Chiang, AC and Reckamp, KL and Kelly, K and Borghaei, H and Gray, JE and Gandara, DR}, title = {Elevated ctDNA Tumor Fraction Is Associated with Improved Mutation Detection but Worse Overall Survival in Advanced Non-Small Cell Lung Cancer: a Lung-MAP Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-3658}, pmid = {40465842}, issn = {1557-3265}, abstract = {PURPOSE: Circulating tumor DNA (ctDNA) is a powerful diagnostic companion to tissue profiling. Tumor fraction (TF) is a global assessment of an individual's ctDNA burden. We evaluated the impact of plasma TF on mutation detection and clinical outcomes in patients with previously treated, advanced NSCLC on Lung-MAP.
EXPERIMENTAL DESIGN: Paired tumor tissue and plasma were collected prospectively from Lung-MAP patients. Plasma was collected within 30 days of a new biopsy with no intervening therapies. Tissue and ctDNA genomic profiling and ctDNA TF levels were assessed by Foundation Medicine. TF was primarily calculated from tumor aneuploidy, defaulting to fragmentomics and maximum somatic allele frequencies when aneuploidy was not detectable. The effect of TF on tissue-plasma mutation concordance, overall survival, and its relation to variant allele frequencies was assessed using linear regression, Lin's coefficient, and Cox modeling/log-rank testing.
RESULTS: 194 patients were eligible for analysis. TF≥1% was significantly associated with improved positive percent agreement (PPA) between ctDNA and tissue across multiple alteration types with the exception of copy number gains. For short variants, PPA improved from 51% when TF<1% to 95% when TF≥1%. TF showed a significant robust correlation with VAF for KRAS, STK11 and TP53 - the three most common mutations. TF<1% were significantly associated with improved patient overall survival compared to TF≥1% or TF≥10%.
CONCLUSIONS: TF provides an accurate, clinically useful assessment of ctDNA plasma levels from patients with refractory, advanced NSCLC. TF levels ≥ 1% are associated with significantly worse overall survival, but improved mutation detection in liquid biopsies.}, }
@article {pmid40465219, year = {2025}, author = {Chalian, M and Park, C}, title = {Use of RADS in Musculoskeletal Imaging: Point-We've Done Enough Talking, Let's Dive In!.}, journal = {AJR. American journal of roentgenology}, volume = {}, number = {}, pages = {}, doi = {10.2214/AJR.25.33285}, pmid = {40465219}, issn = {1546-3141}, }
@article {pmid40464563, year = {2025}, author = {Schiffer, JT and Mudd, JC and Antar, AAR and Spivak, AM and Reeves, DB}, title = {Applications and limitations of the passenger hypothesis for HIV reservoir persistence and cure.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0071425}, doi = {10.1128/jvi.00714-25}, pmid = {40464563}, issn = {1098-5514}, abstract = {Antiretroviral therapy (ART) suppresses HIV replication in people living with HIV (PWH), but a persistent population of reservoir cells prevents cure. Reservoir cells are mostly anatomically dispersed, latently infected CD4+ T cells harboring one copy of chromosomally integrated, replication-competent HIV proviral DNA. Despite their low frequency (0.01%-0.1%) among CD4+ T cells and the quiescence of most genetically intact proviruses, viremia usually recurs within weeks after ART cessation. When PWH are not on ART, the reservoir is sustained through viral infection and infected cell proliferation. During suppressive ART, HIV reservoir cells persist via mechanisms sustaining uninfected CD4+ T cells including antigen-responsive and homeostatic clonal proliferation, programmed cell death, and T cell subset differentiation. Rates of latently infected cell proliferation and death must exist in quasi-equilibrium to explain limited change in reservoir volume over decades of ART, and the rarity of cancers or lymphoproliferative disorders emerging from infected cells. Some reservoir cells are under additional selection forces during ART, illustrated by slightly higher clearance rates of genetically intact versus replication-defective HIV proviral DNA and by a gradual transition to a less transcriptionally active and more clonal reservoir. While a small but meaningful percentage of latently infected cells are negatively selected due to lytic viral replication or elimination by adaptive immune responses, most reservoir cell death occurs independently of harboring intact HIV DNA. Given that HIV is often a passenger in reservoir cells, CD4+ T cell proliferation, targeted death, and subset differentiation may be viable therapeutic targets for curative interventions.}, }
@article {pmid40463521, year = {2025}, author = {Pi, S and Rutter, CM and Pineda-Antunez, C and Chen, JH and Goldhaber-Fiebert, JD and Alarid-Escudero, F}, title = {Discrete-Event Simulation Model for Cancer Interventions and Population Health in R (DESCIPHR): An Open-Source Pipeline.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40463521}, support = {T15 LM007033/LM/NLM NIH HHS/United States ; U01 CA253913/CA/NCI NIH HHS/United States ; U01 CA265750/CA/NCI NIH HHS/United States ; }, abstract = {Simulation models inform health policy decisions by integrating data from multiple sources and forecasting outcomes when there is a lack of comprehensive evidence from empirical studies. Such models have long supported health policy for cancer, the first or second leading cause of death in over 100 countries. Discrete-event simulation (DES) and Bayesian calibration have gained traction in the field of Decision Science because they enable efficient and flexible modeling of complex health conditions and produce estimates of model parameters that reflect real-world disease epidemiology and data uncertainty given model constraints. This uncertainty is then propagated to model-generated outputs, enabling decision makers to determine the optimal strategy to recommend, assess confidence in the recommendation, and estimate the value of collecting additional information. However, there is limited end-to-end guidance on structuring a DES model for cancer progression, estimating its parameters using Bayesian calibration, and applying the calibration outputs to policy evaluation and other downstream tasks. To fill this gap, we introduce the DES Model for Cancer Interventions and Population Health in R (DESCIPHR), an open-source framework and codebase integrating a flexible DES model for the natural history of cancer, Bayesian calibration for parameter estimation, and screening strategy evaluation. We also introduce an automated method to generate data-informed parameter prior distributions and enhance the accuracy and flexibility of a neural network emulator-based Bayesian calibration algorithm. We anticipate that the adaptable DESCIPHR modeling template will facilitate the construction of future decision models evaluating the risks and benefits of health interventions.}, }
@article {pmid40463375, year = {2025}, author = {Fredericks, MN and Kolodner, Z and Waalkes, A and Sawatzki, K and Hao, L and Long, DR and Penewit, K and Midkiff, CC and McCormick, CJ and Beraki, S and Edlefsen, PT and Barrow, J and Greninger, AL and Gale, M and Blair, RV and Salipante, SJ and Fuller, DH and O'Connor, MA}, title = {SIV/SARS-CoV-2 coinfection in rhesus macaques impacts viral shedding, host immunity, the microbiome, and viral evolution.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1587688}, pmid = {40463375}, issn = {1664-3224}, support = {K01 MH123258/MH/NIMH NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; S10 OD030347/OD/NIH HHS/United States ; }, mesh = {Animals ; Macaca mulatta ; *Virus Shedding ; *COVID-19/immunology/virology ; *SARS-CoV-2/immunology/physiology/genetics ; *Simian Immunodeficiency Virus/immunology/physiology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Coinfection/immunology/virology ; Disease Models, Animal ; *Microbiota/immunology ; Antibodies, Viral/immunology/blood ; }, abstract = {People living with HIV (PLWH) have an increased risk of severe COVID-19, including prolonged viral shedding and emergence of mutations. To investigate the simian immunodeficiency virus (SIV) macaque model for HIV/SARS-CoV-2 coinfection, seven SIV+ rhesus macaques were co-infected with SARS-CoV-2. COVID-19 in all macaques was mild. SARS-CoV-2 replication persisted in the upper, but not the lower respiratory tract for 14 days post-infection. Animals showed impaired generation of anti-SARS-CoV-2 antibodies and T-cells. Animals also displayed transient changes in microbial communities in the upper airway and gastrointestinal tract. Evidence of SARS-CoV-2 evolution was observed in the upper respiratory tract. This study demonstrates that SIV/SARS-CoV-2 coinfection in rhesus macaques recapitulates aspects of COVID-19 in PLWH. We show that SIV impairs anti-SARS-CoV-2 immunity, potentially leading to prolonged viral shedding, altered pathogenesis, and viral evolution. This highlights the importance of HIV status in COVID-19 and supports the use of this model for HIV/SARS-CoV-2 coinfection.}, }
@article {pmid40463192, year = {2025}, author = {Walsh, ME and Chetlapalli, K and Upadhyayula, S and King, GA and Ünal, E}, title = {A Conserved Disruption of the Nuclear Permeability Barrier in Meiosis is Controlled by a Kinase-Phosphatase Pair in Saccharomyces cerevisiae.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40463192}, issn = {2692-8205}, support = {R01 AG071801/AG/NIA NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; }, abstract = {In eukaryotic organisms, the nucleus is remodeled to accommodate the space required for chromosome segregation. Remodeling strategies range from closed division, where the nuclear envelope remains intact, to open divisions, where the nuclear envelope is temporarily disassembled. While the budding yeast Saccharomyces cerevisiae undergoes closed mitosis, its meiotic nuclear division strategy is less understood. Here we investigate nuclear permeability during meiosis in budding yeast and discover that meiosis II represents a semi-closed division marked by bidirectional mixing between the nucleus and cytoplasm. This includes nuclear entry of the Ran GTPase activating protein (RanGAP), typically cytoplasmic, although RanGAP relocalization appears to be a consequence, rather than a cause of permeability changes. This intercompartmental mixing occurs without nuclear envelope breakdown or dispersal of nucleoporins and is independent of known nuclear pore complex remodeling events. This phenomenon, termed virtual nuclear envelope breakdown (vNEBD), represents a unique mechanism distinct from other semi-closed divisions. We demonstrate that vNEBD is integrated into the meiotic program and regulated by the conserved meiotic kinase Ime2 and the meiosis-specific protein phosphatase 1 regulatory subunit, Gip1. Remarkably, the vNEBD event is conserved between S. cerevisiae and the distantly related Schizosaccharomyces pombe, indicating a conserved, critical role in meiosis.}, }
@article {pmid40462957, year = {2025}, author = {Esmaeili, S and Swan, DA and Jerome, KR and Schiffer, JT and Walter, M}, title = {Intracellular and extracellular dynamics of herpes simplex virus 1 DNA and infectious particles in epithelial and neuronal cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40462957}, issn = {2692-8205}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus 1 (HSV-1) infection of epithelial cells is lytic, while infection of neurons typically results in long-term latency. However, the rates at which HSV-1 replicates and spreads in epithelial cells versus neurons under low and high multiplicity of infection (MOI) conditions remain undefined. Identifying these rates requires the application of mathematical models to carefully designed viral kinetic experiments. It is also critical to differentiate the dynamics of infectious viral particles versus viral DNA, as both quantities are routinely measured in in vitro experiments and human studies using plaque assays and polymerase chain reactions, respectively. Here, we developed mechanistic mathematical models to describe HSV-1 dynamics after infection of epithelial Vero cells and neuronal N2A cells, at high (3) and low (0.01) MOI. Our model recapitulates the dynamics of cell-free and cell-associated viral DNA and plaque-forming units (PFU). In epithelial cells, the model describes a pre-productive eclipse phase with a mean duration of 10.9 and 12.8 hours prior to HSV DNA replication and PFU production, respectively. Cells exited the eclipse phase as early and late as 2.5 and 32 hours, respectively. Infected cells produced a single PFU for every 224 HSV DNA genomes. PFU egressed at a constant rate, whereas the HSV DNA egress rate increased over time, before saturating at a 15 times higher rate. Under low relative to high MOI conditions, Vero cells spent 7 hours longer in the eclipse phase, had a 12-hour delay prior to egress, and had a longer mean duration of productive infection (14 versus 3.5-hour half-life). Secondary epithelial cell infection in low MOI experiments was overwhelmingly due to cell-to-cell viral spread and originated from a small number of early-producer cells. Neuronal cells produced viruses at a 5-fold lower rate and had a longer (mean: 42 hours) and more variable eclipse phase, with some neurons remaining in eclipse for more than a week. Our results highlighted large differences in HSV egress rates, as well as infected cell eclipse phase duration and death rates, in epithelial cells versus neurons during low and high MOI infection. The observed viral dynamics in neurons reflect a balance between active replication and latency.}, }
@article {pmid40462491, year = {2025}, author = {Karuna, S and Laher, F and Dadabhai, S and Yu, PC and Grove, D and Orrell, C and Makhema, J and Hosseinipour, MC and Mathew, CA and Brumskine, W and Mgodi, N and Andrew, P and Gama, L and Karg, C and Broder, G and Baepanye, K and Lucas, J and Andrasik, M and Takuva, S and Villaran, M and Takalani, A and Tressler, R and Soto-Torres, L and Woodward Davis, AS and Dhai, A and Sanne, IM and Cohen, MS and Corey, L and Gray, G and deCamp, AC and Bar, KJ}, title = {Analytical treatment interruption among women with HIV in southern Africa who received VRC01 or placebo in the Antibody Mediated Prevention Study: ATI stakeholder engagement, implementation and early clinical data.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {6}, pages = {e26495}, pmid = {40462491}, issn = {1758-2652}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1AI068614//HVTN Leadership and Operations Center/ ; UM1AI068619//HPTN Leadership and Operations Center/ ; }, mesh = {Humans ; Female ; *HIV Infections/drug therapy/prevention & control/immunology ; Adult ; Africa, Southern/epidemiology ; *HIV Antibodies ; Viral Load ; *Anti-HIV Agents/administration & dosage/therapeutic use ; *Broadly Neutralizing Antibodies ; HIV-1/immunology ; *Antibodies, Monoclonal/therapeutic use/administration & dosage ; Middle Aged ; CD4 Lymphocyte Count ; Young Adult ; Treatment Interruption ; }, abstract = {INTRODUCTION: Antiretroviral therapy (ART) prevents and treats, but does not eradicate, HIV. Early ART initiation is associated with post-ART virologic control, particularly among African women, and anti-HIV-1 broadly neutralizing antibodies (bnAbs) may modulate immune responses to HIV. We evaluate whether early ART with or without anti-HIV-1 bnAb VRC01, present at HIV acquisition, is associated with later ART-free control in African women and we assess potential associations with observed control.
METHODS: Stakeholder engagement informed analytical treatment interruption (ATI) study design and implementation. Participants who received placebo or VRC01 and acquired HIV in the Antibody Mediated Prevention efficacy trial were assessed for ATI eligibility, including HIV acquisition within 8 weeks of receiving VRC01 or placebo, followed by early ART initiation and ≥1 year of viral suppression. Participation facilitators and barriers were assessed. From May 2021 to February 2024, participants enrolled, stopped ART and received frequent viral load and CD4+ T-cell count monitoring for safety and assessment of meeting ART reinitiation criteria.
RESULTS: Thirteen women enrolled from southern Africa. No ATI-related serious adverse events (AEs), HIV transmissions, pregnancies or ≥Grade 2 AEs were observed. Eight sexually transmitted infections were diagnosed in seven women during ATI. Two participants had tenofovir levels consistent with use during ATI; 2/11 (18%) who completed ATI without antiretroviral use exhibited ART-free control for ≥32 weeks. The median time to confirmed VL≥200 was 5.4 weeks (range 2.7-112). The most common ART reinitiation criterion met was virologic (n = 7). VRC01 receipt proximate to HIV acquisition was not associated with control. Controllers versus non-controllers did not differ by early post-acquisition viral load kinetics, acquired virus characteristics, or time from estimated acquisition to closest infusion or to ART initiation.
CONCLUSIONS: In a safe, well-tolerated ATI, 18% of 11 African women exhibited post-intervention control. Design and implementation lessons inform future ATIs in Africa. Analyses of peri-acquisition and post-ATI host and viral characteristics can inform the development of interventions for HIV cure, prevention and treatment.
CLINICAL TRIAL REGISTRATION: NCT04860323.}, }
@article {pmid40461885, year = {2025}, author = {Flanagan, MR and van den Bruele, AMB and Downs-Canner, SM and Thomas, SM and Gallagher, KK and Jakub, JW and Tevis, SEA and Verdial, FC and Zhang, JQ and Elmore, LC and Mukhtar, RA and Brennan, M and Lillie, M and Gibson, TC and Verosky, A and Plichta, JK and Rosenberger, LH}, title = {ASO Visual Abstract: A Multi-institutional Analysis of Contralateral Axillary Metastases-Advanced Local-Regional Disease Divergent from Stage IV Breast Cancer.}, journal = {Annals of surgical oncology}, volume = {32}, number = {8}, pages = {5590-5591}, doi = {10.1245/s10434-025-17563-8}, pmid = {40461885}, issn = {1534-4681}, }
@article {pmid40461383, year = {2025}, author = {de Marinis, F and Kim, TM and Bonanno, L and Cheng, S and Kim, SW and Tiseo, M and Chu, Q and Proto, C and Sacher, A and Luo, YH and Novello, S and Hao, D and Baik, C and Bazhenova, L and Lee, JS and Cho, BC and Cadranel, J and Diep, TB and Metro, G and Narayanan, P and Yoneshima, Y and de Castro Carpeño, J and Baldotto, C and Nyhus, C and Yang, JC and Sequist, LV and Levy, B and Hartmaier, R and Igwegbe, I and Poole, L and Xu, W and Ahn, MJ}, title = {Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.04.003}, pmid = {40461383}, issn = {1569-8041}, abstract = {BACKGROUND: MET-based resistance following osimertinib treatment for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) is common. We report the primary analysis of the phase II SAVANNAH study (NCT03778229) evaluating savolitinib plus osimertinib in this setting.
PATIENTS AND METHODS: Patients had EGFR-mutated, advanced NSCLC with MET overexpression and/or amplification. MET cut-offs were initially MET immunohistochemistry (IHC)3+/≥50% (3+ intensity in ≥50% of tumor cells) and/or FISH5+ (≥5 MET gene copies or MET/chromosome 7 centromere ratio ≥2), and increased to MET IHC3+/≥90% and/or FISH10+ after a preliminary analysis. Patients received oral savolitinib [300 mg twice daily (b.i.d.) or once daily (o.d.), or 600 mg o.d.] plus osimertinib 80 mg o.d., or savolitinib 300 mg b.i.d. plus placebo. A primary endpoint was investigator-assessed objective response rate (ORR) in patients with progression on first-line osimertinib and MET IHC3+/≥90% and/or FISH10+ status receiving savolitinib 300 mg b.i.d. plus osimertinib (primary efficacy population). Safety was analyzed in all patients receiving savolitinib plus osimertinib.
RESULTS: Of the 365 patients treated, 341 received savolitinib plus osimertinib, with 80 of these included in the primary efficacy population. Investigator-assessed confirmed ORR in the primary efficacy population was 56.3% [95% confidence interval (CI) 44.7% to 67.3%]; the median duration of response (mDoR) was 7.1 months (95% CI 5.6-9.6 months); the median progression-free survival (PFS) was 7.4 months (95% CI 5.5-7.6 months). Blinded independent central review was consistent: confirmed ORR 55.0% (95% CI 43.5% to 66.2%); mDoR 9.9 months (95% CI 6.0-13.7 months); median PFS 7.5 months (95% CI 6.4-11.3 months). The most common any grade adverse events in patients receiving savolitinib plus osimertinib were peripheral edema (46.0%), nausea (40.5%), and diarrhea (23.2%).
CONCLUSIONS: Savolitinib 300 mg b.i.d. plus osimertinib demonstrated high, clinically meaningful and durable responses in patients with EGFR-mutated, advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status following progression on first-line osimertinib. The combination was well tolerated and may provide a new oral targeted treatment approach in this setting.}, }
@article {pmid40460679, year = {2025}, author = {García-Estévez, L and Bardia, A and Rugo, HS and Carey, LA and Diéras, VC and Loibl, S and Piccart, M and Gianni, L and Kalinsky, K and O'Shaughnessy, J and Hurvitz, SA and Harting, E and Valdez, T and Phan, S and Lai, C and Cortés, J}, title = {The association of high body mass index with the safety and efficacy of sacituzumab govitecan in patients with metastatic triple-negative breast cancer from the ASCENT study.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105294}, pmid = {40460679}, issn = {2059-7029}, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Body Mass Index ; *Camptothecin/analogs & derivatives/therapeutic use/analogs & derivatives ; *Immunoconjugates/therapeutic use ; Neoplasm Metastasis ; Obesity/complications ; Treatment Outcome ; *Triple Negative Breast Neoplasms/drug therapy/pathology/mortality/complications ; }, abstract = {BACKGROUND: Sacituzumab govitecan (SG) is a trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) approved in multiple countries for relapsed/refractory metastatic triple-negative breast cancer (mTNBC) based on results from the phase III ASCENT study. The incidence of obesity has grown to epidemic proportions in recent decades; it is unclear what impact this has on treatment outcomes, especially for ADCs like SG that have weight-based dosing. We report the association of body mass index (BMI) with efficacy and safety of SG versus chemotherapy among patients with mTNBC from the ASCENT study.
PATIENTS AND METHODS: This ad hoc subgroup analysis included patients from the intent-to-treat population of ASCENT who received SG at 10 mg/kg of body weight or chemotherapy. BMI, assessed at baseline, was classified as normal (18.5 to <25 kg/m[2]), overweight (25 to <30 kg/m[2]), and obese (≥30 kg/m[2]).
RESULTS: A total of 509 patients were included. Longer progression-free survival was observed with SG versus chemotherapy in patients from all BMI subgroups [normal: 4.2 versus 2.1 months, hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.34-0.67, P < 0.0001; overweight: 4.6 versus 1.5 months, HR 0.31, 95% CI 0.20-0.47, P < 0.0001; obese: 5.9 versus 2.6 months, HR 0.34, 95% CI 0.21-0.53, P < 0.0001]. SG also led to improved overall survival and objective response rates versus chemotherapy in all evaluated BMI subgroups. With SG treatment, the incidence of treatment-emergent adverse events of grade ≥3, and those leading to dose reductions and study drug interruptions, was higher in patients with overweight and obese BMI compared with normal BMI; however, the rates of treatment discontinuation remained low and similar across the subgroups.
CONCLUSIONS: To our knowledge, this is the first study evaluating the association of BMI with outcomes with ADCs. SG demonstrated improved efficacy versus chemotherapy and a manageable safety profile in all evaluated BMI subgroups from ASCENT.}, }
@article {pmid40460374, year = {2025}, author = {Owens, K and Rahman, A and Bozic, I}, title = {Spatiotemporal dynamics of tumor-CAR T-cell interaction following local administration in solid cancers.}, journal = {PLoS computational biology}, volume = {21}, number = {6}, pages = {e1013117}, pmid = {40460374}, issn = {1553-7358}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; *Neoplasms/therapy/immunology/pathology ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen/immunology ; *T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Computer Simulation ; Computational Biology ; Spatio-Temporal Analysis ; }, abstract = {The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a simplified spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can reproduce tumor and CAR T-cell data from small imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors. In our simulations, assuming equal detectable tumor diameters at the time of treatment, low average tumor cell density is a better predictor of treatment success than total tumor burden or volume doubling time. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.}, }
@article {pmid40458939, year = {2025}, author = {Appelbaum, FR}, title = {Graft-versus-leukemia.}, journal = {Haematologica}, volume = {110}, number = {6}, pages = {1243-1244}, pmid = {40458939}, issn = {1592-8721}, }
@article {pmid40457567, year = {2025}, author = {Marc, A and Schiffer, JT and Mentré, F and Perelson, AS and Guedj, J}, title = {Viral Dynamic Models During COVID-19: Are We Ready for the Next Pandemic?.}, journal = {CPT: pharmacometrics & systems pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/psp4.70055}, pmid = {40457567}, issn = {2163-8306}, abstract = {Mathematical models have been used for about 30 years to improve our understanding of virus-host interaction, in particular during chronic infections. During the COVID-19 pandemic, these models have been used to provide insights into the natural history of acute SARS-CoV-2 infection, optimize antiviral treatment strategies, understand factors associated with transmission, and optimize surveillance systems. The impact of modeling has been accelerated by the availability of unprecedented multidimensional immune data from animal and human systems, which enhanced partnerships between experimentalists and theorists and led to exciting new modeling and statistical developments. In this mini review, we examine the lessons learned from the COVID-19 pandemic and discuss the main insights provided by mathematical models of viral dynamics at the different stages of the outbreak. Although we focus on respiratory infection, we also consider the new areas for development in anticipation of future acute infections from new or reemerging pathogens.}, }
@article {pmid40456670, year = {2025}, author = {Hoffman-Censits, J and Tsiatas, M and Chang, PM and Kim, M and Antonuzzo, L and Shin, SJ and Gakis, G and Blais, N and Kim, SH and Smith, A and Arranz Arija, JA and Su, YL and Zagouri, F and Maruzzo, M and Tournigand, C and Forget, F and Schneider, A and Tyroller, K and Jacob, N and Grivas, P and Valderrama, BP}, title = {Avelumab plus sacituzumab govitecan versus avelumab monotherapy as first-line maintenance treatment in patients with advanced urothelial carcinoma: JAVELIN Bladder Medley interim analysis.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2025.05.010}, pmid = {40456670}, issn = {1569-8041}, abstract = {BACKGROUND: Avelumab first-line maintenance is a recommended treatment option for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) without progression following platinum-based chemotherapy (PBC). The JAVELIN Bladder Medley phase II trial is investigating the efficacy and safety of maintenance treatment with avelumab combined with other antitumor agents versus avelumab monotherapy. We report an interim analysis of avelumab plus sacituzumab govitecan (SG) versus avelumab monotherapy.
PATIENTS AND METHODS: Patients with la/mUC without progression after first-line PBC were randomized 2 : 1 to receive avelumab (800 mg every 2 weeks) plus SG (10 mg/kg on days 1 and 8 of 21-day cycles) or avelumab monotherapy (800 mg every 2 weeks). Primary endpoints are investigator-assessed progression-free survival (PFS) and safety. For PFS and overall survival (OS), data in the avelumab monotherapy arm were extended per protocol using propensity score-weighted JAVELIN Bladder 100 data.
RESULTS: At data cut-off (16 September 2024), 38/74 patients (51.4%) in the avelumab plus SG arm and 10/37 patients (27.0%) in the avelumab monotherapy arm were still receiving study treatment. Median PFS with avelumab plus SG versus avelumab monotherapy was 11.17 versus 3.75 months, respectively [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.31-0.76; prespecified efficacy boundary: HR ≤ 0.60]. OS data were immature; median OS was not reached versus 23.75 months, respectively (HR 0.79, 95% CI 0.42-1.50). In patients treated with avelumab plus SG or avelumab monotherapy, any-grade treatment-related adverse events (TRAEs) occurred in 97.3% versus 63.9% (grade ≥3 in 69.9% versus 0%), respectively.
CONCLUSION: In patients with la/mUC without progression after first-line PBC, PFS was prolonged with avelumab plus SG versus avelumab monotherapy as maintenance treatment. TRAEs were more frequent with the combination and were consistent with known safety profiles of SG and avelumab. Combining avelumab with anti-Trop-2 antibody-drug conjugates may be a promising strategy to improve patient outcomes in la/mUC.}, }
@article {pmid40456294, year = {2025}, author = {Tsai, J and Grassberger, C and Nyflot, MJ and Thonglert, K and Zaki, P and Nguyen, MH and Schaub, SK and Apisarnthanarax, S and Bowen, SR}, title = {Functional liver imaging and dosimetry for risk stratification in patients with hepatocellular carcinoma undergoing radiotherapy: validation study.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {209}, number = {}, pages = {110963}, doi = {10.1016/j.radonc.2025.110963}, pmid = {40456294}, issn = {1879-0887}, abstract = {BACKGROUND: Functional liver imaging has potential to personalize management of Hepatocellular Carcinoma (HCC) by mitigating hepatotoxicity risk. We validated functional liver imaging and dosimetric parameters for risk-stratification in an expanded cohort of patients with HCC.
METHODS: We reviewed 109 consecutive patients who underwent Sulfur Colloid (SC)-SPECT/CT scans for radiation therapy (RT) planning and extracted previously reported functional liver imaging metrics. We generated elastic net multivariable Cox models with event-stratified and nested cross-validation folds to predict Overall Survival (OS) and increase in Child-Pugh score ≥ 2 (CP+2). Test-fold patients were risk-stratified, and time-dependent model performance was characterized. ROC analysis generated prognostic cutoffs with confidence intervals to guide functional liver avoidance treatment planning.
RESULTS: Cross-validated model concordance was 0.70 (95% CI: 0.67-0.73) for OS and 0.67 (95% CI: 0.63-0.71) for CP+2. Top-ranked OS predictors included tumor volume (HR=1.56, 1.54-1.58), CP-score (HR=1.36, 1.34-1.38), Liver-GTV V20 (HR=1.310, 1.306-1.314), prior liver-directed therapy (HR=0.83, 0.82-0.85), functional liver volume dosimetry (FLV V20) (HR=1.19, 1.14-1.23), and RT-year (HR=0.89, 0.88-0.91). Top-ranked CP+2 predictors were total liver function (TLF) (HR=0.64, 0.63-0.66), Liver-GTV mean dose (HR=1.40, 1.36-1.49), and CP-score (HR=1.19, 1.16-1.23). Test-fold risk groups were defined for each endpoint (log-rank P<0.001). OS model performance stabilized beyond 2 years; CP+2 model stability peaked within 1 year. Optimal strata for 2-yr OS were FLV V20 < 25.8% and Liver-GTV V20 < 25.4%; 1-yr CP+2 strata were TLF < 0.91 and Liver-GTV mean dose < 18.9 Gy.
CONCLUSION: Functional liver metrics on SC-SPECT/CT were validated alongside clinical and dosimetric factors within robust outcome models. Testing of personalized RT planning for patients with HCC to preserve liver function is warranted in clinical trials.}, }
@article {pmid40455801, year = {2024}, author = {Huang, Y and Prentice, RL}, title = {Biomarker-assisted reporting in nutritional epidemiology: addressing measurement error in exposure-disease associations.}, journal = {Biostatistics (Oxford, England)}, volume = {26}, number = {1}, pages = {}, pmid = {40455801}, issn = {1468-4357}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; R01 CA277133/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/analysis ; Bias ; *Diet/statistics & numerical data ; Cardiovascular Diseases/epidemiology/etiology ; Female ; Proportional Hazards Models ; Self Report ; }, abstract = {In nutritional epidemiology, self-reported dietary data are commonly used to investigate diet-disease relationships. However, the resulting association estimates are often subject to biases due to random and systematic measurement errors. Regression calibration has emerged as a crucial method for addressing these biases by refining self-reported nutrient intake with objective biomarkers, which differ from the true values only by a random "noise" component. This paper presents methodological tools for analyzing nutritional epidemiology cohort studies involving time-to-event data when a biomarker subsample is available alongside dietary assessments. We introduce novel regression calibration methods to tackle two common challenges in this field. First, a widely used approach assumes that the log hazard ratio (HR) follows a linear function of dietary exposure. However, assessing whether this assumption holds-or if a more flexible model is needed to capture potential deviations from linearity-is often necessary. Second, another prevalent analytical strategy involves estimating HRs based on categorized dietary exposure variables. New methods are critically needed to minimize bias in defining category boundaries and estimating hazard ratios within exposure categories, both of which can be distorted by measurement error. We apply these methods to reassess the relationship between sodium and potassium intake and cardiovascular disease risk using data from the Women's Health Initiative.}, }
@article {pmid40455622, year = {2025}, author = {Shaukat, A and Burke, CA and Chan, AT and Grady, WM and Gupta, S and Katona, BW and Ladabaum, U and Liang, PS and Liu, JJ and Putcha, G and Robertson, DJ and Schoen, RE and Meng, Z and Piscitello, A and Sun, CK and Xu, C and Lin, CJ and Lee, LC and Baldo, L and Levin, TR and , }, title = {Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer.}, journal = {JAMA}, volume = {334}, number = {1}, pages = {56-63}, pmid = {40455622}, issn = {1538-3598}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Circulating Tumor DNA/blood ; Colon/diagnostic imaging/pathology ; Colonoscopy ; *Colorectal Neoplasms/diagnosis/blood/pathology ; Cross-Sectional Studies ; *Early Detection of Cancer/methods ; *Precancerous Conditions/blood/diagnosis/pathology ; Prospective Studies ; Sensitivity and Specificity ; *Mass Screening/methods ; }, abstract = {IMPORTANCE: Colorectal cancer screening is widely recommended but underused. Blood-based screening offers the potential for higher adherence compared with endoscopy or stool-based testing but must first be clinically validated in a screening population.
OBJECTIVE: To evaluate the clinical performance of an investigational blood-based circulating tumor DNA test for colorectal cancer detection in an average-risk population using colonoscopy with histopathology as the reference method.
Prospective, multicenter, cross-sectional observational study enrolling participants between May 2020 and April 2022 who were asymptomatic adults aged 45 to 85 years, at average risk of colorectal cancer, and willing to undergo a standard-of-care screening colonoscopy. Participants, staff, and pathologists were blinded to blood test results, and laboratory testing was performed blinded to colonoscopy findings. The study was conducted at 201 centers across 49 US states and the United Arab Emirates. Site-based and mobile phlebotomy were used for blood collection.
EXPOSURES: Participants were required to complete a screening colonoscopy after blood collection.
MAIN OUTCOMES AND MEASURES: The primary end points were sensitivity for colorectal cancer, specificity for advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions), negative predictive value for advanced colorectal neoplasia, and positive predictive value for advanced colorectal neoplasia. The secondary end point was sensitivity for advanced precancerous lesions.
RESULTS: The median age of participants in the evaluable cohort (n = 27 010) was 57.0 years, and 55.8% were women. Sensitivity for colorectal cancer was 79.2% (57/72; 95% CI, 68.4%-86.9%) and specificity for advanced colorectal neoplasia was 91.5% (22 306/24 371; 95% CI, 91.2%-91.9%). The negative predictive value for advanced colorectal neoplasia was 90.8% (22 306/24 567; 95% CI, 90.7%-90.9%) and the positive predictive value for advanced colorectal neoplasia was 15.5% (378/2443; 95% CI, 14.2%-16.8%). All primary end points met prespecified acceptance criteria. The sensitivity for advanced precancerous lesions was 12.5% (321/2567; 95% CI, 11.3%-13.8%), which did not meet the prespecified acceptance criterion.
CONCLUSIONS AND RELEVANCE: In an average-risk colorectal cancer screening population, a blood-based test demonstrated acceptable accuracy for colorectal cancer detection, but detection of advanced precancerous lesions remains a challenge, and ongoing efforts are needed to improve test sensitivity.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04369053.}, }
@article {pmid40455131, year = {2025}, author = {van den Bruele, AB and Rosenberger, LH and Downs-Canner, S and Flanagan, MR}, title = {ASO Author Reflections: Contralateral Axillary Lymph Node Metastasis of Breast Cancer: Time to Re-evaluate Conventional Thinking.}, journal = {Annals of surgical oncology}, volume = {32}, number = {8}, pages = {5578-5579}, pmid = {40455131}, issn = {1534-4681}, }
@article {pmid40455079, year = {2025}, author = {DiPeso, L and Pendyala, S and Huang, HZ and Fowler, DM and Hatch, EM}, title = {Image-based identification and isolation of micronucleated cells to dissect cellular consequences.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40455079}, issn = {2050-084X}, support = {T32CA009657/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35GM124766/GM/NIGMS NIH HHS/United States ; R35 GM124766/GM/NIGMS NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; Scholars Program//Rita Allen Foundation/ ; T32 CA009657/CA/NCI NIH HHS/United States ; RM1HG010461/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Micronuclei, Chromosome-Defective ; Transcriptome ; Cell Line ; *Cell Separation/methods ; Genomic Instability ; *Image Processing, Computer-Assisted/methods ; }, abstract = {Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.}, }
@article {pmid40454483, year = {2025}, author = {Duan, Z and Shi, M and Kumaraswamy, A and Lin, D and Khokhani, D and Wang, Y and Zhang, C and Flores, D and Rodansky, E and Swaim, OA and Storck, WK and Beck, HN and Patel, RA and Sayar, E and Hanratty, BP and Xue, H and Dong, X and Maylin, ZR and Wan, R and Quigley, DA and Sjöström, M and Hu, YM and Zhao, F and Xia, Z and Cheng, S and Yu, X and Feng, FY and Zhang, L and Aggarwal, R and Small, EJ and Ravikumar, V and Rao, A and Bedi, K and Lee, JK and Morrissey, C and Coleman, I and Nelson, PS and Corey, E and Udager, AM and Rebernick, RJ and Cieslik, MP and Chinnaiyan, AM and Yates, JA and Haffner, MC and Wang, Y and Alumkal, JJ}, title = {PROX1 is an early driver of lineage plasticity in prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {11}, pages = {}, pmid = {40454483}, issn = {1558-8238}, support = {P50 CA275741/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R01 GM147365/GM/NIGMS NIH HHS/United States ; R37 CA214955/CA/NCI NIH HHS/United States ; R01 CA291986/CA/NCI NIH HHS/United States ; P50 CA186786/CA/NCI NIH HHS/United States ; R01 CA282005/CA/NCI NIH HHS/United States ; T90 DE030859/DE/NIDCR NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; R01 CA251245/CA/NCI NIH HHS/United States ; }, mesh = {Male ; *Prostatic Neoplasms/pathology/metabolism/genetics ; Prospero-Related Homeobox 1 Protein ; Humans ; *Tumor Suppressor Proteins/genetics/metabolism ; *Homeodomain Proteins/genetics/metabolism ; Animals ; Mice ; Cell Line, Tumor ; DNA Methylation ; *Gene Expression Regulation, Neoplastic ; *Cell Lineage ; *Cell Plasticity ; }, abstract = {Lineage plasticity is recognized as a critical determinant of lethality and resistance to AR pathway inhibitors in prostate cancer. Lineage plasticity is a continuum, ranging from AR activity-low tumors, AR-null tumors that do not express a neuroendocrine prostate cancer (NEPC) program (i.e., double-negative prostate cancer [DNPC]), and AR-null NEPC tumors. Factors upregulated early in lineage plasticity are not well-characterized. The clarification of such factors is essential to identify tumors undergoing lineage plasticity or at risk of this occurring. Our integrative analysis of metastatic prostate cancer patient tumors, patient-derived xenografts, and cell models determined that PROX1 is upregulated early in the lineage plasticity continuum and progressively increases as tumors lose AR activity. We determined DNA methylation is a key regulator of PROX1 expression. PROX1 suppression in DNPC and NEPC reduces cell survival and impacts apoptosis and differentiation, demonstrating PROX1's functional importance. PROX1 is not directly targetable with standard drug development approaches. However, affinity immunopurification demonstrated histone deacetylases (HDACs) are among the top PROX1-interacting proteins; HDAC inhibition depletes PROX1 and recapitulates PROX1 suppression in DNPC and NEPC. Altogether, our results suggest PROX1 promotes the emergence of lineage plasticity, and HDAC inhibition is a promising approach to treat tumors across the lineage plasticity continuum.}, }
@article {pmid40454419, year = {2025}, author = {Stone, D and Takeuchi, R and Dulin, H and Loprieno, MA and Strongin, DE and Sathees, S and Cradick, TJ and Aubert, M and Roychoudhury, P and Gordon, J and Jerome, KR}, title = {Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {2}, pages = {101470}, pmid = {40454419}, issn = {2329-0501}, abstract = {Lipid nanoparticles (LNPs) can efficiently deliver nucleic acid therapeutics to a range of tissues, particularly hepatocytes to treat diseases of the liver. We initially investigated whether three LNPs with different ionizable lipids, previously validated in non-human primates (NHPs), could deliver functional GFP mRNA to human hepatocytes in chimeric NSG-PiZ and FRG mice. After intravenous delivery, GFP expression was observed throughout the livers but was restricted to mouse hepatocytes because the payload mRNA was not internalized by human hepatocytes. LNP transfection was also restricted to mouse hepatocytes in NSG-PiZ mice administered a different LNP containing the ionizable lipid SM-102. In vitro, primary human hepatocytes (PHHs) were transfected by LNPs containing lipids SM-102, LP01, or ALC0315 in the presence of normal mouse serum, but not chimeric NSG-PiZ serum. SM-102 LNP transfection of PHH was also inhibited by naive untransplanted NSG-PiZ serum. However, serum from NSG mice supported PHH transfection by SM-102 LNP. These results suggest that inhibitory factors in NSG-PiZ mouse serum are responsible for the lack of human hepatocyte transduction in chimeric mice. Finally, we found that LNPs displaying trivalent N-acetylgalactosamine (TriGalNAc), which targets them to the asialoglycoprotein receptor, can overcome species restriction, transfecting both mouse and human hepatocytes in chimeric NSG-PiZ mice.}, }
@article {pmid40453059, year = {2024}, author = {DeZern, AE and Goll, JB and Jensen, TL and Nonavinkere Srivatsan, S and Gillis, NK and Abel, GA and Padron, E and Deeg, HJ and Al Baghdadi, T and Liu, JJ and Komrokji, RS and Gore, SD and Saber, W and Bejar, R and Walter, MJ and Lindsley, RC and Sherman, S and DiFronzo, N and Sekeres, MA}, title = {Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study.}, journal = {Blood neoplasia}, volume = {1}, number = {3}, pages = {100026}, pmid = {40453059}, issn = {2950-3280}, }
@article {pmid40451731, year = {2025}, author = {Kmail, ZM and Shannon Dorcy, K and Laing, SS}, title = {Burnout Predictors Among Direct Clinical Services Health Care Professionals in Community Health Centers: A Cross-Sectional Study.}, journal = {American journal of health promotion : AJHP}, volume = {}, number = {}, pages = {8901171251348220}, doi = {10.1177/08901171251348220}, pmid = {40451731}, issn = {2168-6602}, abstract = {PurposeAssess burnout prevalence, identify the healthcare professionals experiencing burnout, and identify organizational predictors of burnout in community health centers (CHCs) nationwide.ApproachIn 2022 the Health Resources and Services Administration administered surveys to assess health center workforce well-being among the 1400+ community health centers that it oversees. Our team statistically evaluated the findings to isolate the factors likely to predict burnout among center healthcare professionals.SettingData completed by staff in 694 CHCs.ParticipantsRespondents were 52 568 healthcare professionals.MethodsChi-squared tests derived homogeneity in burnout among occupations; proportion tests evaluated differences in burnout indicators; and structural equation modeling with latent variables estimated direct and indirect effects of organizational burnout predictors and mediators.ResultsUp to 77% of direct clinical service professionals endorsed at least one symptom of burnout and reported higher burnout rates than management (P < .001). The most significant burnout predictors were engagement (-0.263***), work-life balance (0.281***), workload (0.174***) and professional growth (0.143***). For engagement, a perception of disconnection with the CHC predicted heightened burnout. Work-life balance, workload, and professional growth each had a positive effect on burnout, demonstrating that higher perceived work demands, greater work-life imbalance, and increased professional growth opportunities equated to higher burnout.ConclusionResults highlight the need to redesign healthcare delivery models to mitigate burnout, promote provider engagement and enhance workforce well-being.}, }
@article {pmid40451709, year = {2025}, author = {St Laurent, MP and Psutka, SP}, title = {Reply to Chang-kun Mao, Chao-Yang, and Jun-ting Li's Letter to the Editor re: Marie-Pier St-Laurent, Bernard Bochner, James Catto, et al. Increasing Life Expectancy in Patients with Genitourinary Malignancies: Impact of Treatment Burden on Disease Management and Quality of Life. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.11.026.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.02.004}, pmid = {40451709}, issn = {1873-7560}, }
@article {pmid40451460, year = {2025}, author = {Kang, DW and Ficarra, S and Wilson, RL and Morgans, AK and Nguyen, PL and Rebbeck, TR and Einstein, DJ and Uno, H and Mossanen, M and Hill, DM and Gonzalo-Encabo, P and Norris, MK and Gardiner, J and Tjogas, D and Greer, J and Dieli-Conwright, CM}, title = {Exercise to enhance cardiovascular health among black men with prostate cancer with androgen deprivation therapy (the POWER trial): A study protocol.}, journal = {Contemporary clinical trials}, volume = {155}, number = {}, pages = {107973}, doi = {10.1016/j.cct.2025.107973}, pmid = {40451460}, issn = {1559-2030}, abstract = {BACKGROUND: Black men in the US are 1.8 and 2.2 times more likely to develop and die from prostate cancer (PCa) than non-Hispanic White men, respectively, and have the highest incidence globally. Furthermore, Black men undergoing androgen deprivation therapy (ADT) for PCa face a higher risk of cardiovascular disease (CVD) compared to men of other racial groups. Therefore, we have designed a randomized controlled trial (RCT) to investigate the impact of exercise on CVD risk factors among Black man undergoing ADT.
METHODS: The POWER trial is a dual-arm RCT designed to examine the effects of a 16-week, culturally tailored, remotely supervised cardiovascular and strength exercise program on Black men with PCa receiving ADT. Sixty-two patients will be randomized in a 1:1 allocation to either the exercise intervention or a waitlist control group. The patient population includes adult males who self-identify as Black, receiving ADT for at least four months prospectively at the time of recruitment. The primary outcome is the CVD risk assessed using the Framingham Risk Score. The secondary and exploratory outcomes include physical fitness and function, patient-reported outcomes, and clinical events at a one-year follow-up.
DISCUSSION: The POWER Trial evaluates a culturally tailored exercise program for Black men with PCa undergoing ADT, focusing on improving cardiovascular health. The findings of the study are expected to inform a larger phase clinical trial to examine long-term CVD-related clinical outcomes. Ultimately, our findings and subsequent trials would narrow the gap in health disparities among the communities of Black men with PCa.
TRIAL REGISTRATION: NCT05327465.}, }
@article {pmid40450573, year = {2025}, author = {Stein, MN and Vinceneux, A and Robbrecht, D and Doger, B and Autio, KA and Schweizer, MT and Calvo, E and Medina, L and Van Dongen, M and Deville, JL and Bernard-Tessier, A and Ghosh, D and Shotts, K and Shen, F and Jaiprasart, P and Chaudhary, R and Wu, S and Cartee, L and Schnepp, R and Gaut, D and Lauring, J and Wang, SC and Villalobos, VM and Baldini, C}, title = {Pasritamig, a First-in-Class, Bispecific T-Cell Engager Targeting Human Kallikrein 2, in Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500678}, doi = {10.1200/JCO-25-00678}, pmid = {40450573}, issn = {1527-7755}, abstract = {PURPOSE: We report phase I trial results for pasritamig, a first-in-class, T-cell-engaging bispecific antibody targeting human kallikrein 2 (KLK2) expressed on the surface of prostate cancer (PC) cells.
METHODS: Participants had metastatic castration-resistant PC and ≥1 prior therapy. Pasritamig was escalated from 0.5 mg to 2,000 mg for subcutaneous administration and from 150 mg to 900 mg for intravenous (IV) administration at dosing frequencies ranging from once every week to once every 6 weeks with different step-up dosing schedules. The primary objectives were to determine safety and the recommended phase II dose (RP2D) of pasritamig. Secondary objectives included preliminary assessment of antitumor activity.
RESULTS: One hundred seventy-four participants received pasritamig, with a median of 4 prior lines of systemic therapy. Treatment-related adverse events (TRAEs) occurred in 144 of 174 (82.8%) participants, with 17 of 174 (9.8%) experiencing grade ≥3 TRAEs. The RP2D was determined to be 3.5 mg (day 1), 18 mg (day 8), 300 mg (day 15), and then 300 mg IV once every 6 weeks. In the RP2D safety population (n = 45), infusion-related reactions (11/45, 24.4%), fatigue (7/45, 15.6%), cytokine release syndrome (CRS; 4/45, 8.9%, all grade 1), and lipase increase (4/45, 8.9%) were the most frequent TRAEs; all were grade 1 or 2. In the RP2D efficacy population (n = 33), median radiographic progression-free survival was 7.85 (95% CI, 2.89 to not estimable) months, and 14 of 33 (42.4%) participants achieved a ≥50% decrease from baseline in prostate-specific antigen.
CONCLUSION: Pasritamig demonstrated a favorable safety profile with very low rates of CRS and could be safely administered in an outpatient setting. Preliminary antitumor activity demonstrated proof of concept for KLK2 as a target in PC, warranting further development of pasritamig.}, }
@article {pmid40450382, year = {2025}, author = {Cabahug, JPC and Cruzpero, RC and de Los Santos, LEF and Ford, EC and Yorke, AA}, title = {Radiotherapy medical physics in the Philippines: A contemporary overview.}, journal = {Journal of applied clinical medical physics}, volume = {}, number = {}, pages = {e70129}, doi = {10.1002/acm2.70129}, pmid = {40450382}, issn = {1526-9914}, support = {NCI 3UH3CA211310-04S1//NCI Diversity/ ; }, abstract = {PURPOSE: With cancer ranking as the third leading cause of death in the Philippines and a disparity in healthcare resources across regions, this research aimed to assess the state of radiotherapy medical physics in the country.
METHODOLOGY: The study utilized a comprehensive online survey with 94 structured questions answered by 19 clinics.
RESULTS: Most of the participants were within 1-3 years of training (41%), with a slight majority working in private hospitals (55%). linear accelerators (LINACs) were universally used with one Co-60 unit available, and High Dose Rate (HDR) brachytherapy was common. Intensity-Modulated Radiotherapy (IMRT) and 3D-Conformal Radiotherapy (3D-CRT) are practiced in all 19 clinics, with advanced techniques like Stereotactic Body Radiotherapy (SBRT), Stereotactic Radiosurgery (SRS), and Intraoperative Radiotherapy (IORT) limited to NCR, while modalities such as Volumetric Modulated Arc Therapy (VMAT) (21%) and 2D RT (68%) are more widely practiced. Imaging modalities included the wide adoption of Computed Tomography (CT), though only 64% of respondents had dedicated CT simulators in their clinics. Gynecologic and breast cancers were frequently treated, while bone marrow transplants (total body irradiation) were rare. For quality assurance (QA) devices, Solid Water Phantoms and Scanning Water Tanks (86%) were the most common devices for dosimetry and measurement. 82% reported performing patient-specific QA (PSQA), with EPID dosimetry being the most common (55%) PSQA device used. Quality management practices varied between Qualified Medical Physicists and Medical Physics Trainees, with most Qualified Medical Physicists performing routine checks. Treatment interruptions were mainly due to staffing and machine downtime, rather than power outages or natural disasters. Most clinics had their own systems (86%) to document safety incidents, but only a few reported incidents (32%) to the IAEA SAFRON program. Lastly, participants expressed a willingness to collaborate in research despite limited time.
CONCLUSION: This study provides an understanding of the current landscape of radiation therapy physics in the Philippines, highlighting the need to address workforce disparities, ensure equitable cancer treatment access, optimize dosimetric tools and QA devices, and prioritize resource allocation and research collaboration to advance radiation oncology practices.}, }
@article {pmid40448843, year = {2025}, author = {Hasenstab, KA and Lu, J and Leong, LT and Bossard, E and Pylarinou-Sinclair, E and Devi, K and Cunha, GM}, title = {Relationship between spleen volume and diameter for assessment of response to treatment on CT in patients with hematologic malignancies enrolled in clinical trials.}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {40448843}, issn = {2366-0058}, abstract = {PURPOSE: Investigate spleen diameter (d) and volume (v) relationship in patients with hematologic malignancies (HM) by determining volumetric thresholds that best correlate to established diameter thresholds for assessing response to treatment. Exploratorily, interrogate the impact of volumetric measurements in response categories and as a predictor of response.
METHODS: Secondary analysis of prospectively collected clinical trial data of 382 patients with HM. Spleen diameters were computed following Lugano criteria and volumes using deep learning segmentation. d and v relationship was estimated using power regression model, volumetric thresholds ([Formula: see text]) for treatment response estimated; threshold search to determine percentual change ([Formula: see text] and minimum volumetric increase ([Formula: see text]) that maximize agreement with Lugano criteria performed. Spleen diameter and volume predictive performance for clinical response investigated using random forest model.
RESULTS: [Formula: see text] describes the relationship between spleen diameter and volume. [Formula: see text] for splenomegaly was 546 cm³. [Formula: see text], [Formula: see text], and [Formula: see text] for assessing response resulting in highest agreement with Lugano criteria were 570 cm[3], 73%, and 170 cm[3], respectively. Predictive performance for response between diameter and volume were not significantly different (P=0.78).
CONCLUSION: This study provides empirical spleen volume threshold and percentual changes that best correlate with diameter thresholds, i.e., Lugano criteria, for assessment of response to treatment in patients with HM. In our dataset use of spleen volumetric thresholds versus diameter thresholds resulted in similar response assessment categories and did not signal differences in predictive values for response.}, }
@article {pmid40448577, year = {2025}, author = {Shadman, M and Munir, T and Ma, S and Lasica, M and Tani, M and Robak, T and Flinn, IW and Brown, JR and Ghia, P and Ferrant, E and Tam, CS and Janowski, W and Jurczak, W and Xu, L and Tian, T and Lefebure, M and Agresti, S and Hirata, J and Tedeschi, A}, title = {Zanubrutinib and Venetoclax for Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With and Without Del(17p)/TP53 Mutation: SEQUOIA Arm D Results.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2500758}, doi = {10.1200/JCO-25-00758}, pmid = {40448577}, issn = {1527-7755}, abstract = {PURPOSE: Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or TP53 mutation (TP53mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naïve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with TP53-aberrant disease.
PATIENTS AND METHODS: Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities). Patients received zanubrutinib from cycle 1 and venetoclax from cycle 4 (ramp-up) to cycle 28, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)-guided stopping criteria.
RESULTS: Between November 2019 and July 2022, 114 patients were enrolled: 66 (58%) with TP53-aberrant disease, 47 (41%) without TP53-aberrant disease, and 1 with missing TP53 results. At a median follow-up of 31.2 months, 85 patients (75%) remained on zanubrutinib monotherapy; 29 patients (25%) discontinued zanubrutinib because of adverse event, uMRD-guided stopping criteria, PD, or other. In the intention-to-treat population, 59% of patients achieved peripheral blood uMRD. The 24-month progression-free survival estimate was 92% (95% CI, 85% to 96%). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).
CONCLUSION: Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53-aberrant disease.}, }
@article {pmid40447729, year = {2025}, author = {Sankaranarayanan, A and Khachaturov, G and Smythe, KS and Mittal, S}, title = {Quantitative benchmarking of nuclear segmentation algorithms in multiplexed immunofluorescence imaging for translational studies.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {836}, pmid = {40447729}, issn = {2399-3642}, mesh = {Humans ; *Cell Nucleus/metabolism ; Benchmarking ; *Algorithms ; *Fluorescent Antibody Technique/methods ; *Image Processing, Computer-Assisted/methods ; *Translational Research, Biomedical/methods ; }, abstract = {Multiplexed imaging techniques require identifying different cell types in the tissue. To utilize their potential for cellular and molecular analysis, high throughput and accurate analytical approaches are needed in parsing vast amounts of data, particularly in clinical settings. Nuclear segmentation errors propagate in all downstream steps of cell phenotyping and single-cell spatial analyses. Here, we benchmark and compare the nuclear segmentation tools commonly used in multiplexed immunofluorescence data by evaluating their performance across 7 tissue types encompassing ~20,000 labeled nuclei from human tissue samples. Pre-trained deep learning models outperform classical nuclear segmentation algorithms. Overall, Mesmer is recommended as it exhibits the highest nuclear segmentation accuracy with 0.67 F1-score at an IoU threshold of 0.5 on our composite dataset. Pre-trained StarDist model is recommended in case of limited computational resources, providing ~12x run time improvement with CPU compute and ~4x improvement with the GPU compute over Mesmer, but it struggles in dense nuclear regions.}, }
@article {pmid40447568, year = {2025}, author = {Hazelwood, E and Canson, DM and Deslandes, B and Wang, X and Kho, PF and Legge, D and Constantinescu, AE and Lee, MA and Bishop, DT and Chan, AT and Gruber, SB and Hampe, J and Le Marchand, L and Woods, MO and Pai, RK and Schmit, SL and Figueiredo, JC and Zheng, W and Huyghe, JR and Murphy, N and Gunter, MJ and Richardson, TG and Whitehall, VLJ and Vincent, EE and Glubb, DM and O'Mara, TA}, title = {Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5043}, pmid = {40447568}, issn = {2041-1723}, support = {MC_UU_00032/03//RCUK | Medical Research Council (MRC)/ ; C18281/A29019//Cancer Research UK (CRUK)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; APP1179170//Department of Health | National Health and Medical Research Council (NHMRC)/ ; U01 CA167551/CA/NCI NIH HHS/United States ; APP177524//Department of Health | National Health and Medical Research Council (NHMRC)/ ; C18281/A30905//Cancer Research UK (CRUK)/ ; T32 ES013678/ES/NIEHS NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P01 CA196569/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; 218495/Z/19/Z//Wellcome Trust (Wellcome)/ ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; Female ; Male ; *Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Gene Expression Regulation, Neoplastic ; Transcriptome ; Sex Factors ; Polymorphism, Single Nucleotide ; *RNA Splicing/genetics ; Semaphorins/genetics ; Gene Expression Profiling ; }, abstract = {Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS. Most likely causal genes with evidence of cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. Notably, SEMA4D, encoding a protein targeted by an investigational CRC therapy, emerges as a key risk gene. We also identify a female-specific association with CRC risk for CCM2 expression and subsite-specific associations, including LAMC1 with rectal cancer risk. These findings offer valuable insights into CRC molecular mechanisms and support promising therapeutic avenues.}, }
@article {pmid40447392, year = {2025}, author = {Svatek, RS and Ankerst, DP and D' Amico, AV and Flaig, TW and Ford, LG and Goldkorn, A and Hernandez, J and Kumar, AP and Leach, RJ and Lerner, S and Liss, MA and McConkey, DJ and Minasian, L and Morilak, D and Mueller, EJ and Parekh, DJ and Platz, EA and Sudarshan, S and Unger, JM}, title = {A festschrift in honor of Ian M. Thompson Jr., MD.}, journal = {Urologic oncology}, volume = {43}, number = {7}, pages = {423-435}, doi = {10.1016/j.urolonc.2024.10.030}, pmid = {40447392}, issn = {1873-2496}, }
@article {pmid40445115, year = {2025}, author = {Liang, M and Zhao, Y and Lin, DW and Cooperberg, M and Zheng, Y}, title = {Estimating optimally tailored active surveillance strategy under interval censoring.}, journal = {Biometrics}, volume = {81}, number = {2}, pages = {}, pmid = {40445115}, issn = {1541-0420}, support = {R01 CA236558/NH/NIH HHS/United States ; U24 CA086368/NH/NIH HHS/United States ; }, mesh = {Humans ; *Prostatic Neoplasms/pathology/diagnosis ; Male ; *Watchful Waiting/statistics & numerical data/methods ; Computer Simulation ; Disease Progression ; Biopsy/statistics & numerical data ; Cost-Benefit Analysis ; Models, Statistical ; Statistics, Nonparametric ; }, abstract = {Active surveillance (AS) using repeated biopsies to monitor disease progression has been a popular alternative to immediate surgical intervention in cancer care. However, a biopsy procedure is invasive and sometimes leads to severe side effects of infection and bleeding. To reduce the burden of repeated surveillance biopsies, biomarker-assistant decision rules are sought to replace the fix-for-all regimen with tailored biopsy intensity for individual patients. Constructing or evaluating such decision rules is challenging. The key AS outcome is often ascertained subject to interval censoring. Furthermore, patients will discontinue participation in the AS study once they receive a positive surveillance biopsy. Thus, patient dropout is affected by the outcomes of these biopsies. This work proposes a non-parametric kernel-based method to estimate a tailored AS strategy's true positive rates (TPRs) and true negative rates (TNRs), accounting for interval censoring and immediate dropouts. We develop a weighted classification framework based on these estimates to estimate the optimally tailored AS strategy and further incorporate the cost-benefit ratio for cost-effectiveness in medical decision-making. Theoretically, we provide a uniform generalization error bound of the derived AS strategy, accommodating all possible trade-offs between TPRs and TNRs. Simulation and application to a prostate cancer surveillance study show the superiority of the proposed method.}, }
@article {pmid40444925, year = {2025}, author = {Jacobs, JM and Traeger, L and Freese, M and Barata, A and Newcomb, R and Rabideau, D and Horick, N and DeFilipp, Z and Chen, YB and Gray, T and Pepper, J and Caruso, E and Amonoo, HL and Lee, SJ and Greer, JA and Temel, JS and El-Jawahri, A}, title = {BMT-CARE App: A Randomized Controlled Trial of a Psychosocial Digital Application for Caregivers of Patients Undergoing Hematopoietic Stem-Cell Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {20}, pages = {2265-2275}, doi = {10.1200/JCO-25-00713}, pmid = {40444925}, issn = {1527-7755}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; Quality of Life ; *Mobile Applications ; Adult ; *Hematologic Neoplasms/therapy/psychology ; Anxiety ; Depression ; Aged ; Stress Disorders, Post-Traumatic/psychology ; }, abstract = {PURPOSE: Family and friend caregivers of patients undergoing hematopoietic stem-cell transplantation (HSCT) struggle with immense caregiving burden, leading to substantial quality of life (QOL) impairments and psychological distress. Yet, interventions to address caregivers' needs are limited.
MATERIALS AND METHODS: We conducted a randomized controlled trial of a psychosocial digital application (BMT-CARE App) versus usual care for adult caregivers of patients with hematologic malignancies undergoing HSCT. The BMT-CARE App included five modules combining psychoeducation and evidence-based behavior change strategies. Participants completed self-report measures at baseline and day 60 post-HSCT. The primary end point was QOL at day 60 assessed by the CareGiver Oncology QOL (CarGOQOL) measure. We also assessed caregiving burden (Caregiver Reaction Assessment), anxiety and depression symptoms (Hospital Anxiety and Depression Scale), and post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist [PCL-5]). We used analysis of covariance adjusting for baseline scores to assess the effect of the intervention on study outcomes.
RESULTS: Between February 2023 and July 2024, we enrolled 125 of 174 approached caregivers (71.8%). Participants assigned to the BMT-CARE App used the app for a median of 146.9 minutes (range, 0-384.8). At day 60, BMT-CARE App caregivers reported clinically and significantly better QOL than those assigned to usual care (adjusted means = 76.3 v 69.9, P = .006). BMT-CARE App participants also reported significantly lower caregiving burden (11.2 v 12.3, P = .023), depression (3.8 v 5.6, P = .002), and PTSD symptoms (26.1 v 31.3, P = .012). The groups did not differ significantly in anxiety symptoms at day 60.
CONCLUSION: The BMT-CARE App led to significantly improved QOL, caregiving burden, depression, and PTSD symptoms among HSCT caregivers. This intervention should be tested in a multicenter study with a diverse HSCT caregiver population to determine generalizability and scalability.}, }
@article {pmid40443012, year = {2025}, author = {Brixner, D and Richardson, T and Lockhart, CM and Ramsey, S and Fox, J and Pritchard, D and Mcleod, H and Bobolts, L and Bourbeau, B and Crum, E}, title = {Optimization of oncology biomarker testing in managed care: Best practices and consensus recommendations from an AMCP Market Insights program.}, journal = {Journal of managed care & specialty pharmacy}, volume = {31}, number = {6-a Suppl}, pages = {S1-S14}, pmid = {40443012}, issn = {2376-1032}, mesh = {Humans ; *Managed Care Programs/standards/organization & administration ; Consensus ; *Biomarkers, Tumor/analysis ; *Precision Medicine/methods/standards/economics ; Delphi Technique ; *Neoplasms/diagnosis/therapy ; *Medical Oncology/standards ; Practice Guidelines as Topic ; Cost-Benefit Analysis ; Surveys and Questionnaires ; }, abstract = {Precision medicine in oncology using actionable molecular biomarkers to guide treatment selection has been associated with favorable outcomes; however, many potentially eligible patients do not receive it. This Academy of Managed Care Pharmacy Market Insights program sought to characterize unmet needs in biomarker testing among managed care stakeholders, to develop best practice and consensus recommendations to support addressing these needs, and to gain insights on potential quality measures related to biomarker testing. The program used a modified Delphi process and included in-depth interviews with expert panelists, a national survey of managed care professionals, and a consensus survey of experts. Areas of unmet need in biomarker testing identified were education, guidelines and protocols, timeliness, process, and equity. Twenty-two best practices were suggested by managed care experts and other stakeholders; 9 of these best practices achieved consensus. These consensus recommendations addressed biomarker test ordering and test performance, treatment decisions based on biomarker testing, cost-effectiveness of biomarker testing, and health disparities in access to biomarker testing. Opportunities for education and improvements in infrastructure to implement these recommendations were identified. Further investigation is needed to develop quality measures; although, valuable insights were gained.}, }
@article {pmid40442371, year = {2025}, author = {Nugent, PJ and Park, H and Wladyka, CL and Yelland, JN and Sinha, S and Chen, KY and Bynum, C and Quarterman, G and Lee, SC and Hsieh, AC and Subramaniam, AR}, title = {Decoding post-transcriptional regulatory networks by RNA-linked CRISPR screening in human cells.}, journal = {Nature methods}, volume = {22}, number = {6}, pages = {1237-1246}, pmid = {40442371}, issn = {1548-7105}, support = {GM119835//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; GM008268//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; CA230617//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; CA276308//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; GM135362//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1846521//National Science Foundation (NSF)/ ; }, mesh = {Humans ; *CRISPR-Cas Systems ; *Gene Regulatory Networks ; RNA, Guide, CRISPR-Cas Systems/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; HEK293 Cells ; Ribosomes/metabolism ; RNA, Messenger/genetics/metabolism ; *RNA/genetics/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {RNAs undergo a complex choreography of metabolic processes that are regulated by thousands of RNA-associated proteins. Here we introduce ReLiC, a scalable and high-throughput RNA-linked CRISPR approach to measure the responses of diverse RNA metabolic processes to knockout of 2,092 human genes encoding all known RNA-associated proteins. ReLiC relies on an iterative strategy to integrate genes encoding Cas9, single-guide RNAs (sgRNAs) and barcoded reporter libraries into a defined genomic locus. Combining ReLiC with polysome fractionation reveals key regulators of ribosome occupancy, uncovering links between translation and proteostasis. Isoform-specific ReLiC captures differential regulation of intron retention and exon skipping by SF3B complex subunits. Chemogenomic ReLiC screens decipher translational regulators upstream of messenger RNA (mRNA) decay and identify a role for the ribosome collision sensor GCN1 during treatment with the anti-leukemic drug homoharringtonine. Our work demonstrates ReLiC as a powerful framework for discovering and dissecting post-transcriptional regulatory networks in human cells.}, }
@article {pmid40441807, year = {2025}, author = {Seaton, KE and Paez, CA and Yu, C and Karuna, ST and Gamble, T and Miner, MD and Heptinstall, J and Zhang, L and Gao, F and Yacovone, M and Spiegel, H and Dumond, JB and Anderson, M and Piwowar-Manning, E and Dye, B and Tindale, I and Proulx-Burns, L and Trahey, M and Takuva, S and Takalani, A and Bailey, VC and Kalams, SA and Scott, H and Mkhize, NN and Weiner, JA and Ackerman, ME and McElrath, MJ and Pensiero, M and Barouch, DH and Montefiori, D and Tomaras, GD and Corey, L and Cohen, MS and Huang, Y and Mahomed, S and Siegel, M and Kelley, CF and , }, title = {Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, a V2 specific HIV-1 broadly neutralising antibody, infused intravenously or subcutaneously in people without HIV-1 in the USA (HVTN 140/HPTN 101 part A): a first-in-human, phase 1 randomised trial.}, journal = {The lancet. HIV}, volume = {12}, number = {6}, pages = {e405-e415}, doi = {10.1016/S2352-3018(25)00012-8}, pmid = {40441807}, issn = {2352-3018}, mesh = {Humans ; Adult ; Female ; Male ; Young Adult ; *HIV Antibodies/administration & dosage/adverse effects/immunology ; *HIV-1/immunology ; Middle Aged ; Adolescent ; *HIV Infections/prevention & control/immunology/drug therapy ; *Antibodies, Neutralizing/administration & dosage/adverse effects/immunology ; United States ; *Broadly Neutralizing Antibodies/administration & dosage/adverse effects ; Infusions, Intravenous ; *Antibodies, Monoclonal/administration & dosage/pharmacokinetics/adverse effects ; }, abstract = {BACKGROUND: PGDM1400LS is a human monoclonal antibody targeting the HIV envelope V2 apex with a lysine-serine modification intended to enhance serum and tissue half-lives and is being considered for use in combination monoclonal antibody trials. We sought to test whether PGDM1400LS was safe and had favourable serum concentration, pharmacokinetics, and neutralising ability in healthy adults.
METHODS: HVTN 140/HPTN 101 part A is an open-label, dose escalation, first-in-human phase 1 trial of PGDM1400LS given intravenously or subcutaneously to healthy adults aged 18-50 years without HIV-1. The study enrolled participants at four sites in the USA, across five groups, each receiving one dose of PGDM1400-LS intravenously (group 1: 5 mg/kg; group 2: 20 mg/kg; and group 4: 40 mg/kg) or subcutaneously (group 3: 20 mg/kg; and group 5: 40 mg/kg). Participants in group 1 were enrolled sequentially without random assignment. Participants in groups 2 and 3 were block randomised and enrolled simultaneously after group 1 safety review. Groups 4 and 5 followed the same process, contingent on groups 2 and 3 safety review. The primary endpoints were safety and tolerability of PGDM1400LS, serum concentration of PGDM1400LS, and serum neutralising activity after single administration of PGDM1400LS. Serum PGDM1400LS concentrations collected at seven timepoints (day 0, day 3, day 6, day 28, day 56, day 112, and day 168) were assessed via an anti-idiotype binding assay and characterised via non-compartmental pharmacokinetic analysis. Serum neutralisation activity (ID80) was assessed by a TZM-bl assay. The study is registered with ClinicalTrials.gov, NCT05184452.
FINDINGS: Between Nov 15, 2021, and March 4, 2022, 15 participants were enrolled into the five study groups (three participants per group) with 6 months of follow-up. Ten of 15 participants were female, 14 of 15 participants were non-Hispanic, and 11 of 15 participants were White, with a median age of 27 years (range 24-47). PGDM1400LS was safe and well tolerated, with mild to moderate solicited symptoms. Serum concentrations showed dose proportionality by administration route, with peak concentrations observed immediately after intravenous infusion (range 95·7-727·4 μg/mL) or on day 6 after subcutaneous infusion (205·6-547·1 μg/mL). The median elimination half-life was 55 days (range 48-59), representing a 2-to-3-times increase versus parental PDGM1400. Estimated subcutaneous (vs intravenous) bioavailability was 50-60%. ID80 titres showed agreement with concentration-predicted ID80 titres, indicating maintenance of neutralisation activity in vivo.
INTERPRETATION: PGDM1400LS is a promising candidate for combination monoclonal antibody efficacy trials going forward.
FUNDING: National Institute of Allergy and Infectious Diseases-National Institutes of Health.}, }
@article {pmid40440319, year = {2025}, author = {Triplette, M and Omernik, B and Snidarich, M and Heffner, JL and Brooks, E and Crothers, K and Brown, MC and Murphy, NR and Louie, T}, title = {Tailored Patient Navigation to Support Lung Cancer Screening and Smoking Cessation in LGBTQ+ Individuals: A Pilot Study.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1513/AnnalsATS.202502-215OC}, pmid = {40440319}, issn = {2325-6621}, abstract = {RATIONALE: Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. People who identify as LGBTQ+ are more likely to smoke; however, there are limited interventions to support lung cancer prevention in this community. Through prior community-engaged work we developed a patient navigation intervention to support smoking cessation and lung cancer screening (LCS) for LGBTQ+ adults.
OBJECTIVE: To conduct a prospective pilot study of the patient navigation intervention to evaluate patient satisfaction, acceptability and knowledge change as well as LCS care completion and smoking cessation.
METHODS: We enrolled participants who currently smoked, identified as LGBTQ+ and were eligible for LCS into a patient navigation intervention and assessed outcomes over a 90-day period. We administered pre- and post-intervention surveys, tracked navigation and LCS activities in the electronic health record and verified tobacco cessation with exhaled carbon monoxide (CO) measurements. Primary outcomes included post-intervention Acceptability of Intervention Measure (AIM) scores, the Patient Satisfaction with Navigator Interpersonal Relationship (PSN-I) score, and knowledge change on two validated measures. Secondary outcomes included being appropriately up-to-date on LCS and smoking cessation, measured as reported >7 day floating abstinence and end-of-study CO-confirmed ≥30 day cessation.
RESULTS: Forty-one participants enrolled in the study and participated in the navigation program, with 34 completing post-intervention surveys at day 90. Acceptability (mean AIM score 4.5) and patient satisfaction (mean PSN-I score 40.8) were both high. Fifty-nine percent of individuals were appropriately up-to-date on LCS at day 90 compared to 22% at baseline. Of post-survey respondents, 41% reported a period of >7 day smoking abstinence during the study, with 18% reporting CO-confirmed abstinence of ≥30 days at study end.
CONCLUSIONS: Tailored patient navigation is a promising approach to enhance LCS uptake and smoking cessation in LCS-eligible LGBTQ+ individuals.
CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov NCT05304390. Primary Source of Funding. This work was funded through a grant from LUNGevity Foundation to Dr. Triplette.}, }
@article {pmid40440315, year = {2025}, author = {Agrawal, P and Khechaduri, A and Salladay, KR and MacCamy, A and Ralph, DK and Riker, A and Stuart, AB and Siddaramaiah, LK and Shen, X and Matsen, FA and Montefiori, D and Stamatatos, L}, title = {Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-like antibodies.}, journal = {PLoS pathogens}, volume = {21}, number = {5}, pages = {e1013039}, doi = {10.1371/journal.ppat.1013039}, pmid = {40440315}, issn = {1553-7374}, abstract = {Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be one component of an effective HIV-1 vaccine elicited response. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-like antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.}, }
@article {pmid40440038, year = {2025}, author = {Ding, Y and Naresh, KN}, title = {Primary myelofibrosis involving lymph nodes with the same mutational profile in bone marrow.}, journal = {Blood}, volume = {145}, number = {22}, pages = {2672}, doi = {10.1182/blood.2025028556}, pmid = {40440038}, issn = {1528-0020}, }
@article {pmid40439580, year = {2025}, author = {Bondeelle, L and Cheng, GS and Bergeron, A}, title = {What's new in the management of pulmonary complications in allogeneic stem cell transplantation?.}, journal = {Expert review of respiratory medicine}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/17476348.2025.2513519}, pmid = {40439580}, issn = {1747-6356}, abstract = {INTRODUCTION: As survival increases after allogeneic hematopoietic stem cell transplantation (allo-HCT), several organ complications have emerged, including those involving the lung, which require a multidisciplinary management approach. The constant evolution of allo-HCT procedures, advances in diagnostic tools for infections and pulmonary disease, as well as new treatment approaches, require frequent updating of knowledge in this field.
AREAS COVERED: We review the multiple infectious and noninfectious lung complications that occur both early and late after allo-HCT. This includes an updated description of these complications, risk factors, diagnostic approach and outcome. A literature search was performed using PubMed-indexed journals.
EXPERT OPINION: The diagnosis of pulmonary complications after allo-HCT remains challenging, further complicated by the frequent association of co-infections and/or links between infection and noninfectious complications. The development of metagenomic next-generation sequencing (mNGS) should enhance the diagnostic yield of bronchoalveolar lavage, but its clinical relevance remains to be evaluated. A better understanding of the pathophysiology of the lung chronic graft-versus-host disease (GVHD) and improved phenotyping are essential for advancing its diagnostic and therapeutic management. This requires a revision of diagnostic criteria and the identification of new biomarkers of early disease.}, }
@article {pmid40438119, year = {2025}, author = {Creighton, RL and Hughes, SM and Hladik, F and Gornalusse, GG}, title = {The intestinal interferon system and specialized enterocytes as putative drivers of HIV latency.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1589752}, pmid = {40438119}, issn = {1664-3224}, mesh = {Humans ; *Enterocytes/immunology/virology/metabolism ; *HIV Infections/immunology/virology/metabolism ; *Virus Latency/immunology ; *Interferons/metabolism/immunology ; *HIV-1/physiology/immunology ; CD4-Positive T-Lymphocytes/immunology/virology ; Animals ; Virus Activation ; Intestinal Mucosa/immunology/metabolism ; Signal Transduction ; }, abstract = {The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4[+] T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4[+] T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.}, }
@article {pmid40438096, year = {2025}, author = {Ackerley, CG and Edupuganti, S and Yu, C and Roxby, AC and Seaton, KE and Bekker, LG and Allen, M and DeRosa, SC and Yates, NL and Heptinstall, J and Mkhize, NN and Malahleha, M and Mngadi, K and Daniels, B and Innes, C and Furch, BD and Koutsoukos, M and Ferrari, G and Morris, L and Montefiori, DC and McElrath, MJ and Tomaras, GD and Laher, F and Moodie, Z}, title = {Retrospective analysis of sex-disaggregated immune responses to ALVAC-HIV and bivalent subtype C gp120/MF59 HIV vaccines.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1557009}, pmid = {40438096}, issn = {1664-3224}, mesh = {Humans ; *AIDS Vaccines/immunology/administration & dosage ; Male ; Female ; Adult ; Retrospective Studies ; *HIV Infections/immunology/prevention & control/virology ; *HIV Envelope Protein gp120/immunology ; HIV Antibodies/immunology/blood ; *HIV-1/immunology ; Young Adult ; Adolescent ; Antibodies, Neutralizing/immunology/blood ; Antibody-Dependent Cell Cytotoxicity ; Sex Factors ; Immunogenicity, Vaccine ; *Squalene/immunology/administration & dosage ; }, abstract = {INTRODUCTION: Generally, individuals assigned female at birth (AFAB) develop greater immunogenicity to various vaccines than individuals assigned male at birth (AMAB). Little is known about sex-disaggregated immunogenicity to HIV-1 vaccines. We disaggregated immune responses to an experimental HIV vaccine regimen.
METHODS: We retrospectively analyzed data from HVTN 100, a clinical trial conducted in South Africa during which 143 adults AMAB and 109 AFAB aged 18-40 years without HIV received ALVAC-HIV vCP2438 plus bivalent subtype C gp120/MF59 or placebo at 0, 1, 3, 6, and 12 months. Eligible data were from per-protocol vaccine recipients at month 6.5. We measured IgG binding antibodies, neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and CD4+ IFNγ and/or II-2 responses. We compared sex-based differences in response rates using Barnard's test and response magnitudes using Wilcoxon Rank Sum test. P-values were Holm-adjusted for multiple comparisons.
RESULTS: Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; padj = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; padj = 0.05) to vaccine-matched antigen TV1.C gp120 compared to AMAB. Vaccine recipients AMAB had higher CD4+ T cell response rates to 2/3 vaccine-matched antigens at month 6.5 (ZM96.C gp120, [54.1% versus 36.8%; padj = 0.04]; 1086.C gp120, [44.1% versus 29.4%; padj = 0.05]) than AFAB. CD4+ T cell response magnitudes were similar by sex. IgG binding antibody response rate to B.CaseA V1V2 antigen (associated with reduced HIV acquisition risk in the RV144 trial) was 56.8% among AMAB vaccine recipients versus 38.9% among AFAB (padj = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses.
DISCUSSION: We identified sex-based differences in immune responses to an HIV vaccine regimen, but they varied by immunologic assay. While vaccine recipients AFAB demonstrated higher ADCC responses, AMAB exhibited higher CD4+ T cell response rates. Future analyses should investigate whether vaccine factors such as platform, dosing and adjuvants contribute to sex-based differences in immunogenicity of experimental HIV vaccines.}, }
@article {pmid40435511, year = {2025}, author = {Wudhikarn, K and Herr, MM and Chen, M and Martens, MJ and Baird, JH and Gowda, L and Rangarajan, HG and Abid, MB and Kharfan-Dabaja, MA and Williams, KM and Ganguly, S and Young, JH and Sharma, A and Fatobene, G and Jain, T and Kanakry, CG and Modi, D and Grover, NS and Salem, B and Batista, MV and Vergidis, P and Yin, DE and Beitinjaneh, AM and Kelkar, AH and Nishihori, T and Holter-Chakrabarty, J and Gergis, U and Smith, M and El Boghdadly, Z and Dandoy, CE and Murthy, HS and Huppler, AR and Perales, MA and Chemaly, RF and Hill, JA and Riches, M and Auletta, JJ}, title = {Infection after CD19 chimeric antigen receptor T cell therapy for large B cell lymphoma: Real-world analysis from CIBMTR.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016141}, pmid = {40435511}, issn = {2473-9537}, abstract = {Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 R/R LBCL patients receiving commercial CD19 CAR T-cell (n=2804 axicabtagene ciloleucel, n=546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 (24.9%) patients within 100 days post-infusion, resulting in an infection density of 0.43 per 100 patient-days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 (3.2%) patients, respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient-days. After a 24-month median follow-up, 1482 (44%) patients had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0%). Patients with Karnofsky score ≤80, infection history pre-CAR-T, axicabtagene ciloleucel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell-associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell. Furthermore, results identify patients at heightened risk for infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.}, }
@article {pmid40435447, year = {2025}, author = {Nakasone, ES and Cohen, SA}, title = {Secondary Acute Myeloid Leukemia following Treatment for Metastatic Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Cautionary Sequel to an Exceptional Response.}, journal = {Pancreas}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPA.0000000000002520}, pmid = {40435447}, issn = {1536-4828}, }
@article {pmid40435434, year = {2025}, author = {Daca-Álvarez, M and Brunori, A and Carbone, A and Carbonell, C and Tangen, CM and Unger, JM and Lucia, MS and Oliva, M and De Censi, A and Brenner, DR and Thompson, IM and Balaguer, F}, title = {Emerging Strategies for Drug-Based Cancer Risk Reduction.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e473708}, doi = {10.1200/EDBK-25-473708}, pmid = {40435434}, issn = {1548-8756}, mesh = {Humans ; *Neoplasms/prevention & control/epidemiology/drug therapy/etiology ; Risk Factors ; Chemoprevention/methods ; Risk Reduction Behavior ; Female ; }, abstract = {Chemoprevention has emerged as a promising strategy to reduce cancer incidence by using pharmacologic agents that interrupt the carcinogenesis process. This review discusses emerging insights and recent advancements in chemoprevention, emphasizing novel approaches in several cancer types. Specifically, we examine breast cancer prevention, focusing on optimized endocrine therapy dosing to enhance adherence and minimize adverse effects while maintaining efficacy. Additionally, the potential of glucagon-like peptide-1 receptor agonists to mitigate obesity-related cancer risks is evaluated, highlighting their role in addressing an increasingly prevalent risk factor in the general population. The review further explores strategies targeting colorectal cancer (CRC), specifically in familial adenomatous polyposis, a hereditary CRC syndrome that exemplifies the complex interplay between chemoprevention, genetic risk, and patient management. In prostate cancer, we highlight the evidence supporting the use of 5-alpha reductase inhibitors, detailing their effectiveness in reducing cancer incidence as well as their safety profile. Across these areas, this review underscores the importance of precision medicine, advocating for personalized approaches that balance efficacy, safety, and quality-of-life considerations. Ultimately, advancing chemopreventive strategies through targeted research and clinical trials is essential for reducing cancer burden and improving patient outcomes.}, }
@article {pmid40435263, year = {2025}, author = {Marsh, NM and MacEwen, MJS and Chea, J and Kenerson, HL and Kwong, AA and Locke, TM and Miralles, FJ and Sapre, T and Gozali, N and Hart, ML and Bammler, TK and MacDonald, JW and Sullivan, LB and Atilla-Gokcumen, GE and Ong, SE and Scott, JD and Yeung, RS and Sancak, Y}, title = {Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.}, journal = {Science advances}, volume = {11}, number = {22}, pages = {eadu9512}, pmid = {40435263}, issn = {2375-2548}, support = {R01 GM129090/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; S10 OD021502/OD/NIH HHS/United States ; R01 CA279997/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; F31 AG072716/AG/NIA NIH HHS/United States ; R35 GM136234/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amino Acids, Branched-Chain/metabolism ; *Carcinoma, Hepatocellular/metabolism/genetics/pathology ; Humans ; *Liver Neoplasms/metabolism/pathology/genetics ; *Mitochondria/metabolism ; *Calcium Signaling ; Cell Line, Tumor ; Calcium Channels/metabolism/genetics ; Kruppel-Like Transcription Factors/metabolism/genetics ; Gene Expression Regulation, Neoplastic ; }, abstract = {Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.}, }
@article {pmid40434773, year = {2025}, author = {Andrews, LIB and Halloran, ME and Neuzil, KM and van der Laan, L and Huang, Y and Andriesen, J and Patel, M and Fisher, LH and Janes, H and Rouphael, N and Walsh, SR and Theodore, DA and Tieu, HV and Sobieszczyk, M and El Sahly, HM and Baden, LR and Falsey, AR and Campbell, TB and Kelley, CF and Healy, CM and Immergluck, L and Luft, B and Hirsch, I and de Bruyn, G and Truyers, C and Priddy, F and Sumner, KM and Flannery, B and Follmann, D and Gilbert, PB and , }, title = {Evaluating the Test-Negative Design for COVID-19 Vaccine Effectiveness Using Randomized Trial Data: A Secondary Cross-Protocol Analysis of 5 Randomized Clinical Trials.}, journal = {JAMA network open}, volume = {8}, number = {5}, pages = {e2512763}, pmid = {40434773}, issn = {2574-3805}, mesh = {Humans ; *COVID-19 Vaccines/therapeutic use ; *COVID-19/prevention & control/diagnosis ; *Vaccine Efficacy ; *Randomized Controlled Trials as Topic ; SARS-CoV-2/immunology ; Adult ; Female ; Male ; Middle Aged ; *Research Design ; }, abstract = {IMPORTANCE: The test-negative design (TND) has been widely used to assess postmarketing COVID-19 vaccine effectiveness but requires further evaluation for this application.
OBJECTIVE: To determine whether the TND reliably evaluates vaccine effectiveness against symptomatic COVID-19 using placebo-controlled vaccine efficacy randomized clinical trials (RCTs).
This secondary cross-protocol analysis constructed TND study datasets from study sites in 16 countries across 5 continents using the blinded phase cohorts of 5 harmonized phase 3 COVID-19 Prevention Network RCTs: COVE (Coronavirus Vaccine Efficacy and Safety), AZD1222, ENSEMBLE, PREVENT-19 (Prefusion Protein Subunit Vaccine Efficacy Novavax Trial COVID-19), and VAT00008. Participants included adults who received the intended number of doses, experienced COVID-19-like symptoms, and obtained SARS-CoV-2 testing. Start dates ranged from July 27, 2020, to October 19, 2021; data cutoff dates ranged from March 26, 2021, to March 15, 2022. Statistical analysis was performed from May 11, 2023, to February 25, 2025.
INTERVENTIONS: Participants received vaccines consisting of messenger RNA-1273 (COVE; 2 doses 28 days apart), ChAdOx1 nCoV-19 (AZD1222; 2 doses 28 days apart), Ad26.COV2.S (ENSEMBLE; 1 dose), NVX-CoV2373 (PREVENT-19; 2 doses 21 days apart), CoV2 preS dTM-AS03 (VAT00008; D614) (2 doses 21 days apart), or CoV2 preS dTM-AS03 (D614 plus B.1.351) (VAT00008; 2 doses 21 days apart) or placebo.
MAIN OUTCOMES AND MEASURES: Main outcomes were symptomatic COVID-19 according to each trial's primary efficacy definition and the Centers for Disease Control and Prevention definition. Vaccine effectiveness was estimated using targeted maximum likelihood estimation under a semiparametric logistic regression model and ordinary logistic regression. Noncase exchangeability, a core TND assumption for unbiased estimation, was also assessed by estimating vaccine efficacy against non-COVID-19 illness.
RESULTS: Among the 12 157 participants included in the analysis, mean (SD) age was 45 (15) years, 6414 were female (53%), 5858 were vaccinated (48%), 2835 experienced primary COVID-19 (23%), and 2992 experienced Centers for Disease Control and Prevention-defined COVID-19 (25%). TND vaccine effectiveness estimates were concordant with RCT vaccine efficacy estimates (concordance correlation coefficient, 0.86 [95% CI, 0.58-0.96] for both outcomes). The semiparametric method had 48% smaller variance estimates than ordinary logistic regression. Noncase exchangeability was generally supported with a median vaccine efficacy against non-COVID-19 illness of 7.7% (IQR, 2.7%-16.8%) across trial cohorts and most 95% CIs including 0.
CONCLUSIONS AND RELEVANCE: In this cross-protocol analysis, the TND provided reliable inferences on COVID-19 vaccine effectiveness in health care-seeking populations for multiple vaccines and symptom definitions when confounding and selection bias were absent. A machine-learning approach for robust confounding control in postmarketing TND studies was also introduced.}, }
@article {pmid40427141, year = {2025}, author = {Dahlberg, A and Stevenson, P and Bhatt, NS and Burroughs, L and Carpenter, PA and Summers, C and Tarlock, K and Thakar, MS and Milano, F and Deeg, HJ and Bleakley, M}, title = {Disease Burden at the Time of Transplantation Is a Primary Predictor of Outcomes in Pediatric MDS: A Single-Center Experience.}, journal = {Cancers}, volume = {17}, number = {10}, pages = {}, pmid = {40427141}, issn = {2072-6694}, abstract = {BACKGROUND: Hematopoietic cell transplantation (HCT) remains the only curative therapy for pediatric myelodysplastic syndrome (MDS) in all but rare cases. While HCT outcomes for pediatric MDS are similar across the largest registry and single-center trials, factors identified as contributing to inferior outcomes vary from study to study. We performed an analysis to provide more clarity on the prognostic implications of disease characteristics, including blast burden and cytogenetic abnormalities, in the current era.
METHODS: We conducted a retrospective analysis of 36 consecutive children (<18 years of age at HCT) who underwent allogeneic HCT for MDS between June 2000 and October 2019 at the Fred Hutchinson Cancer Center.
RESULTS: Overall survival (OS) was 77% (95% CI 64-92%) and relapse-free survival (RFS) was 71% (95% CI 57-88%) at 2 years post-HCT. Patients with <5% blasts by morphology in the bone marrow at the time of HCT showed superior 2-year OS at 87% (95% CI 74-100%) as compared to 54% (95% CI 32-93%) in patients with ≥5% blasts, consistent with an HR of 4.6 (CI 1.14-18.7, p = 0.03). The inferior outcomes in patients with ≥5% blasts were due to increased relapse incidence (HR 7.6, CI 1.5-39.3) with no difference in NRM or acute GVHD.
CONCLUSIONS: OS and RFS were comparable to what has been observed in other large, single-center studies (OS 77%, RFS 71% at 2 years) and compared favorably to outcomes from the largest multi-center retrospective analyses.}, }
@article {pmid40425844, year = {2025}, author = {Kwan, EM and Ng, SWS and Tolmeijer, SH and Emmett, L and Sandhu, S and Buteau, JP and Iravani, A and Joshua, AM and Francis, RJ and Subhash, V and Lee, ST and Scott, AM and Martin, AJ and Stockler, MR and Donnellan, G and Annala, M and Herberts, C and Davis, ID and Hofman, MS and Azad, AA and Wyatt, AW and , }, title = {Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40425844}, issn = {1546-170X}, support = {PCF Challenge Award//Prostate Cancer Foundation (PCF)/ ; Young Investigator Award//Prostate Cancer Foundation (PCF)/ ; BC Trainee Award//Michael Smith Foundation for Health Research (MSFHR)/ ; NHMRC Investigator Fellowship #1177837//Department of Health | National Health and Medical Research Council (NHMRC)/ ; NHMRC Practitioner Fellowship APP1102604//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, abstract = {The prostate-specific membrane antigen (PSMA)-targeted radioligand [[177]Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [[177]Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10[-4]) on [[177]Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [[177]Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [[177]Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [[177]Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [[177]Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .}, }
@article {pmid40425554, year = {2025}, author = {Borot, F and Humbert, O and Ehmsen, JT and Fields, E and Kohli, S and Radtke, S and Swing, K and Pande, D and Enstrom, MR and Laszlo, GS and Mayuranathan, T and Ali, AM and Weiss, MJ and Yen, JS and Newby, GA and Walter, RB and Liu, DR and Mukherjee, S and Kiem, HP}, title = {Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4899}, pmid = {40425554}, issn = {2041-1723}, support = {R01 HL156647/HL/NHLBI NIH HHS/United States ; K99 HL163805/HL/NHLBI NIH HHS/United States ; P51 OD010425/OD/NIH HHS/United States ; R00 HL163805/HL/NHLBI NIH HHS/United States ; R50 CA274319/CA/NCI NIH HHS/United States ; R35 GM118062/GM/NIGMS NIH HHS/United States ; U01 AI142756/AI/NIAID NIH HHS/United States ; R01 CA266556/CA/NCI NIH HHS/United States ; P01 HL053749/HL/NHLBI NIH HHS/United States ; R01 HL136135/HL/NHLBI NIH HHS/United States ; RM1 HG009490/HG/NHGRI NIH HHS/United States ; R01 HL151765/HL/NHLBI NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Gene Editing/methods ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism/immunology ; *Genetic Therapy/methods ; Hematopoietic Stem Cells/metabolism/drug effects ; Gemtuzumab/pharmacology ; *Immunotherapy/methods ; Polymorphism, Single Nucleotide ; CRISPR-Cas Systems ; Mice ; }, abstract = {The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (>70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.}, }
@article {pmid40425412, year = {2025}, author = {Swaminathan, M and Holt, SK and Gore, JL and Nyame, YA and Wright, J and Shah, A and Sparks, JA and Makris, UE and Grivas, P and Suarez-Almazor, M and Psutka, S and Singh, N}, title = {Association Between Rheumatoid Arthritis, Frailty Status, and Mortality in Older Adults with Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {102369}, doi = {10.1016/j.clgc.2025.102369}, pmid = {40425412}, issn = {1938-0682}, abstract = {BACKGROUND: To evaluate the associations between rheumatoid arthritis (RA) and all-cause (ACM) and cancer-Specific mortality (CSM) in older adults with bladder cancer and examine how frailty may affect these associations.
METHODS: Retrospective cohort study derived from the Surveillance Epidemiology and End Results (SEER) cancer registry and linked to Medicare claims data (SEER-Medicare). The cohort consisted of patients ≥ 65 years diagnosed with bladder cancer between 2004 and 2017. RA and frailty status were derived using validated administrative algorithms. ACM and CSM as derived from the SEER registry.
RESULTS: Frailty modified the relationship between RA and mortality outcomes (interaction P value for ACM: .002 and for CSM: .007). We observed that RA was associated with a higher risk of CSM (aHR 1.17, 95% CI, 1.01-1.35) and ACM (aHR 1.12, 95% CI, 1.05-1.20) in nonfrail patients. In frail patients with bladder cancer, RA was not independently associated with CSM (aHR 0.81, 95% CI, 0.62-1.06) or ACM (aHR 0.93, 95% CI, 0.83-1.05).
CONCLUSION: Frailty is associated with adverse health outcomes. As people are living longer, it is becoming increasingly prevalent among patients with chronic conditions such as RA. We observed that RA is associated with increased risk of ACM and CSM among nonfrail older adults with bladder cancer. The lack of an association between RA and mortality in frail patients with RA suggests that the effect of frailty on mortality may overpower the effect that RA may exert-this information can help prognosticate outcomes in patients with bladder cancer, RA, and frailty.}, }
@article {pmid40425247, year = {2025}, author = {Tatunay, K and Cohen, S and Naylor, LV and Handford, CL and Jacobson, A and Shankaran, V and Oelschlager, B and Grady, WM and Sjoding, B and Lally, E and Facchini, L and Sun, Q and Laurino, MY and Pritchard, C and Konnick, EQ and Dubard-Gault, ME}, title = {Does paired genetic testing improve targeted therapy choices and screening recommendations for patients with upper gastrointestinal cancers and their families? A prospective cohort of 42 patients.}, journal = {BMJ open}, volume = {15}, number = {5}, pages = {e091745}, pmid = {40425247}, issn = {2044-6055}, mesh = {Humans ; Male ; Female ; *Genetic Testing/methods ; Prospective Studies ; Middle Aged ; Aged ; *Gastrointestinal Neoplasms/genetics/diagnosis/therapy ; *Esophageal Neoplasms/genetics/diagnosis/therapy ; *Early Detection of Cancer/methods ; Adult ; *Molecular Targeted Therapy ; *Stomach Neoplasms/genetics/diagnosis/therapy ; Genetic Predisposition to Disease ; }, abstract = {OBJECTIVES: Our study was designed to assess whether paired normal-tumour testing increased access to targeted therapy, clinical trials and influenced cancer screening recommendations given to patients and their families.
DESIGN: Prospective cohort study.
SETTING: Academic cancer centre in the Pacific Northwest region of the USA.
PARTICIPANTS: Patients newly diagnosed between 01 January 2021 and 31 December 2022 with cancers of the oesophagus, gastro-oesophageal junction and stomach (CEGEJS) were included. All other cancer diagnoses such as head and neck, duodenal and lower gastrointestinal tract cancers were excluded.
INTERVENTION: Paired germline and tumour genetic test within 90 days of new patient visit.
PRIMARY OUTCOME MEASURES: Number of targeted therapies received (or not) when eligible, follow-up treatment data and number of inherited predispositions to cancers identified. No secondary outcome measures.
RESULTS: Of 42 patients, 32 (76.2%) were eligible for at least one targeted therapy. 19 patients received immunotherapy, when 16 had a biomarker predicting immunotherapy benefit, and benefit of immunotherapy was unclear for 3. Another 11 did not have this biomarker, and 6 of them received immunotherapy. Six pathogenic variants were identified in four high-risk genes. By 01 January 2024, 18 patients (42.9%) had died of complications of cancer.
CONCLUSION: More than 75% of patients who received tumour testing were eligible for a targeted therapy regardless of their stage at diagnosis, emphasising the need to expand access to testing with staging workup to improve survival outcomes. Six families received personalised screening recommendations, thanks to this study.}, }
@article {pmid40422973, year = {2025}, author = {Zeller, M and Chang, J and Trevisan, G and Gauger, PC and Zhang, J}, title = {Nextclade data set for the ORF5-based lineage classification of PRRSV-1.}, journal = {Microbiology resource announcements}, volume = {14}, number = {6}, pages = {e0030325}, pmid = {40422973}, issn = {2576-098X}, abstract = {A Nextclade data set for PRRSV-1 ORF5 based on a global nomenclature for standardized lineage classification was developed. This tool enables rapid sequence analysis, visualization, and comparison with reference strains and vaccines. By providing accessibility, it facilitates broader adoption of PRRSV-1 classification frameworks for research and surveillance.}, }
@article {pmid40421959, year = {2025}, author = {Spencer, KR and King, GG}, title = {MDM2 as a therapeutic target in advanced biliary tract cancers.}, journal = {The oncologist}, volume = {30}, number = {5}, pages = {}, pmid = {40421959}, issn = {1549-490X}, support = {//Boehringer Ingelheim Pharmaceuticals, Inc/ ; }, mesh = {Humans ; *Proto-Oncogene Proteins c-mdm2/genetics/antagonists & inhibitors/metabolism ; *Biliary Tract Neoplasms/drug therapy/pathology/genetics ; Molecular Targeted Therapy ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.}, }
@article {pmid40421022, year = {2025}, author = {Paktinat, S and Gravett, MG and Tobey, C and Kirby, A and Horner, W and Shaffer, R and Fialkow, M and Nguyen, NP and Gornalusse, GG and Kalatehjari, M and Hughes, SM and Hladik, F and Vojtech, L}, title = {Extracellular vesicles from human semen induce unique tolerogenic phenotypes in vaginal dendritic cells and regulatory T lymphocytes.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1564002}, pmid = {40421022}, issn = {1664-3224}, mesh = {Humans ; *Dendritic Cells/immunology/metabolism ; Female ; *Semen/immunology/metabolism ; *T-Lymphocytes, Regulatory/immunology/metabolism ; *Extracellular Vesicles/immunology/metabolism ; *Immune Tolerance ; Cell Differentiation/immunology ; *Vagina/immunology/cytology ; Male ; Phenotype ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Cells, Cultured ; Pregnancy ; Coculture Techniques ; }, abstract = {INTRODUCTION: The regulation of immune responses to promote tolerance to the fetus is critical for successful pregnancy. An understudied aspect of this process is the initiation of regulation pre-conception via exposure to semen. Our study aimed to understand how semen impacts recipient dendritic cells (DCs) and their subsequent role in shaping CD4 T cell differentiation.
METHODS: Monocyte-derived DCs (MoDCs) were exposed to semen extracellular vesicles (SEV) or vesicle-depleted semen plasma (VDSP). Phenotypic and functional markers were analyzed using flow cytometry. We also exposed epithelial sheets from vaginal tissue to SEV and VDSP, and measured the number and marker expression of emigrating cells. Finally, we tested how SEV- or VDSP-exposed DCs altered CD4 T cell differentiation by co-culturing exposed MoDCs or tissue emigrated cells with autologous naïve CD4 T cells.
RESULTS: MoDCs exhibited a significant increase of CD141, CD1a, CD38, and ILT4 expression when exposed to SEV or VDSP. A unique feature of semen-treated MoDCs was expression of indoleamine 2,3-dioxygenase (IDO), a potent contributor to the induction of regulatory T cells (Tregs). SEV but not VDSP significantly increased the emigration of intraepithelial DCs. Additionally, SEV significantly enhanced the expression of multiple immunoregulatory markers in the emigrated DCs. After co-culture, we observed significantly more FOXP3+ Tregs expressing high levels of TIGIT in the groups that were initially exposed to SEV.
DISCUSSION: These findings indicate that exposure to SEV induces a tolerogenic program in DCs that can direct differentiation of a unique memory Treg subset, primed for expansion and presumably destined to support a successful pregnancy.}, }
@article {pmid40420384, year = {2025}, author = {Hansen, SG and Schell, JB and Marshall, EE and Ojha, S and Feltham, S and Morrow, D and Hughes, CM and Gilbride, RM and Ford, JC and Cleveland-Rubeor, HC and McArdle, MR and Whitmer, T and Barber-Axthelm, A and Bochart, R and Smedley, J and Oswald, K and Fast, R and Shoemaker, R and Kosmider, E and Edlefsen, PT and Lifson, JD and Malouli, D and Früh, K and Picker, LJ}, title = {Glycoprotein L-deleted single-cycle rhesus cytomegalovirus vectors elicit MHC-E-restricted CD8+ T cells that protect against SIV.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {}, number = {}, pages = {}, doi = {10.1093/jimmun/vkaf104}, pmid = {40420384}, issn = {1550-6606}, support = {U19 AI128741/AI/NIAID NIH HHS/United States ; P01 AI174856/AI/NIAID NIH HHS/United States ; R01 AI059457/AI/NIAID NIH HHS/United States ; }, abstract = {Strain 68-1 rhesus CMV (RhCMV) vectors induce immune responses that mediate early, complete replication arrest of SIV infection in ∼60% of vaccinated rhesus macaques (RMs). This unique efficacy depends on the ability of these vectors to elicit effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by MHC-E, rather than MHC-Ia. These efficacious responses still occurred when spread of the 68-1 vector was impaired by deletion of the viral anti-host intrinsic immunity factor phosphoprotein 71 (pp71), but efficacy was lost with a more stringent attenuation strategy based on destabilization of Rh108, the ortholog of the essential human CMV (HCMV) transcription factor UL79 that is required for late viral gene expression. Although unable to produce infectious progeny (ie single-cycle infection), Rh108-deficient vectors elicited durable, high frequency, EM-biased, SIV-specific CD8+ T-cell responses in RMs, but these responses were MHC-Ia-restricted and therefore non-efficacious. Here, we tested a different single-cycle attenuation strategy based on deletion (Δ) of the glycoprotein L (gL) that is essential for viral entry but allows for late gene expression and viral assembly. ΔgL 68-1 RhCMV/SIV vectors, grown on gL-complementing fibroblasts, were robustly immunogenic at doses above 105 PFU, generating high frequency, EM-biased, SIV-specific CD8+ T-cell responses that were also unconventionally restricted, including the MHC-E restriction associated with efficacy. Indeed, these single-cycle vectors manifested replication arrest efficacy in 70% of vaccinated RMs, further linking MHC-E restriction with efficacy, and demonstrating that 68-1 RhCMV/SIV efficacy does not require vector dissemination within the host.}, }
@article {pmid40419513, year = {2025}, author = {Raychaudhuri, S and Gem, H and Chung, K and McLean, JS and Kerns, KA and Hullar, MAJ and Elmorr, E and Appelbaum, JB and Percival, MM and Walter, RB and Halpern, AB and Minot, SS and Kim, K and Zevin, AS and Rashidi, A}, title = {Distal gut colonization by oral bacteria during intensive chemotherapy: direct evidence from strain-level analysis of paired samples.}, journal = {NPJ biofilms and microbiomes}, volume = {11}, number = {1}, pages = {88}, pmid = {40419513}, issn = {2055-5008}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; n/a//Kuni Foundation/ ; P30 CA015704/CA/NCI NIH HHS/United States ; n/a//American Academy of Oral Medicine Research Advancement Committee/ ; T32HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Feces/microbiology ; *Bacteria/classification/isolation & purification/genetics/drug effects ; *Mouth/microbiology ; Male ; Female ; Saliva/microbiology ; *Gastrointestinal Microbiome ; Middle Aged ; Adult ; Aged ; *Antineoplastic Agents/therapeutic use/adverse effects ; }, abstract = {Oral bacteria have been found in the colon in pathologies such as inflammatory bowel disease. To ascertain niche coalescence, 2 elements are essential: (i) paired oral/fecal samples and (ii) strain-level resolution. We profiled the microbiota in 283 samples from 39 patients undergoing intensive chemotherapy at baseline (saliva: 49, plaque: 51, stool: 43), week 2 (saliva: 18, plaque: 17, stool: 17), week 3 (saliva: 18, plaque: 21, stool: 21), and week 4 (saliva: 8, plaque: 10, stool: 10) of chemotherapy. Through strain-level analysis of paired samples, we demonstrate strong evidence for a breakdown of niche separation in most patients. The extent of overlap increased with time, particularly in patients with intestinal mucositis. Our findings provide definitive evidence for ectopic colonization of the distal gut by oral bacteria in a disease state, likely facilitated by intestinal mucositis. Microbiota contribution by the mouth to the colon may have consequences for the host.}, }
@article {pmid40419509, year = {2025}, author = {Dobersch, S and Yamamoto, N and Schutter, A and Cavender, SM and Robertson, TM and Kartha, N and Samraj, AN and Doron, B and Poole, LA and Wladyka, CL and Zhang, A and Jang, GH and Mahalingam, AH and Barreto, G and Raghavan, S and Narla, G and Notta, F and Eisenman, RN and Hsieh, AC and Kugel, S}, title = {HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4866}, pmid = {40419509}, issn = {2041-1723}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; R01 GM135362/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA255015/CA/NCI NIH HHS/United States ; PF-24-1196662-01-RMC//American Cancer Society (American Cancer Society, Inc.)/ ; GM135362//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 5R37CA241472-03//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35 CA231989/CA/NCI NIH HHS/United States ; 465590102//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; R37 CA230617/CA/NCI NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; 1R01CA255015-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; K08 CA260442/CA/NCI NIH HHS/United States ; }, mesh = {*HMGA2 Protein/metabolism/genetics ; *Pancreatic Neoplasms/metabolism/pathology/genetics ; Animals ; Humans ; *Carcinoma, Pancreatic Ductal/genetics/metabolism/pathology ; Mice ; RNA-Binding Proteins/metabolism/genetics ; Methylation ; Cell Line, Tumor ; Protein Phosphatase 2/metabolism/genetics ; Gene Expression Regulation, Neoplastic ; *Leucine/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; }, abstract = {Basal pancreatic ductal adenocarcinoma (PDAC) has the worst overall survival and is the only subtype that serves as an independent poor prognostic factor. We identify elevated levels of LIN28B and its downstream target, HMGA2, in basal PDAC. Notably, LIN28B significantly accelerates KRAS-driven PDAC progression in a mouse model. Here, we show that HMGA2 promotes basal PDAC pathogenesis by enhancing mRNA translation downstream of LIN28B. Mechanistically, HMGA2 suppresses leucine carboxyl methyltransferase 1 (LCMT1) at the chromatin level, reducing PP2A methylation and activity. This leads to increased phosphorylation of S6K and eIF4B, boosting mRNA translation. Additionally, HMGA2 downregulates B56α (PPP2R5A), disrupting functional PP2A holoenzyme assembly and further sustaining phosphorylated S6K levels. Impaired PP2A function mimics HMGA2's effects, reinforcing increased mRNA translation and basal lineage features. This work uncovers a critical link between the LIN28B/HMGA2 axis, protein synthesis, and PDAC lineage specificity via LCMT1-mediated PP2A methylation and B56α-PP2A disruption.}, }
@article {pmid40419022, year = {2025}, author = {Ahmed, S and Blosser, C and Israni, AK and Engels, EA}, title = {Reply to "Real-world registry evidence beware: Old-world risk analysis may not be applicable to new world belatacept utilization".}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajt.2025.05.027}, pmid = {40419022}, issn = {1600-6143}, }
@article {pmid40419020, year = {2025}, author = {Mehta, RS and Schmidt, G and Williams, K and Patel, SA and Schetelig, J and Savani, B and Askar, M and Petersdorf, E and Ringden, O and Kanakry, CG and Kanakry, JA and Stefanski, H and Arrieta-Bolaños, E and Betts, B and Benjamin, C and Gadalla, S and Wang, T and Saultz, J and Spellman, S and Jurdi, NE and Bolon, YT and Lee, SJ}, title = {Choosing Between HLA-Mismatched Unrelated and Haploidentical Donors: Donor Age Considerations.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.019}, pmid = {40419020}, issn = {2666-6367}, abstract = {Haploidentical donors and HLA-mismatched unrelated donors (MMUDs) are increasingly utilized for hematopoietic cell transplantation (HCT), with post-transplantation cyclophosphamide (PTCy) emerging as an effective graft-versus-host disease (GVHD) prophylaxis strategy. Despite the growing use of these donor types, comparative data to guide donor selection remain limited. Donor age is a known predictor of HCT outcomes, yet its specific impact when choosing between haploidentical and MMUD donors with PTCy-based prophylaxis has not been thoroughly explored. This study aimed to evaluate the influence of donor age on HCT outcomes in patients receiving haploidentical or MMUD HCT with PTCy-based GVHD prophylaxis, hypothesizing that younger donors (<30 years) would be associated with improved outcomes compared to older donors (≥30 years) regardless of donor type. We conducted a retrospective analysis of 7116 patients with hematologic malignancies from the Center for International Blood and Marrow Transplant Research database, transplanted between 2013 and 2021. Donors were categorized into four groups: younger haploidentical (<30 years), older haploidentical (≥30 years), younger MMUD (<30 years), and older MMUD (≥30 years). The primary outcome was GVHD-free relapse-free survival (GRFS), defined as the absence of grade III to IV acute GVHD, chronic GVHD requiring systemic immunosuppressive therapy (IST), relapse, or death. Secondary outcomes included overall survival, treatment-related mortality (TRM), relapse, grade III to IV acute GVHD, overall chronic GVHD, and chronic GVHD requiring IST. Comparisons were made between (1) younger MMUD versus older haploidentical and (2) younger haploidentical versus older MMUD groups using multivariable Cox proportional hazards models. In multivariable analysis, the older MMUD group exhibited inferior GRFS (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.06 to 1.36; P = .003), higher TRM (HR 1.49; 95% CI, 1.13 to 1.96; P = .005), and increased grade III to IV acute GVHD (HR 2.88; 95% CI, 1.43 to 5.80; P = .003) compared to the younger haploidentical group. The younger MMUD group had modest GRFS improvement over the older haploidentical group (HR 0.87; 95% CI, 0.78 to 0.98; P = .02) and significantly reduced risks of grade II to IV acute GVHD (HR 0.67; 95% CI, 0.51 to 0.88; P = .003) and chronic GVHD (HR 0.78; 95% CI, 0.65 to 0.94; P = .009). Younger donor age is associated with superior HCT outcomes, emphasizing the importance of prioritizing donors aged <30 years regardless of donor type when feasible.}, }
@article {pmid40415587, year = {2025}, author = {Yang, Z and Rizopoulos, D and Heijnsdijk, EAM and Newcomb, LF and Erler, NS}, title = {Personalized Biopsy Schedules Using an Interval-Censored Cause-Specific Joint Model.}, journal = {Statistics in medicine}, volume = {44}, number = {10-12}, pages = {e70134}, pmid = {40415587}, issn = {1097-0258}, support = {R21 CA253910/CA/NCI NIH HHS/United States ; CA253910/NH/NIH HHS/United States ; }, mesh = {Humans ; Biopsy/methods/statistics & numerical data ; *Prostatic Neoplasms/pathology/diagnosis ; Male ; Disease Progression ; *Precision Medicine/methods ; *Models, Statistical ; Computer Simulation ; Likelihood Functions ; Watchful Waiting ; }, abstract = {Active surveillance (AS), where biopsies are conducted to detect cancer progression, has been acknowledged as an efficient way to reduce the overtreatment of prostate cancer. Most AS cohorts use fixed biopsy schedules for all patients. However, the ideal test frequency remains unknown, and the routine use of such invasive tests burdens the patients. An emerging idea is to generate personalized biopsy schedules based on each patient's progression-specific risk. To achieve that, we propose the interval-censored cause-specific joint model (ICJM), which models the impact of longitudinal biomarkers on cancer progression while considering the competing event of early treatment initiation. The underlying likelihood function incorporates the interval-censoring of cancer progression, the competing risk of treatment, and the uncertainty about whether cancer progression occurred since the last biopsy in patients that are right-censored or experience the competing event. The model can produce patient-specific risk profiles up to a horizon time. If the risk exceeds a certain threshold, a biopsy is conducted. The optimal threshold can be chosen by balancing two indicators of the biopsy schedules: The expected number of biopsies and the expected delay in detection of cancer progression. A simulation study showed that our personalized schedules could considerably reduce the number of biopsies per patient by 41%-52% compared to the fixed schedules, though at the cost of a slightly longer detection delay.}, }
@article {pmid40414351, year = {2025}, author = {Ahmed, SO and El Fakih, R and Kharfan-Dabaja, MA and Syed, F and Mufti, G and Chabannon, C and Rondelli, D and Mohty, M and Al Ahmari, AA and Gauthier, J and Ruella, M and Perales, MA and Hashmi, S and Alfraih, F and Ghorashian, S and Alzahrani, M and Abba, Z and Koh, M and Pasquini, M and Ruggeri, A and Garderet, L and Albabtain, A and Weisdorf, D and Greinix, H and Samarkandi, H and Hamad, N and Atsuta, Y and Hamadani, M and Hari, P and Majhail, NS and Greco, R and Alzahrani, H and Sureda, A and Yakoub-Agha, I and Alahmari, AD and Niederwieser, D and Aljurf, M}, title = {Setting up a Chimeric Antigen Receptor T Cell Therapy Program: A Framework for Delivery from the Worldwide Network for Blood & Marrow Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.012}, pmid = {40414351}, issn = {2666-6367}, abstract = {Chimeric antigen receptor T cell (CAR-T) therapy is a genetically engineered cellular therapy that is currently integrated into the management of hematologic malignancies. Institutions treating patients with CAR-T therapy need to establish a framework of delivery that covers all the main components of the patient journey including intake of patients into the program from referring centers, patient selection according to established eligibility criteria, apheresis, logistics, bridging therapy, infusion, and postinfusion care. A CAR-T therapy program, with its unique requirements, needs to be delivered by a multidisciplinary team. Prior to the establishment of the program, a well-structured business plan should be developed with a clear financial and/or reimbursement model. Consideration should be given to overall capacity and staffing requirements. Standard operating procedures and guidelines are vital for ensuring that quality standards are clearly defined and adhered to. Institutions should develop a research plan for CAR-T therapy that may incorporate not only industry-sponsored trials, but also in-house manufacturing of investigational CAR-T products. This report presents recommendations from a group of international experts, highlighting the priorities and considerations when developing a new CAR-T program.}, }
@article {pmid40413188, year = {2025}, author = {Zanti, M and O'Mahony, DG and Parsons, MT and Dorling, L and Dennis, J and Boddicker, NJ and Chen, W and Hu, C and Naven, M and Yiangou, K and Ahearn, TU and Ambrosone, CB and Andrulis, IL and Antoniou, AC and Auer, PL and Baynes, C and Bodelon, C and Bogdanova, NV and Bojesen, SE and Bolla, MK and Brantley, KD and Camp, NJ and Campbell, A and Castelao, JE and Cessna, MH and Chang-Claude, J and Chen, F and Chenevix-Trench, G and , and Conroy, DM and Czene, K and De Nicolo, A and Domchek, SM and Dörk, T and Dunning, AM and Eliassen, AH and Evans, DG and Fasching, PA and Figueroa, JD and Flyger, H and Gago-Dominguez, M and García-Closas, M and Glendon, G and González-Neira, A and Grassmann, F and Hadjisavvas, A and Haiman, CA and Hamann, U and Hart, SN and Hartman, MBA and Ho, WK and Hodge, JM and Hoppe, R and Howell, SJ and , and Jakubowska, A and Khusnutdinova, EK and Ko, YD and Kraft, P and Kristensen, VN and Lacey, JV and Li, J and Lim, GH and Lindström, S and Lophatananon, A and Luccarini, C and Mannermaa, A and Martinez, ME and Mavroudis, D and Milne, RL and Muir, K and Nathanson, KL and Nuñez-Torres, R and Obi, N and Olson, JE and Palmer, JR and Panayiotidis, MI and Patel, AV and Pharoah, PDP and Polley, EC and Rashid, MU and Ruddy, KJ and Saloustros, E and Sawyer, EJ and Schmidt, MK and Southey, MC and Tan, VK and Teo, SH and Teras, LR and Torres, D and Trentham-Dietz, A and Truong, T and Vachon, CM and Wang, Q and Weitzel, JN and Yadav, S and Yao, S and Zirpoli, GR and Cline, MS and Devilee, P and Tavtigian, SV and Goldgar, DE and Couch, FJ and Easton, DF and Spurdle, AB and Michailidou, K}, title = {Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4852}, pmid = {40413188}, issn = {2041-1723}, support = {HHSN261201800009C/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; HHSN261201000091C/CA/NCI NIH HHS/United States ; HHSN261201800016C/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA064277/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; P50 CA116201/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; R01 CA264971/CA/NCI NIH HHS/United States ; U01 CA199277/CA/NCI NIH HHS/United States ; R01 CA225662/CA/NCI NIH HHS/United States ; R01 CA163353/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; HHSN261201800032C/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; NU58DP006344/DP/NCCDPHP CDC HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN261201800011C/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA098663/CA/NCI NIH HHS/United States ; HHSN261201800021C/CA/NCI NIH HHS/United States ; HHSN261201800016I/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; U01 CA164920/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN261201800015C/CA/NCI NIH HHS/United States ; HHSN261201800001C/CA/NCI NIH HHS/United States ; HHSN261201800031C/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U24 CA258058/CA/NCI NIH HHS/United States ; R01 CA185623/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; R01 CA100598/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Case-Control Studies ; *BRCA2 Protein/genetics ; *Breast Neoplasms/genetics ; *BRCA1 Protein/genetics ; Genetic Predisposition to Disease ; Genetic Testing ; Germ-Line Mutation ; Middle Aged ; }, abstract = {Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.}, }
@article {pmid40413129, year = {2025}, author = {Raychaudhuri, R and Cheng, HH and Gulati, R and Schweizer, MT and Lin, A and Yezefski, T and Khan, HM and Yu, EY and Hawley, JE and Nelson, PS and Pritchard, CC and Montgomery, B}, title = {Results from a Phase 2 Study of Induction Docetaxel and Carboplatin Followed by Maintenance Rucaparib in the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer with DNA Homologous Recombination Repair Deficiency.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.04.026}, pmid = {40413129}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: Our aim was to determine whether induction chemotherapy followed by PARP inhibitor (PARPi) maintenance improves outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring alterations in homologous recombination repair (HRR) genes in comparison to a historical control cohort treated with PARPi monotherapy.
METHODS: This single-arm, open-label, investigator-initiated phase 2 trial (NCT02985021) enrolled 18 patients with mCRPC with pathogenic alterations in HRR genes between 2018 and 2021 at a single center. Patients received four cycles of induction chemotherapy with docetaxel (60 mg/m[2]) and carboplatin (area under the curve 5) every 21 d, followed by maintenance rucaparib (600 mg twice daily) until progression or unacceptable toxicity. The primary outcome was radiographic progression-free survival (rPFS). Subsequent to study inception, multiple other studies reported alterations in genes of the BRCA complex (BRCA-C: BRCA1, BRCA2, PALB2) as most predictive of PARPi response; therefore, a post hoc analysis comparing patients with alterations in BRCA-C genes to a historical control cohort was performed.
KEY FINDINGS AND LIMITATIONS: After median follow-up of 40.3 mo (interquartile range 38.5-not reached [NR]), the median rPFS for all patients was 8.1 mo (95% confidence interval [CI] 6.5-31.2), similar to a historical control cohort treated with PARPi monotherapy. Among the 12 patients with BRCA-C alterations, median rPFS was 17.7 mo (95% CI 7.5-NR; p = 0.05). A key limitation is the single-arm design.
Induction platinum-based chemotherapy followed by maintenance PARPi therapy did not improve outcomes for patients with mCRPC broadly selected for HRR deficiency. However, results were promising in the more stringently selected group with BRCA-C gene alterations. Further studies comparing this approach to PARPi monotherapy are warranted.}, }
@article {pmid40412400, year = {2025}, author = {Leng, T and Kessou, L and Heitner, J and Guédou, FA and Béhanzin, L and Olodo, M and Diabaté, S and Silhol, R and Dimitrov, D and Vickerman, P and Alary, M and Boily, MC and Mitchell, KM}, title = {Potential impact and cost-effectiveness of oral HIV pre-exposure prophylaxis for men who have sex with men in Cotonou, Benin: a mathematical modelling study.}, journal = {The Lancet. Global health}, volume = {13}, number = {6}, pages = {e1111-e1121}, doi = {10.1016/S2214-109X(25)00098-1}, pmid = {40412400}, issn = {2214-109X}, mesh = {Humans ; Male ; *Cost-Benefit Analysis ; *Pre-Exposure Prophylaxis/economics/methods ; *HIV Infections/prevention & control/epidemiology ; Benin/epidemiology ; *Homosexuality, Male/statistics & numerical data ; Adult ; Models, Theoretical ; *Anti-HIV Agents/economics/administration & dosage/therapeutic use ; Administration, Oral ; Young Adult ; Middle Aged ; Adolescent ; }, abstract = {BACKGROUND: Oral HIV pre-exposure prophylaxis (PrEP) can effectively reduce HIV incidence. A 2020-21 demonstration project assessed the feasibility and health outcomes of offering oral PrEP to men who have sex with men (MSM) in Cotonou, Benin. We evaluated the epidemiological impact and cost-effectiveness of this project and the potential scale-up of oral HIV PrEP for MSM in Cotonou.
METHODS: We calibrated an HIV transmission-dynamic model structured by age and risk within a Bayesian framework to MSM-specific HIV prevalence and treatment data, parameterised with project behavioural and cost (including PrEP drug, implementation, and HIV care costs) data. We estimated the impact and cost-effectiveness of the 2020-21 Cotonou demonstration project (PrEP coverage, 5-10% of all MSM who are not living with HIV in Grand Cotonou; and adherence, 13-21% taking at least four of seven required doses [ie, at least four doses per week for daily users and at least four of seven expected doses given reported sexual activity for on-demand users]) and of its potential scale-up over 5 years (from 2022 to 2027), reaching 30% coverage of MSM in Grand Cotonou and with demonstration project adherence levels. We additionally modelled ideal PrEP adherence (100% taking at least four of seven required doses). We estimated the percentage of cumulative new HIV infections averted among participating MSM over 1 year and among all MSM in Grand Cotonou and their female partners over 20 years, and cost-effectiveness as cost per disability-adjusted life-year (DALY) averted over 20 years. Costs and DALYs were discounted 3% annually.
FINDINGS: We found that the demonstration project averted an estimated 21·5% (95% uncertainty interval 16·6 to 26·2) of HIV infections among participants over 1 year. With ideal adherence, cases that would be averted increased to 95·2% (90·8 to 98·8). A 5-year PrEP scale-up could avert 3·2% (1·6 to 4·8) of HIV infections among all MSM and female partners over 20 years, at US$388 (36 to 2792) per DALY averted. With ideal adherence, this decreased to -$28 (-126 to 589) per DALY averted.
INTERPRETATION: Low adherence to PrEP restricted the impact of the demonstration project. At 30% coverage among MSM by 2027, PrEP scale-up would be cost-effective at a $1225 threshold with 86·6% probability, and it could be more cost-effective if high adherence could be reached without substantially increasing costs.
FUNDING: Canadian Institutes of Health Research and US National Institutes of Health.
TRANSLATION: For the French translation of the abstract see Supplementary Materials section.}, }
@article {pmid40412394, year = {2025}, author = {Bansi-Matharu, L and Moolla, H and Citron, DT and Stover, J and Pickles, M and Martin-Hughes, R and Boily, MC and Nyirenda, R and Mudimu, E and Ten Brink, D and Johnson, LF and Mugurungi, O and Cambiano, V and Dimitrov, D and Smith, J and Glaubius, R and Taramusi, I and Mpofu, A and Phillips, A and Bershteyn, A}, title = {Identifying gaps in the HIV treatment cascade in Africa: a model comparison study.}, journal = {The Lancet. Global health}, volume = {13}, number = {6}, pages = {e1006-e1019}, doi = {10.1016/S2214-109X(25)00121-4}, pmid = {40412394}, issn = {2214-109X}, mesh = {Humans ; *HIV Infections/epidemiology/drug therapy/transmission ; Female ; Male ; Adult ; Adolescent ; Young Adult ; Middle Aged ; Malawi/epidemiology ; Zimbabwe/epidemiology ; South Africa/epidemiology ; *Anti-HIV Agents/therapeutic use ; Africa/epidemiology ; Incidence ; Prevalence ; }, abstract = {BACKGROUND: Although HIV incidence has considerably decreased in eastern, central, and southern Africa, new HIV infections continue to be a major public health challenge in the region. We aimed to investigate where in the HIV treatment cascade new transmissions are occurring in Malawi, Zimbabwe, and South Africa (the three countries involved in the Modelling to Inform HIV Programmes in Sub-Saharan Africa project).
METHODS: In this model comparison study, we used six well described and independently calibrated HIV transmission dynamics models that have been used to inform HIV policy in Africa (Optima HIV, EMOD, Goals, Thembisa, PopART-IBM, and HIV Synthesis) to estimate and predict the proportion of annual new HIV transmissions attributable to people living with HIV who are undiagnosed, have been diagnosed but have not yet started antiretroviral therapy (ART), are receiving ART, and have interrupted ART in Malawi, Zimbabwe, and South Africa from 2010 to 2040 stratified by the age and sex of the individual acquiring HIV.
FINDINGS: Despite the different model structures and underlying assumptions, the six models were well aligned in relation to key HIV epidemic characteristics (including population estimates and HIV prevalence) in each of the three settings. There was, however, considerable variation in the predicted number of new infections, particularly in Malawi and Zimbabwe where this number ranged from fewer than 10 000 new infections to over 30 000 new infections in 2024. Most model results suggested that the mean age of HIV acquisition has been increasing since 2000, with men acquiring HIV at an older age than women in all three settings. All models attributed fewer than 5% of transmissions to individuals who had been diagnosed but had not yet started ART. In Malawi, the proportion of transmissions attributable to undiagnosed people with HIV in 2024 ranged from 33·3% to 75·3% across the models, and transmissions attributable to individuals who had experienced interrupted treatment ranged from 8·4% to 20·1%. In Zimbabwe, the proportion of transmissions attributable to undiagnosed individuals in 2024 ranged from 29·8% to 64·6% across the models and the proportion of transmissions attributable to individuals who had interrupted treatment ranged from 4·7% to 21·5%. In South Africa, 21·8-46·4% of transmissions in 2024 were attributable to undiagnosed individuals and 27·6-58·9% of transmissions were attributable to individuals who had interrupted treatment.
INTERPRETATION: Across the three study settings, a substantial proportion of new HIV transmissions were attributable to undiagnosed individuals and people who have received interrupted ART, reinforcing the importance of continuing HIV testing and ART re-engagement and retention interventions.
FUNDING: The Bill & Melinda Gates Foundation.}, }
@article {pmid40411791, year = {2025}, author = {Heffner, JL and Baker, K and Georgiou, K and Graham, AL and Kelly, MM and Konstantinou, P and Lamprou, E and Lele, C and Lok, KZ and Orzechowski, M and Ruiz, RA and Serfozo, E and Karekla, M}, title = {ACT on Vaping: Pilot Randomized Controlled Trial of a Novel Digital Health App with Text Messaging for Young Adult Vaping Cessation.}, journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntaf112}, pmid = {40411791}, issn = {1469-994X}, abstract = {BACKGROUND: There is no published evidence to support the efficacy of any digital vaping cessation program for young adults (YAs) at differing levels of readiness to quit. In this pilot randomized controlled trial, we evaluated the preliminary acceptability and efficacy of a program for vaping cessation based on acceptance and commitment therapy (ACT on Vaping), delivered via a smartphone app and text messaging.
METHODS: YAs age 18-30 (n=61) were randomized 1:1 to ACT on Vaping (n=31) or incentivized text message control (n=30). Outcome data were collected at 3 months post-randomization. Results were compared against a priori benchmarks for acceptability (satisfaction of ≥ 3.5 on 5-point scale) and efficacy relative to control (meeting at least one of three): ≥ 1-point difference in Contemplation Ladder change scores; ≥ 5 percentage difference in 24-hour quit attempts, ≥ 5 percentage difference in cotinine-confirmed 30-day point prevalence abstinence (PPA) from all non-therapeutic nicotine/tobacco.
RESULTS: Satisfaction with ACT on Vaping averaged 3.8, exceeding the acceptability benchmark. A higher proportion of participants in the ACT on Vaping arm reported a 24-hour quit attempt (87.5% vs. 75.9%), exceeding the efficacy benchmark. Both change in quit readiness (+0.96 in ACT on Vaping vs. +0.72 in control) and cotinine-confirmed 30-day PPA (4.2% in ACT on Vaping vs. 0% in control) were descriptively higher for ACT on Vaping but did not reach the benchmark level for efficacy.
CONCLUSIONS: ACT on Vaping had promising acceptability and preliminary efficacy. A fully-powered trial of ACT on Vaping is warranted to evaluate its efficacy.
IMPLICATIONS: Digital interventions are a promising yet under-researched approach for reaching and supporting young adults to quit vaping. This proof-of-concept pilot randomized controlled trial evaluated a novel mobile health application and associated text messaging program (ACT on Vaping) for young adult vaping cessation and found preliminary evidence for acceptability and efficacy relative to an incentivized text message control arm, warranting evaluation in a fully-powered trial as a next step.}, }
@article {pmid40410231, year = {2025}, author = {Dhodapkar, KM and Castellino, S and Kapadia, S and Azeem, MI and Horvat, A and Lawrence, T and DeRyckere, D and Dhodapkar, MV}, title = {Immune-aging at diagnosis determines T-cell recovery in childhood leukemia survivors.}, journal = {npj aging}, volume = {11}, number = {1}, pages = {39}, pmid = {40410231}, issn = {2731-6068}, support = {R01 AR077926/AR/NIAMS NIH HHS/United States ; NIH CA238471/GF/NIH HHS/United States ; P30 CA138292/CA/NCI NIH HHS/United States ; R35CA197603/GF/NIH HHS/United States ; SCOR//Leukemia and Lymphoma Society/ ; R35 CA197603/CA/NCI NIH HHS/United States ; R01 CA238471/CA/NCI NIH HHS/United States ; }, abstract = {We show that T cells in survivors of childhood leukemia exhibit distinct profiles dominated by aging-associated changes and consistent with premature immune aging. Immune profiles during survivorship in biospecimens (n = 251) from uniformly-treated children with B-acute lymphoblastic leukemia recapitulate heterogeneity at diagnosis in individual patients and correlate with genetic-risk subtypes. These data suggest that pre-therapy immune aging may determine variance in immune status during survivorship.}, }
@article {pmid40409951, year = {2025}, author = {Thomas, AB and Van Son, CR and Nelson, LA and Fergadiotis, G and Barbosa-Leiker, C}, title = {A Principle-Based Concept Analysis of Supported Conversation for Adults With Aphasia.}, journal = {Research and theory for nursing practice}, volume = {}, number = {}, pages = {}, doi = {10.1891/RTNP-2024-0094}, pmid = {40409951}, issn = {1541-6577}, abstract = {Background and Purpose: Supported Conversation for Adults with Aphasia (SCA[™]), an evidence-based framework to improve communicative access, is a unique concept to nursing with theoretical and technical components. Effective communication is essential in all patient interactions, and SCA™ could aid health care professionals in meeting the needs of people with aphasia. Methods: A principle-based concept analysis was conducted using a systematic and conceptually driven literature search. A review of literature from 1998 to 2024 contained in CINAHL, PubMed, and PsycINFO databases was performed on the concept of SCA[™] The concept was explored for (a) definitional clarity (epistemological principle), (b) relevance to nursing (pragmatic principle), (c) consistency in meaning (linguistic principle), and (d) differentiation from related concepts (logical principle). Results: The final dataset consisted of 49 articles. Findings revealed that (a) SCA[™] is composed of theoretical and technical components used to acknowledge and reveal the competence of a person with aphasia, but there is a vague use and a lack of definitional clarity; (b) the philosophical framework and techniques outlined by the concept are relevant and useful for nursing; (c) there is variability in the use, nomenclature, and conceptualization of SCA[™]; and (d) the concept is poorly differentiated from other similar concepts. Implications for Practice: Nurses working with people diagnosed with aphasia and other communication disorders should consider SCA[™] and its application in nursing practice. Findings from this concept analysis stress the importance of an interdisciplinary approach to future SCA[™] studies, as nursing can lend its distinct viewpoint to integrate SCA[™] techniques into practice.}, }
@article {pmid40409691, year = {2025}, author = {Lee, SJ and Williams, KM and Sarantopoulos, S and Kitko, CL and Cutler, C and Pidala, J and Hill, GR and DeFilipp, Z and Greinix, HT and Wolff, D and Paczesny, S and Cuvelier, GDE and Schultz, KR and Pavletic, SZ}, title = {NIH Chronic Graft-Versus-Host Disease Consensus Conference 2025 Update.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.016}, pmid = {40409691}, issn = {2666-6367}, abstract = {In 2020, the third NIH Consensus Development Project on Criteria for Chronic Graft-versus-Host Disease (GVHD) Clinical Trials was held with the goals of identifying gaps in understanding, prevention and treatment of chronic graft-versus-host disease (GVHD) and making actionable recommendations that would advance the field. An interim meeting was held in October 2024 to review progress on the 2020 recommendations. Each group was charged with reviewing their previous recommendations, assessing whether the field is on track to eventually achieve the goals, and considering whether recommendations should be modified in light of new data or insufficient progress. This manuscript summarizes the Working Groups' reports and helps define the research agenda for future studies in chronic GVHD. Overall, modest progress has been made on most initiatives. Some studies in progress will address key recommendations and results are eagerly anticipated.}, }
@article {pmid40409689, year = {2025}, author = {Kampouri, E and Handley, G and Phan, TL and Lee, YJ and Shaw, R and Carpenter, PA and Dadwal, SS and Chemaly, RF and Papanicolaou, GA and Ogata, M and Boeckh, M and Zerr, DM and Hill, JA}, title = {American Society for Transplantation and Cellular Therapy Series #9: Management of Human Herpesvirus 6B After Hematopoietic Cell Transplantation and Chimeric Antigen Receptor-T-Cell Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.001}, pmid = {40409689}, issn = {2666-6367}, abstract = {The Practice Guidelines Committee and the Transplant Infectious Disease Special Interest Group of the American Society for Transplantation and Cellular Therapy developed guidelines focusing on human herpesvirus 6B (HHV-6B). A compendium-style approach was used to address a series of standalone frequently asked questions (FAQs), supported by tables and figures to spotlight key concepts. Adult and pediatric infectious disease and hematopoietic cell transplantation (HCT) content experts developed these FAQs and finalized recommendations after consensus was reached. This ninth topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to HHV-6B infections after HCT and chimeric antigen receptor-T-cell therapy.}, }
@article {pmid40409326, year = {2025}, author = {Wu, RL and Houser, KV and Gaudinski, MR and Widge, AT and Awan, SF and Carter, CA and Holman, LA and Saunders, J and Hendel, CS and Eshun, A and Whalen, WR and Wang, X and Arthur, A and Cunningham, JE and Beck, A and Casazza, JP and Yamshchikov, GV and Rothwell, RS and Strom, L and Dittakavi, T and Happe, M and Hickman, SP and Conan-Cibotti, M and Carlton, K and Zhang, L and Huang, Y and Capparelli, EV and Castro, M and Lin, BC and O'Connell, S and Flach, BS and Bailer, RT and Narpala, SR and Serebryannyy, L and McDermott, AB and Arnold, FJ and Gall, JG and Vazquez, S and Berkowitz, NM and Gordon, IJ and Chen, GL and Kwong, PD and Huang, J and Pierson, TC and Connors, M and Mascola, JR and Zhou, T and Doria-Rose, NA and Koup, RA and Dropulic, LK and , }, title = {Safety and pharmacokinetics of N6LS, a broadly neutralising monoclonal antibody for HIV: a phase 1, open-label, dose-escalation study in healthy adults.}, journal = {The lancet. HIV}, volume = {12}, number = {7}, pages = {e485-e495}, doi = {10.1016/S2352-3018(25)00041-4}, pmid = {40409326}, issn = {2352-3018}, mesh = {Humans ; Adult ; Male ; Female ; Young Adult ; *HIV Infections/drug therapy/immunology/prevention & control ; Healthy Volunteers ; *HIV Antibodies/administration & dosage/adverse effects/immunology ; *HIV-1/immunology ; Middle Aged ; Adolescent ; *Broadly Neutralizing Antibodies/administration & dosage/adverse effects ; *Antibodies, Neutralizing/administration & dosage/adverse effects/immunology ; *Antibodies, Monoclonal/administration & dosage/pharmacokinetics/adverse effects ; Injections, Subcutaneous ; }, abstract = {BACKGROUND: Broadly neutralising antibodies (bNAbs) have shown promise as both prevention and treatment strategies against HIV-1. The clinical effectiveness of bNAbs depends on enhancing their neutralisation breadth and extending their serum half-lives. In this study, we aimed to assess the safety, tolerability, pharmacokinetic profile, and neutralisation activity in serum of N6LS, a HIV-1 bNAb.
METHODS: In this first-in-human, dose-escalation, open-label, phase 1 trial, healthy adult participants (aged 18-50 years) who were HIV-1 negative were recruited to the National Institutes of Health Clinical Center (Bethesda, MD, USA). Three groups received one intravenous administration of N6LS at 5 mg/kg (n=3), 20 mg/kg (n=3), or 40 mg/kg (n=3); one group received one subcutaneous administration of 5 mg/kg N6LS (n=3); two groups received three administrations of either 5 mg/kg subcutaneous (n=5) or 20 mg/kg intravenous (n=5) N6LS every 12 weeks; and two groups received one subcutaneous administration of either 5 mg/kg (n=5) or 20 mg/kg (n=5) N6LS with ENHANZE drug product (EDP), recombinant human hyaluronidase PH20. The primary objectives were the safety and tolerability of N6LS with and without EDP. All participants who received N6LS were included in the primary safety analyses. This trial is registered at ClinicalTrials.gov, NCT03538626, and is complete.
FINDINGS: Between June 18, 2018, and April 11, 2022, we enrolled 33 healthy adults (19 female individuals and 14 male individuals). One participant did not receive N6LS and one participant was lost to follow-up after 8 weeks. N6LS had an encouraging safety profile similar to other HIV-1 bNAbs, with no serious adverse events. Local reactogenicity was observed after administration of N6LS, with the most common symptom being mild to moderate injection site pain or tenderness in subcutaneous groups, reported in six of eight participants. All ten participants who received N6LS with EDP had mild to severe injection site erythema, which, despite being graded as severe in size, was generally not noticed by participants or deemed bothersome, and resolved without intervention. Systemic reactogenicity was mild in all groups. N6LS had an overall mean serum half-life of 48·6 days and retained its broad and potent neutralisation characteristics in serum. EDP administration increased N6LS bioavailability. No functional anti-drug antibodies to N6LS were detected following administration.
INTERPRETATION: N6LS showed a promising safety and pharmacokinetics profile while retaining its potent neutralisation characteristics in serum, making it a promising candidate for inclusion in HIV-1 prevention and therapeutic combination strategies. The addition of EDP can enable safe subcutaneous administration of higher doses and larger volumes of N6LS, supporting additional methods for prophylactic and therapeutic bNAb administration.
FUNDING: US National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health.}, }
@article {pmid40408282, year = {2025}, author = {Marsh, TL and Johnston, JM and Homan, C and Townshend-Bulson, LJ and Kim, NJ and VoPham, T and Li, X and He, Q and McMahon, BJ and Ioannou, GN and Feng, Z}, title = {HCC surveillance in hepatitis C: A longitudinal algorithm improves alpha-fetoprotein screening.}, journal = {Hepatology communications}, volume = {9}, number = {6}, pages = {}, pmid = {40408282}, issn = {2471-254X}, support = {P20 CA252732/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *alpha-Fetoproteins/analysis/metabolism ; *Carcinoma, Hepatocellular/diagnosis/blood/virology ; *Algorithms ; *Liver Neoplasms/diagnosis/blood/virology ; Male ; Female ; Middle Aged ; *Hepatitis C/complications ; Bayes Theorem ; Sensitivity and Specificity ; Aged ; *Early Detection of Cancer/methods ; Alaska/epidemiology ; Liver Cirrhosis/blood ; Longitudinal Studies ; Adult ; *Hepatitis C, Chronic/complications/blood ; }, abstract = {BACKGROUND: Surveillance for HCC remains important after hepatitis C cure. Improved sensitivity of screening with alpha-fetoprotein (AFP) by using a parametric empirical Bayes (PEB) algorithm, which incorporates an individual patient's longitudinal AFP measurements, was previously demonstrated in a retrospective analysis of clinical trial data prior to widespread hepatitis C cure.
METHODS: We analyzed de-identified data extracted from the medical records of participants in the Alaska Hepatitis C Study, which aims to enroll all Alaska Native persons living in Alaska with a history of hepatitis C.We compared the performance characteristics of AFP as a screening test using the PEB method versus a fixed cutoff (FC) method in an observational setting, separately for HCC surveillance in active and cured hepatitis C.
RESULTS: The PEB and FC methods were applied to AFP levels from participants with F3/F4 fibrosis who had active hepatitis C (173 no HCC, 14 HCC) or after they achieved hepatitis C cure (162 no HCC, 12 HCC). Compared to a fixed 20 ng/mL cutoff, demonstrating 91.2% specificity in active hepatitis C, PEB increased sensitivity from 64.3% to 71.4%. After cure, a fixed 7.2 ng/mL cutoff demonstrated 91.2% specificity, and PEB increased sensitivity from 58.3% to 91.7%.
CONCLUSIONS: The PEB algorithm can increase sensitivity and lead to earlier detection of HCC among patients with F3/F4 fibrosis, both in active and even more so in cured hepatitis C. Lower AFP levels after cure indicate that for either PEB or FC methods, screening parameters, such as cutoffs for a target specificity, should be specified separately by hepatitis C treatment status for HCC surveillance.}, }
@article {pmid40407323, year = {2025}, author = {Landazuri Vinueza, J and Salisbury, NJH and Dye, KN and Roman, A and Galloway, DA}, title = {Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts.}, journal = {mBio}, volume = {16}, number = {6}, pages = {e0083225}, pmid = {40407323}, issn = {2150-7511}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; T32 AI083203/NH/NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/virology/genetics/pathology ; *Fibroblasts/virology/metabolism ; *Merkel cell polyomavirus/physiology/genetics ; *Cell Proliferation ; Cell Line, Tumor ; *Catenins/metabolism/genetics ; *Skin Neoplasms/virology ; Tumor Virus Infections/virology ; Virus Replication ; }, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen, and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-Catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that lysine-specific histone demethylase 1 (LSD1, also known as KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.IMPORTANCEMerkel cell polyomavirus (MCPyV), the only known human oncogenic polyomavirus, is the primary cause of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer. MCC is driven by two viral proteins: small T (ST) and large T (LT). While the virus can replicate in skin fibroblasts, it is still unknown which type of skin cell becomes cancerous. We found that ST binds to a host protein, δ-catenin in fibroblasts, potentially playing a role in the virus lifecycle, but this interaction is missing in the cancer cells. Our study provides evidence that the cells in which the virus replicates and causes cancer are different.}, }
@article {pmid40406922, year = {2025}, author = {, and Rautalin, I and Volovici, V and Stark, BA and Johnson, CO and Kaprio, J and Korja, M and Krishnamurthi, RV and Nair, BS and Ranta, A and Rinkel, GJE and Vergouwen, MDI and Abate, YH and Abbastabar, H and Abd-Allah, F and Abdelkader, A and Abdi, P and Abdollahi, A and Abdullahi, A and Abiodun, OO and Aboagye, RG and Abouzid, M and Abtahi, D and Abu Rumeileh, S and Abualhasan, A and Abualruz, H and Abukhadijah, HJ and Abu-Zaid, A and Adamu, LH and Addo, IY and Adedoyin, RA and Adegboye, OA and Adra, S and Adzigbli, LA and Agyemang-Duah, W and Ahinkorah, BO and Ahmad, A and Ahmad, D and Ahmadzade, AM and Ahmed, A and Ahmed, H and Ahmed, SA and Aji, B and Akkaif, MA and Al-Ajlouni, Y and Al-Aly, Z and Albashtawy, M and Ali, MU and Alif, SM and Alimohamadi, Y and Aljunid, SM and Alomari, MA and Alrawashdeh, A and Alsabri, MA and Salman, RA and Altaf, A and Al-Tammemi, AB and Alvis-Guzman, N and Alwafi, H and Al-Wardat, M and Al-Worafi, YM and Aly, H and Alyahya, MSI and Alzoubi, KH and Amani, R and Amin, TT and Amindarolzarbi, A and Amusa, GA and Anderlini, D and Angappan, D and Anil, A and Anuoluwa, BS and Anwar, S and Anyasodor, AE and Apostol, GLC and Arabloo, J and Areda, D and Ärnlöv, J and Artamonov, AA and Artanti, KD and Arumugam, A and Aryan, Z and Asghari-Jafarabadi, M and Ashemo, MY and Ashraf, T and Athar, M and Athari, SS and Aujayeb, A and Awotidebe, AW and Azadnajafabad, S and Aziz, S and Azzam, AY and Babu, GR and Bagheri, N and Bahrami Taghanaki, P and Bahramian, S and Bai, R and Baig, AA and Bako, AT and Baltatu, OC and Bam, K and Banach, M and Bandyopadhyay, S and Banik, B and Bardhan, M and Barker-Collo, SL and Bärnighausen, TW and Barqawi, HJ and Barua, L and Bastan, MM and Basu, S and Bell, SL and Bensenor, IM and Berhie, AY and Beyene, KA and Bhagavathula, AS and Bhaskar, S and Bhat, AN and Bhat, V and Bhatti, GK and Bhatti, JS and Bijani, A and Bikbov, B and Birhan, MM and Birhanu, MM and Bitra, VR and Boloor, A and Borhany, H and Breitner, S and Brenner, H and Bugiardini, R and Bulamu, NB and Butt, ZA and Cabral, LS and Caetano Dos Santos, FL and Calina, D and Cámera, LA and Campos, LA and Campos-Nonato, I and Capodici, A and Carvalho, F and Castañeda-Orjuela, CA and Catapano, AL and Cegolon, L and Chadwick, J and Chakraborty, C and Chakraborty, PA and Chakraborty, S and Chandika, RM and Chanie, GS and Chattu, VK and Chaudhary, AA and Chi, G and Chichagi, F and Ching, PR and Chopra, H and Choudhari, SG and Chowdhury, EK and Chu, DT and Chung, SC and Columbus, A and Criqui, MH and da Silva, AG and Dabbagh Ohadi, MA and Dadras, O and Dai, X and Dalal, K and Dalli, LL and D'Amico, E and Dashti, M and Davletov, K and De la Cruz-Góngora, V and Debopadhaya, S and Delgado-Enciso, I and Derviševic, E and Devanbu, VGC and Dewan, SMR and Dhane, AS and Dibas, M and Do, TC and Do, THP and Dohare, S and Doheim, MF and Dokova, KG and Dongarwar, D and D'Oria, M and Doshi, OP and Doshi, RP and Dowou, RK and Dsouza, HL and Dutta, S and Dziedzic, AM and E'mar, AR and Edvardsson, D and Efendi, D and Efendi, F and El Nahas, N and Elgendy, IY and Elhadi, M and Eltaha, C and Eltahir, ME and Emeto, TI and Fabin, N and Fagbamigbe, AF and Fahim, A and Fakhradiyev, IR and Fares, J and Faris, PS and Fauk, NK and Fazylov, T and Fekadu, G and Ferreira, N and Fetensa, G and Fischer, F and Foschi, M and Fridayani, NKY and Gaipov, A and Gajjar, AA and Gandhi, AP and Ganesan, B and Garg, RK and Gebregergis, MW and Gebrehiwot, M and Gebremeskel, TG and Getie, M and Ghadimi, DJ and Ghadirian, F and Ghahramani, S and Ghasemzadeh, A and Ghazy, RM and Gholamalizadeh, M and Ghozy, S and Gil, AU and Gilani, JA and Gnedovskaya, EV and Goleij, P and Goulart, AC and Goulart, BNG and Guan, SY and Gupta, S and Habibzadeh, F and Hadei, M and Hadi, NR and Hamidi, S and Hanifi, N and Hankey, GJ and Harlianto, NI and Haro, JM and Hasan, F and Hasani, H and Hasnain, MS and Hassan Zadeh Tabatabaei, MS and Haubold, J and Havmoeller, RJ and Hay, SI and Hbid, Y and Heidari, G and Heidari, M and Hemmati, M and Hiraike, Y and Hoan, NQ and Holla, R and Hosseinzadeh, M and Hostiuc, S and Huang, J and Huynh, HH and Hwang, BF and Ibitoye, SE and Ikeda, N and Ikiroma, A and Ilaghi, M and Ilesanmi, OS and Ilic, IM and Ilic, MD and Islam, MR and Ismail, NE and Iso, H and Isola, G and Iwagami, M and Jacob, L and Jafarzadeh, A and Jain, A and Jairoun, AA and Jakovljevic, M and Jatau, AI and Jawaid, T and Jayapal, SK and Jonas, JB and Joseph, N and Jürisson, M and Kadashetti, V and Kalani, R and Kamal, VK and Kamireddy, A and Kanchan, T and Kandel, H and Karami, J and Karaye, IM and Karimi, Y and Karimi Behnagh, A and Kashoo, FZ and Kayode, GA and Kazemi, F and Kesse-Guyot, E and Khader, YS and Khaing, IK and Khan, F and Khan, MJ and Khatatbeh, H and Khatatbeh, MM and Khayat Kashani, HR and Kheirallah, KA and Khidri, FF and Khormali, M and Khosla, AA and Kim, K and Kim, YJ and Kisa, A and Kisa, S and Kivimäki, M and Kolahi, AA and Kompani, F and Korzh, O and Kostev, K and Kothari, N and Krishan, K and Krishna, V and Krishnamoorthy, V and Kuddus, M and Kulimbet, M and Kunutsor, SK and Kurniasari, MD and Kusuma, D and Kytö, V and La Vecchia, C and Lahariya, C and Lai, DTC and Lai, H and Laksono, T and Lallukka, T and Latief, K and Latifinaibin, K and Le, NHH and Le, TTT and Lee, M and Lee, SW and Lee, WC and Lee, YH and Lenzi, J and Leonardi, M and Li, MC and Li, X and Lim, SS and Lin, J and Liu, X and Lohner, V and Lorenzovici, L and Lotufo, PA and Lucchetti, G and Lusk, JB and Lutzky Saute, R and M Amin, HI and Malhotra, AK and Malhotra, K and Malik, AA and Malta, DC and Mansournia, MA and Mantovani, LG and Manu, E and Marateb, HR and Marino, M and Maroufi, SF and Martinez-Piedra, R and Martini, S and Martorell, M and Marzo, RR and Mathangasinghe, Y and Mathews, E and Maugeri, A and McPhail, SM and Mehmood, A and Mehndiratta, MM and Mehrabani-Zeinabad, K and Menezes, RG and Meo, SA and Meretoja, A and Mestrovic, T and Mettananda, CDK and Miazgowski, T and Micheletti Gomide Nogueira de Sá, AC and Minervini, G and Minh, LHN and Mirica, A and Mirrakhimov, EM and Mirza-Aghazadeh-Attari, M and Mishra, AK and Mithra, P and Mohamed, AZ and Mohamed, AI and Mohammad, AM and Mohammadi, S and Mohammadian-Hafshejani, A and Mohammed, S and Mokdad, AH and Molinaro, S and Momani, S and Moni, MA and Moodi Ghalibaf, A and Moradi, M and Moradi, Y and Moraga, P and Morawska, L and Msherghi, A and Munjal, K and Murray, CJL and Nagarajan, AJ and Naik, GR and Najdaghi, S and Nakhostin Ansari, N and Nargus, S and Davani, DN and Natto, ZS and Nauman, J and Nayak, VC and Nazri-Panjaki, A and Negoi, RI and Nematollahi, S and Newton, CRJ and Nguyen, DH and Nguyen, HTH and Nguyen, HQ and Nguyen, PT and Nguyen, VT and Niazi, RK and Nigatu, YT and Nikoobar, A and Nogueira de Sá, AT and Nomura, S and Noubiap, JJ and Nugen, F and Nzoputam, CI and Oancea, B and Oduro, MS and Ojo-Akosile, TR and Okati-Aliabad, H and Okeke, SR and Okekunle, AP and Olagunju, AT and Olaiya, MT and Oliveira, AB and Oliveira, GMM and Olorukooba, AA and Olufadewa, II and Ornello, R and Ortiz-Prado, E and Osuagwu, UL and Ouyahia, A and Owolabi, MO and Ozair, A and P A, MP and Padron-Monedero, A and Padubidri, JR and Panagiotakos, D and Panos, GD and Panos, LD and Pantazopoulos, I and Parikh, RR and Park, S and Patel, J and Patel, UK and Patoulias, D and Pedersini, P and Peprah, EK and Pereira, G and Perianayagam, A and Perico, N and Perna, S and Petermann-Rocha, FE and Philip, AK and Piradov, MA and Plotnikov, E and Polibin, RV and Postma, MJ and Pradhan, J and Prasad, M and Puvvula, J and Qasim, NH and Qian, G and Raggi, A and Rahim, F and Rahimi-Movaghar, V and Rahman, M and Rahman, MA and Rahmani, AM and Rahmanian, M and Rajaa, S and Rajabpour Sanati, A and Rajpoot, PL and Rajput, P and Ramadan, MM and Ramasamy, SK and Ramazanu, S and Rane, A and Rashedi, S and Rashidi, MM and Rathish, D and Rawaf, S and Razo, C and Reddy, MMRK and Redwan, E and Remuzzi, G and Rezaei, N and Rezaei, N and Rezaeian, M and Rocha, HAL and Rodriguez, JAB and Roever, L and Romoli, M and Romozzi, M and Ross, AG and Rout, HS and Roy, N and Roy, P and Saad, AMA and Saadatian, Z and Sabour, S and Sacco, S and Saddik, BA and Sadeghi, E and Saeed, U and Saheb Sharif-Askari, F and Sahebkar, A and Sahoo, PM and Sajib, MRUZ and Salaroli, LB and Saleh, MA and Samodra, YL and Samuel, VP and Samy, AM and Santric-Milicevic, MM and Saravanan, A and Sarkar, T and Sarode, GS and Sarode, SC and Sartorius, B and Satpathy, M and Schlaich, MP and Schneider, IJC and Schuermans, A and Selvaraj, S and Senthilkumaran, S and Sepanlou, SG and Sethi, Y and Seylani, A and Shaaban, AN and Shafie, M and Shahwan, MJ and Shaikh, MA and Shaikh, SZ and Shamim, MA and Shamsi, A and Shamsutdinova, A and Shanawaz, M and Shannawaz, M and Sharifan, A and Sharifi Rad, J and Sharma, V and Shashamo, BB and Shetty, M and Shetty, PK and Shigematsu, M and Shittu, A and Shiue, I and Shlobin, NA and Shorofi, SA and Siddig, EE and Singh, B and Singh, P and Singh, P and Singh, S and Sobia, F and Solanki, R and Solanki, S and Soraneh, S and Spartalis, M and Srinivasamurthy, SK and Stanaway, JD and Stanikzai, MH and Starodubova, AV and Sun, J and Sun, Z and Swain, CK and Szarpak, L and Tabaee Damavandi, P and Tabatabaei, SM and Tabatabaeizadeh, SA and Tabche, C and Taiba, J and Talaat, IM and Tamuzi, JL and Tan, KK and Temsah, MH and Teramoto, M and Thakur, R and Thankappan, KR and Thayakaran, R and Thirunavukkarasu, S and Ticoalu, JHV and Tiwari, K and Tonelli, M and Topor-Madry, R and Tovani-Palone, MR and Tran, AT and Tran, JT and Tran, TH and Tran Minh Duc, N and Truelsen, TC and Truyen, TTTT and Tsai, DH and Ullah, A and Unim, B and Unnikrishnan, B and Unsworth, CA and Usman, JS and Vahdati, S and Vaithinathan, AG and Valizadeh, R and Van den Eynde, J and Varghese, J and Vasankari, TJ and Venketasubramanian, N and Vervoort, D and Villafañe, JH and Vinayak, M and Vladimirov, SK and Wafa, HA and Waheed, Y and Wahood, W and Walde, MT and Wang, Y and Wickramasinghe, ND and Willeit, P and Wolde, AA and Wolfe, CDA and Wubie, YM and Xiao, H and Xu, S and Xu, X and Yamagishi, K and Yano, Y and Yarahmadi, A and Yaribeygi, H and Yaya, S and Ye, P and Yon, DK and Yonemoto, N and Yu, C and Zanghì, A and Zare, I and Zastrozhin, M and Zhang, C and Zhang, Y and Zhang, ZJ and Zhang, Z and Zhao, H and Zhou, SC and Zhumagaliuly, A and Zia, H and Zielinska, M and Zyoud, SH and Roth, GA and Feigin, VL}, title = {Global, Regional, and National Burden of Nontraumatic Subarachnoid Hemorrhage: The Global Burden of Disease Study 2021.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2025.1522}, pmid = {40406922}, issn = {2168-6157}, support = {001/WHO_/World Health Organization/International ; }, abstract = {IMPORTANCE: Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure.
OBJECTIVE: To estimate the worldwide burden of SAH.
Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021.
EXPOSURES: SAH and 14 modifiable risk factors.
MAIN OUTCOMES AND MEASURES: Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs).
RESULTS: In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution.
CONCLUSIONS AND RELEVANCE: Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.}, }
@article {pmid40405591, year = {2025}, author = {Feng, E and Feng, E and Berg, T and Nguyen, IS and Nguyen, LG and Chen, W and Zhang, M and Quigley, D and Sharifi, M and Li, H and Coleman, I and Nelson, PS and Sjöström, M and Zhao, SG}, title = {Identifying prognostic targets in metastatic prostate cancer beyond AR.}, journal = {FEBS open bio}, volume = {}, number = {}, pages = {}, doi = {10.1002/2211-5463.70059}, pmid = {40405591}, issn = {2211-5463}, support = {1DP2CA271832-01/GF/NIH HHS/United States ; P50CA097186/GF/NIH HHS/United States ; R50CA274336/GF/NIH HHS/United States ; PC190039//DoD/ ; PC210122//DoD/ ; PC200334//DoD/ ; PC230420//DoD/ ; //Institute for Prostate Cancer Research/ ; //Prostate Cancer Foundation/ ; //Swedish Cancer Society (Cancerfonden)/ ; //Swedish Prostate Cancer Foundation (Prostatacancerförbundet)/ ; //Hjelms Stiftelse för Medicinsk Forskning/ ; }, abstract = {Genome-wide screens using CRISPR/RNAi can identify new therapeutic vulnerabilities in prostate cancer. In this study, we combine DepMap functional screen data with a large gene expression database (N = 1012) and clinical outcomes to identify potentially druggable targets. Eight genes (CYC, CYP51A1, DHFR, EBP, KIF15, PPM1D, SQLE, and UMPS) demonstrated strong dependency in cell lines and were also associated with worse prognosis clinically, representing potential therapeutic targets in metastatic prostate cancer. Four of these (DHFR, EBP, KIF15, and PPM1D) demonstrated higher expression in neuroendocrine prostate cancer. Furthermore, all but one (KIF15) were not significantly decreased from pretreatment to posttreatment, suggesting that they may remain targetable postabiraterone therapy. All eight genes showed evidence of protein expression in prostate cancers or cell lines. These potentially druggable targets associated with prostate cancer cell line dependency and worse clinical outcomes have also demonstrated literature support as potential targets, supporting further research into their potential clinical relevance as therapeutic targets in prostate cancer.}, }
@article {pmid40404994, year = {2025}, author = {Jones, DC and Elz, AE and Hadadianpour, A and Ryu, H and Glass, DR and Newell, EW}, title = {Cell simulation as cell segmentation.}, journal = {Nature methods}, volume = {22}, number = {6}, pages = {1331-1342}, pmid = {40404994}, issn = {1548-7105}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; U19AI128914//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 CA264646/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; Computer Simulation ; CD8-Positive T-Lymphocytes/metabolism ; Carcinoma, Renal Cell/pathology/immunology/genetics ; Lymphocytes, Tumor-Infiltrating ; Kidney Neoplasms/pathology/genetics/immunology ; Algorithms ; Tumor Microenvironment ; Gene Expression Profiling/methods ; Chemokine CXCL13/metabolism ; Computational Biology/methods ; Transcriptome ; Neutrophils ; }, abstract = {Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render these data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation, in a method called Proseg (probabilistic segmentation), to rapidly infer morphologically plausible cell boundaries. Benchmarking applied to datasets generated by three commercial platforms shows superior performance and computational efficiency of Proseg when compared to existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult-to-segment tumor-infiltrating immune cells such as neutrophils and T cells. Last, through improvements in our ability to delineate subsets of tumor-infiltrating T cells, we show that CXCL13-expressing CD8[+] T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from samples from patients with renal cell carcinoma.}, }
@article {pmid40404528, year = {2025}, author = {Lee, W and Chung, JY and Baidoo, KE and Nambiar, D and Basuli, F and Coleman, I and Bakht, M and Li, C and Shin, J and Jeong, SU and Cho, YM and Beltran, H and Nelson, PS and Sowalsky, AG and Choyke, PL and Escorcia, FE}, title = {Glypican-3 as a Radiotheranostic Target for Neuroendocrine Prostate Cancer.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.05.007}, pmid = {40404528}, issn = {1873-7560}, }
@article {pmid40403387, year = {2025}, author = {Mahalingam, D and Saeed, A and Powell, SF and Huerta, M and Sahai, V and Coveler, AL and Davis, EJ and Steeghs, N and Mulcahy, M and Raufi, AG and Cavalcante, L and Cervantes, A and Berlin, J and Weisskittel, T and Ugolkov, A and Mazar, AP and Mikrut, W and Smith, S and Giles, FJ and Carneiro, BA}, title = {Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine plus nab-paclitaxel in previously untreated metastatic pancreatic cancer.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105122}, pmid = {40403387}, issn = {2059-7029}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Albumins/administration & dosage ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; *Carcinoma, Pancreatic Ductal/drug therapy ; *Deoxycytidine/administration & dosage/analogs & derivatives ; Gemcitabine ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors ; Neoplasm Metastasis ; *Paclitaxel/administration & dosage ; *Pancreatic Neoplasms/drug therapy/pathology/mortality ; }, abstract = {INTRODUCTION: The purpose of this study was to assess the efficacy and safety of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine/nab-paclitaxel (GnP) in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
MATERIAL AND METHODS: In a nonrandomized, Simon's two-stage, phase II study, patients with mPDAC received elraglusib 15 mg/kg on days 1 and 4 each week and GnP on days 1, 8, and 15 in a 28-day cycle. The primary endpoint was disease control rate (DCR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs).
RESULTS: A total of 42 patients, who were enrolled and treated, had a median age of 67 years and were 57.1% male. Overall, 38 patients received elraglusib at 15 mg/kg and 4 at 9.3 mg/kg with GnP. DCR was 35.7% [95% confidence interval (CI) 21.6% to 52.0%], and ORR was 26.2%. The median PFS and OS were 5.4 months (95% CI 4.4-9.2 months) and 11.9 months (95% CI 7.8-16.5 months), respectively. Most common TEAEs were visual impairment (83.3%), fatigue (69%), and nausea (66.7%). Grade ≥3 TEAEs occurred in 85.7% of patients and included neutropenia (52.4%), leukopenia (42.9%), and fatigue (21.4%). The dose of elraglusib was reduced to 9.3 mg/kg due to increased exacerbation of GnP-related toxicities and frequent dose interruptions and reductions of elraglusib.
CONCLUSIONS: Elraglusib/GnP showed preliminary clinical activity. In terms of safety, elraglusib resulted in a modest exacerbation of GnP-related toxicities, leading to a dose reduction of elraglusib to 9.3 mg/kg twice a week. Based on the initial efficacy and safety data, the study was amended to a randomized phase II study that will evaluate the 9.3 mg/kg dose.}, }
@article {pmid40402477, year = {2025}, author = {Li, T and Su, YR and Lee, JM and O'Meara, ES and Miglioretti, DL and Kerlikowske, K and Henderson, L and Houssami, N}, title = {Tomosynthesis vs Digital Mammography Screening in Women with a Family History of Breast Cancer.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {40402477}, issn = {2374-2445}, abstract = {IMPORTANCE: Evidence on screening outcomes with digital breast tomosynthesis (DBT) vs digital mammography (DM) in women with a family history of breast cancer is limited.
OBJECTIVE: To compare the performance of DBT and DM screening in women with a family history of breast cancer overall and subdivided by breast cancer family history category, breast density, age group, screening interval, and screening round, and to describe characteristics of cancers detected on screening vs interval cancers.
In this comparative cohort study at imaging facilities affiliated with the Breast Cancer Surveillance Consortium, adult women 18 years and older with a self-reported family history of breast cancer who underwent DBT or DM from 2011 to 2018 were included, with a 1-year follow-up for breast carcinoma. Data analysis was performed between November 2023 and August 2024.
EXPOSURES: DBT or DM.
MAIN OUTCOMES AND MEASURES: The main outcomes were absolute risk difference (ARD) between DBT and DM for recall rate, cancer detection rate, interval cancer rate, advanced cancer rate, biopsy rate, positive predictive values, sensitivity, and specificity, with inverse probability of treatment weighting.
RESULTS: A total of 208 945 women with a family history of breast cancer undergoing 502 357 screening examinations were included in the sample. Median (IQR) age was 58 (50-66) and 57 (49-66) years for the DBT and DM groups, respectively. Adjusted ARDs (DBT vs DM) were significant for recall rate (-1.51%; 95% CI, -2.42% to -0.59%) and specificity (1.56%; 95% CI, 0.65%-2.46%) in the overall cohort of 121 698 DBT and 380 561 DM examinations and among women with 1 first-degree relative (recall rate ARD, -1.72%; 95% CI, -2.70% to -0.74%; specificity ARD, 1.75%; 95% CI, 0.81%-2.69%). Among those with only second-degree relatives, the biopsy rate for DBT was significantly higher (ARD, 0.39%; 95% CI, 0.18%-0.61%). Significant ARDs were observed for the ductal carcinoma in situ detection rate (-0.71 per 1000 examinations; 95% CI, -1.03 to -0.38 per 1000 examinations) in women with almost entirely fatty breasts; recall rate (-1.90%; 95% CI, -2.88% to -0.92%) and specificity (1.93%; 95% CI, 0.97%-2.89%) in women with scattered fibroglandular densities. Significant ARDs were also observed for the positive predictive value for recall (1.75%; 95% CI, 0.84%-2.67%) in heterogeneously dense breasts, as well as the biopsy rate (0.48%; 95% CI, 0.16%-0.80%) and advanced cancer rate (-0.61 per 1000 examinations; 95% CI, -1.02 to -0.20 per 1000 examinations) in extremely dense breasts. DBT screening had a higher proportion than DM of screen-detected early-stage, invasive cancers with favorable prognostic characteristics.
CONCLUSIONS AND RELEVANCE: In this cohort study of women with a family history of breast cancer, DBT screening reduced recall rates and increased specificity compared to DM, particularly in women with 1 first-degree relative with breast cancer and those with scattered fibroglandular breast density, and reduced advanced cancer rates in women with extremely dense breasts.}, }
@article {pmid40402042, year = {2025}, author = {Moosavi, D and Curtis, KR and Randolph, TW and Kahsai, OJ and Ammar, H and Lim, U and Cheng, I and Wilkens, LR and Le Marchand, L and Lampe, JW and Hullar, MAJ}, title = {Stability and Variability of the Human Fecal Microbiome Over Two Years in the Multiethnic Cohort Study: A Metagenomic Analysis.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1770}, pmid = {40402042}, issn = {1538-7755}, abstract = {BACKGROUND: Understanding the longitudinal variability of the gut microbiome is essential for advancing microbiome-based measurements and designing robust sampling protocols in observational and intervention studies of cancer and other health outcomes. The aim of this study was to explore the temporal variability and stability of the fecal microbiome over a 2-year period, using intraclass correlation (ICC) analysis of metagenomic sequencing data.
METHODS: We studied 25 older adults from the Multiethnic Cohort Adiposity Phenotype Study (MEC-APS, 2013-2016). Stool samples were collected every six months over a two-year period (5 samples) and analyzed using metagenomic sequencing. The temporal stability was evaluated using ICCs across taxonomic levels, diversity, and functional genes and pathways.
RESULTS: The microbial community showed stability in alpha diversity and overall structure, with no significant changes across time points (Shannon diversity, p = 0.95). Taxonomic composition showed strong reliability over time, with median ICCs of 0.7 at the genus level and 0.75 at species level. Functional genes also demonstrated good stability (median ICC = 0.68). However, microbial pathways were more variable, with a fair median ICC of 0.49.
CONCLUSION: While the fecal microbiome was generally stable, some taxa and functions were more dynamic and responsive to external influences.
IMPACT: Findings highlight the need for reliable microbiome measurements and sampling strategies to reduce bias in studies of the microbiome and cancer.}, }
@article {pmid40399683, year = {2025}, author = {Rademaker, G and Hernandez, GA and Seo, Y and Dahal, S and Miller-Phillips, L and Li, AL and Peng, XL and Luan, C and Qiu, L and Liegeois, MA and Wang, B and Wen, KW and Kim, GE and Collisson, EA and Kruger, SF and Boeck, S and Ormanns, S and Guenther, M and Heinemann, V and Haas, M and Looney, MR and Yeh, JJ and Zoncu, R and Perera, RM}, title = {PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40399683}, issn = {1476-4687}, abstract = {To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs[1]. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines[2], in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates-7-dehydrocholesterol and 7-dehydrodesmosterol-with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.}, }
@article {pmid40399555, year = {2025}, author = {Lammi, V and Nakanishi, T and Jones, SE and Andrews, SJ and Karjalainen, J and Cortés, B and O'Brien, HE and Ochoa-Guzman, A and Fulton-Howard, BE and Broberg, M and Haapaniemi, HH and Kanai, M and Pirinen, M and Schmidt, A and Mitchell, RE and Mousas, A and Mangino, M and Huerta-Chagoya, A and Sinnott-Armstrong, N and Cirulli, ET and Vaudel, M and Kwong, ASF and Maiti, AK and Marttila, MM and Posner, DC and Rodriguez, AA and Batini, C and Minnai, F and Dearman, AR and Warmerdam, CAR and Sequeros, CB and Winkler, TW and Jordan, DM and Rešcenko, R and Miano, L and Lane, JM and Chung, RK and Guillen-Guio, B and Leavy, OC and Carvajal-Silva, L and Aguilar-Valdés, K and Frangione, E and Guare, L and Vergasova, E and Marouli, E and Striano, P and Zainulabid, UA and Kumar, A and Ahmad, HF and Edahiro, R and Azekawa, S and , and , and , and , and , and , and , and , and , and Luoh, SW and Erikstrup, C and Pedersen, OBV and Lerner-Ellis, J and Colombo, A and Grzymski, JJ and Ishii, M and Okada, Y and Beckmann, ND and Kumari, M and Wagner, R and Heid, IM and John, C and Short, PJ and Magnus, P and Ansone, L and Valenti, LVC and Lee, SA and Wain, LV and Verdugo, RA and Banasik, K and Geller, F and Franke, LH and Rakitko, A and Duncan, EL and Renieri, A and Tsilidis, KK and de Cid, R and Niavarani, A and Abner, E and Tusié-Luna, T and Verma, SS and Smith, GD and Timpson, NJ and Madduri, RK and Cho, K and Daly, MJ and Ganna, A and Schulte, EC and Richards, JB and Ludwig, KU and Marks-Hultström, M and Zeberg, H and Ollila, HM}, title = {Genome-wide association study of long COVID.}, journal = {Nature genetics}, volume = {57}, number = {6}, pages = {1402-1417}, pmid = {40399555}, issn = {1546-1718}, support = {S10 OD026880/OD/NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; S10 OD030463/OD/NIH HHS/United States ; R01 AI170850/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study ; *COVID-19/genetics ; SARS-CoV-2 ; *Forkhead Transcription Factors/genetics ; Polymorphism, Single Nucleotide ; Male ; Female ; Genetic Predisposition to Disease ; Case-Control Studies ; Pandemics ; Middle Aged ; *Pneumonia, Viral/genetics ; Post-Acute COVID-19 Syndrome ; }, abstract = {Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.}, }
@article {pmid40398621, year = {2025}, author = {Spellman, SR and Xu, K and Oloyede, T and Ahn, KW and Akhtar, O and Bolon, YT and Broglie, L and Bloomquist, J and Bupp, C and Chen, M and Devine, SM and El-Jurdi, N and Hamadani, M and Hengen, M and Huppler, AH and Jaglowski, S and Kuxhausen, M and Lee, SJ and Moskop, A and Page, KM and Pasquini, MC and Perez, W and Phelan, R and Rizzo, D and Saber, W and Stefanski, HE and Steinert, P and Tuschl, E and Visotcky, A and Vogel, R and Auletta, JJ and Shaw, BE and Allbee-Johnson, M}, title = {Current Activity Trends and Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy - A Report from the CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.014}, pmid = {40398621}, issn = {2666-6367}, abstract = {The Center for International Blood and Marrow Transplant Research (CIBMTR) compiles annual summary slides describing trends in hematopoietic cell transplantation (HCT) and cellular therapy (CT) practice and outcomes. This year's report includes all patients receiving their first autologous and/or allogeneic HCT/CT in the United States between 2013 and 2023 or chimeric antigen receptor T-cell (CAR-T) therapy from 2016 and 2023, reported to the CIBMTR. A relative proportion of allogeneic and autologous HCT/CT was generated as percentage of total for donor type and for patient age, disease indication, graft-versus-host disease (GVHD) prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. New for this year, disease risk stratification reflects the European LeukemiaNet cytogenetic risk score for acute myeloid leukemia (AML) and the Revised International Prognostic Scoring System for myelodysplastic syndromes (MDS). Use of allogeneic HCT increased substantially in 2023, recovering from a decline in activity during the COVID-19 pandemic, with growth predominately in the 65- to 74-year-old age group. Overall, matched unrelated donors (MUDs) continue to be the most common allogeneic donor source (45%) followed by haploidentical related donors (Haplo; 21%), matched related donors (MRDs; 18%), mismatched unrelated donors (MMUDs; (12%), and cord blood (Cord; 3%). These trends hold in the adult patient population, with a notable doubling of MMUD utilization since 2020 driven by the rapid shift to post-transplantation cyclophosphamide-based GVHD prophylaxis (PTCy) in this setting. In the pediatric setting, Haplo was the most common donor source, surpassing MRD use in 2023 followed by MUD, Cord, and MMUD use. Autologous HCT continued to decline slightly, whereas use of CAR-T therapy has rapidly increased since commercial approval in 2017, with lymphoma and multiple myeloma reaching 45% and 16%, respectively, in 2023. Significant recent changes in GVHD prophylaxis in the adult allogeneic HCT setting have occurred. PTCy is most common in Haplo HCT with >90% since 2016. Among other donor sources, the most rapid adoption is in MMUD HCT at 82% in 2023. In MRDs and MUDs, PTCy use differs by conditioning intensity, with non-myeloablative/reduced-intensity conditioning (NMA/RIC) higher (58% and 64%, respectively), reflecting the standard of care established by BMT CTN 1703, compared with myeloablative (MAC; 43% and 46%, respectively). In pediatrics, calcineurin inhibitor ± others remains the most common GVHD prevention strategy for use of MRDs (88%) and MUDs (68%). Although common in the pediatric Haplo HCT setting at 68% in 2023, use of PTCy is less common across other mismatched donor types in which use of abatacept or ex-vivo T-cell depletion/CD34 selection accounts for 28% and 17% in MMUDs, respectively. Three-year overall survival continues to significantly improve among patients receiving allogeneic (62.1% vs. 55.8%) and autologous (82.6% vs. 79.6%) HCT when comparing HCT from 2017 to 2022 versus 2012 to 2016 (P < .001), respectively. In both the adult and pediatric settings, primary cause of mortality after 100 days post-HCT remains primary disease in both allogeneic (47% and 45%, respectively) and autologous (60% and 79%, respectively). HCT/CT and CAR-T use continues to grow. Relapse remains the primary cause of death in the malignant setting, supporting further efforts to mitigate risk.}, }
@article {pmid40398620, year = {2025}, author = {Burleigh, K and Stratton, KG and Smith, JL and Jensen, MC and Turtle, CJ and Keenan, C and Annesley, C and Summers, C and Webb-Robertson, BJ and Hirayama, AV and Gardner, RA and Gustafson, HH}, title = {Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, pmid = {40398620}, issn = {2666-6367}, abstract = {CD19 chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, approximately 20% of patients fail to achieve a complete remission (CR), and some develop severe, life-threatening toxicities. Understanding the biological mechanisms underlying both dysfunctional responses and severe toxicity is essential for optimizing patient management and improving therapeutic efficacy. This study aimed to (1) characterize cytokine profiles associated with dysfunctional responses and severe toxicity following CAR-T infusion, (2) examine the timing and trajectory of cytokine changes in relation to treatment outcomes, and evaluate potential strategies for mitigating toxicity and treatment failure. We conducted a comprehensive analysis of serum cytokine profiles in 86 adult and pediatric patients undergoing autologous CD19 CAR-T therapy for B-ALL. Patients were categorized into three groups: (1) Dysfunctional response-Patients who failed to achieve a minimal residual disease-negative CR (MRD-CR) by Day 63 or who experienced recurrence of CD19+ disease in the setting ongoing CAR-T cell detection before Day 63. (2) Functional response with severe cytokine release syndrome (CRS) and/or neurotoxicity (NTX)-Patients with best response of MRD-CR by Day 63 who experienced grade 3 or higher CRS or NTX. (3) Functional response without severe CRS or NTX-Patients with best response of MRD-CR by Day 63 who did not experience grade ≥3 CRS or NTX. Cytokine levels were measured during the first-week postinfusion and correlated with treatment efficacy, toxicity outcomes, complete blood counts, and CAR-T expansion dynamics. This analysis aimed to better understand how cytokine profiles relate to patient outcomes and immune responses in CAR-T therapy. Patients with dysfunctional response exhibited decreased neutrophils, platelets, and levels of granulocytic cytokines (suggestive of low bone marrow reserve) alongside elevated pro-inflammatory cytokines by Day 1. Functional response with severe toxicity patients showed a progressive rise in proinflammatory cytokines, reaching similar levels to dysfunctional response patients by Day 7. We observed that high cytokines at both the Day 1 and Day 7 time points were associated with poor survival. These findings remained significant when adjusting for high disease burden, a known predictor of severe inflammatory toxicity and lack of response. Early post-CAR-T infusion inflammation is associated with both dysfunctional response and severe toxicity-even after adjusting for disease burden. This suggests that inflammation, in addition to disease burden, plays a role in determining patient outcome. Therefore, strategies aimed at reducing the pro-inflammatory state prior to or early after CAR-T cell infusion may improve outcomes for R/R B-ALL patients.}, }
@article {pmid40398416, year = {2025}, author = {Aditham, AK and Radford, CE and Carr, CR and Jasti, N and King, NP and Bloom, JD}, title = {Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.}, journal = {Cell host & microbe}, volume = {33}, number = {6}, pages = {988-1003.e10}, pmid = {40398416}, issn = {1934-6069}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; }, mesh = {*Rabies virus/immunology/genetics ; *Antibodies, Viral/immunology ; *Glycoproteins/genetics/immunology ; *Viral Envelope Proteins/genetics/immunology ; *Antigens, Viral/genetics/immunology ; Humans ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Animals ; Rabies/immunology/virology ; *Immune Evasion ; Mutation ; Epitopes/immunology/genetics ; }, abstract = {Rabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single-amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for G function and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.}, }
@article {pmid40397836, year = {2025}, author = {Ramsey, SD and Sun, Q and Fedorenko, CR and Li, L and Panattoni, LE and Kreizenbeck, KL and Shankaran, V}, title = {Telehealth and Emergency Department Use Among Commercially Insured, Medicaid, and Medicare Patients Receiving Systemic Cancer Therapy in Washington State After COVID-19.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400217}, doi = {10.1200/CCI-24-00217}, pmid = {40397836}, issn = {2473-4276}, mesh = {Humans ; *COVID-19/epidemiology/virology/prevention & control ; *Telemedicine/statistics & numerical data ; *Medicaid/statistics & numerical data ; *Medicare/statistics & numerical data ; Washington/epidemiology ; *Emergency Service, Hospital/statistics & numerical data ; Male ; Female ; *Neoplasms/therapy/epidemiology ; United States/epidemiology ; Aged ; Middle Aged ; SARS-CoV-2 ; Insurance, Health/statistics & numerical data ; Adult ; SEER Program ; }, abstract = {PURPOSE: In oncology, telehealth services were adopted as a means of mitigating the risk of COVID-19 transmission. We hypothesized that Medicaid enrollees would have less access to telehealth than commercially insured or Medicare enrollees during the pandemic, resulting in higher rates of emergency department (ED) visits during systemic cancer treatment.
METHODS: Linking Washington State SEER records with commercial, Medicaid, and Medicare records, we evaluated adults with new solid tumor malignancies who received initial systemic treatment before the COVID-19 pandemic (January 1, 2017-December 31, 2019) and after the pandemic (March 1, 2020-November 30, 2021). Poisson and logistic regressions were used to evaluate differences in the number of office visits, telehealth visits, and ED visits in the 3 months after starting systemic anticancer treatment between insurance groups before versus after the pandemic.
RESULTS: Among 2,936 commercial, 2,039 Medicaid, and 7,333 Medicare enrollees who met inclusion criteria, office-based visits fell substantially for all groups during the COVID-19 period. Medicare enrollees had fewer telehealth visits while Medicaid had more telehealth visits, compared with commercial enrollees. ED visits declined for all patients, but there were no differences between insurance groups.
CONCLUSION: In Washington State, COVID-19 resulted in a substantial decrease in office-based visits, with an accompanying increase in telehealth visits partially offsetting the difference in overall access to care. ED visit rates fell substantially, without differences between insurance groups.}, }
@article {pmid40397817, year = {2025}, author = {Watling, CZ and Petrick, JL and Graubard, BI and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, M and Kang, JH and Koshiol, J and Huang, WY and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Palmer, JR and Rosenberg, L and Sesso, HD and Shrubsole, M and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Hofmann, J and Purdue, MP and Campbell, PT and Barupal, D and McGlynn, KA}, title = {Circulating per- and polyfluoroalkyl substances and liver cancer risk: a nested case-control analysis of individual participant data from 12 prospective cohorts.}, journal = {Environmental health perspectives}, volume = {}, number = {}, pages = {}, doi = {10.1289/EHP16980}, pmid = {40397817}, issn = {1552-9924}, abstract = {BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been associated with numerous deleterious health outcomes including liver damage. However, whether exposure to PFAS is associated with liver cancer risk remains unclear.
METHODS: We conducted a matched nested case-control study among 12 prospective cohort studies located in the United States. Pre-diagnostic PFAS, namely perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS), were measured from blood samples among 853 individuals who developed liver cancer and 853 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression for liver cancer risk by study-specific quartiles of concentrations and per 90[th] vs. 10[th] percentile incremental increase.
RESULTS: In the main multivariable-adjusted model, circulating PFOS, PFOA, and PFHxS levels were not associated with liver cancer risk (OR per 90[th] vs. 10[th] percentile increase: 1.00, 95% CI: 0.79-1.28; 0.92, 0.73-1.15; and 0.95, 0.75-1.21, respectively). However, when analyses were stratified by sex, PFOA concentrations were positively associated with liver cancer risk in males (OR per 90[th] vs. 10[th] percentile increase: 1.62 95% CI:1.07-2.45), whereas an inverse association was observed amongst females (OR per 90[th] vs. 10[th] percentile increase:0.68, 0.50-0.92; p-interaction=0.005). Analyses separating liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, showed no evidence of heterogeneity, although associations were stronger but not significant for HCC. No evidence of interaction was observed by time to diagnosis, time period of blood draw, body mass index, alcohol intake, ethnicity, or diabetes status.
CONCLUSIONS: In the largest study to date, none of the measured circulating PFAS were associated with liver cancer risk; however, PFOA associations appeared to differ by sex and further research is needed to explore these apparent differences by sex. https://doi.org/10.1289/EHP16980.}, }
@article {pmid40397323, year = {2025}, author = {Wadden, E and Yogeswaran, V and Ray, RM and Vasbinder, A and Shadyab, AH and Xiao, Q and Richey, PA and Saquib, N and Sun, Y and Jung, SY and Pichardo, MS and Manson, JE and Anderson, G and Simon, M and Stefanick, ML and Reding, K and Barac, A and Cheng, RK}, title = {Social determinants of cardiovascular disease in women with and without breast cancer.}, journal = {Breast cancer research and treatment}, volume = {212}, number = {2}, pages = {371-386}, pmid = {40397323}, issn = {1573-7217}, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/complications ; Middle Aged ; *Social Determinants of Health ; *Cardiovascular Diseases/epidemiology/etiology ; Aged ; Socioeconomic Factors ; Risk Factors ; Proportional Hazards Models ; Women's Health ; }, abstract = {PURPOSE: Social determinants of health (SDOH) may impact cardiovascular (CV) risk in women with and without breast cancer (BC).
METHODS: In 153,401 participants without prevalent CV disease from the Women's Health initiative (WHI), we assessed key SDOH factors: geographic region, rurality, insurance status, and household income. Multivariable Cox proportional hazards models were used to assess associations between SDOH factors and a composite CV outcome, which included incident myocardial infarction, incident stroke, hospitalization for heart failure, or CV death.
RESULTS: In the final cohort, 10,954 (mean ± standard deviation [SD] age 62 ± 7 years) women developed BC, and 142,144 (mean age 63 ± 7 years) women remained free of BC. During a median follow-up time of 13 years, 18,148 women experienced the composite CV outcome. Rurality, low household income, and non-private insurance were associated with an increased risk of the composite CV outcome and CV death, both in women with and without BC.
CONCLUSIONS: SDOH factors are associated with an increased risk of CV events among women, irrespective of BC status. These associations highlight the importance of socioeconomic factors across cardiovascular health outcomes.}, }
@article {pmid40394842, year = {2025}, author = {Ghodsi, A and Demirci, RA and Chen, DL and Nelson, PS and Schweizer, MT and Yu, EY and Iravani, A}, title = {The Role of SPECT/CT in 177 Lu-PSMA-617 Theranostics: Case-based Review of Response and Progression Patterns.}, journal = {Clinical nuclear medicine}, volume = {50}, number = {8}, pages = {e453-e460}, doi = {10.1097/RLU.0000000000005986}, pmid = {40394842}, issn = {1536-0229}, mesh = {Humans ; Male ; *Dipeptides/therapeutic use ; *Disease Progression ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Lutetium/therapeutic use ; Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/radiotherapy/pathology ; *Radioisotopes/therapeutic use ; *Single Photon Emission Computed Tomography Computed Tomography ; *Theranostic Nanomedicine ; Treatment Outcome ; Prostate-Specific Antigen ; }, abstract = {Lutetium-177 prostate-specific membrane antigen-617 (Lu-PSMA) has demonstrated efficacy in improving progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Post-treatment single photon emission tomography/computed tomography (SPECT/CT) imaging is an emerging tool for monitoring treatment response, enabling the tracking of functional changes during therapy. While quantitative SPECT analysis can predict patient outcomes, qualitative assessments are more practical and time-efficient in clinical settings. This case-based review examines treatment responses based on post-treatment SPECT/CT imaging, categorizing them into favorable response, progression, and mixed response patterns to improve interpretation and guide therapeutic adjustments, aiming to optimize management of mCRPC with Lu-PSMA therapy.}, }
@article {pmid40394810, year = {2025}, author = {Marks, DI and Cassaday, RD and Ribera, JM and Schuh, AC and Park, JH and Chiaretti, S and Stelljes, M}, title = {Identifying people with acute lymphoblastic leukemia who are most suitable for treatment with inotuzumab ozogamicin: a plain language summary.}, journal = {Expert review of hematology}, volume = {18}, number = {5}, pages = {345-349}, doi = {10.1080/17474086.2025.2493325}, pmid = {40394810}, issn = {1747-4094}, }
@article {pmid40394759, year = {2025}, author = {Christofferson, RC and Giovanni, JE and Koumans, EH and Ategbole, M and Clark, SD and Godfred-Cato, S and Menon, MP and Sastalla, I and Schweitzer, BK and Uyeki, TM}, title = {A Systematic Review of Prolonged SARS-CoV-2 Shedding in Immunocompromised Persons.}, journal = {Influenza and other respiratory viruses}, volume = {19}, number = {5}, pages = {e70121}, pmid = {40394759}, issn = {1750-2659}, mesh = {Humans ; *Immunocompromised Host ; *COVID-19/virology/immunology ; *SARS-CoV-2/physiology/isolation & purification/genetics ; *Virus Shedding ; RNA, Viral ; }, abstract = {BACKGROUND: Although reports have documented prolonged SARS-CoV-2 RNA detection in immunocompromised patients, few studies have systematically analyzed data on duration of SARS-CoV-2 in respiratory specimens of immunocompromised patients.
METHODS: A systematic review was undertaken to describe SARS-CoV-2 RNA and infectious virus detection in immunocompromised patients from published data between January 1, 2020 and July 1, 2022. Patients were included if there was ≥ 1 positive SARS-CoV-2 RNA result in respiratory specimens collected > 20 days since symptom onset or first positive SARS-CoV-2 RT-PCR result.
RESULTS: Of the 183 patients, 175 were symptomatic with 83 (47.4%) that experienced intermittent relapsing symptoms, while pneumonia was reported in 122 (66.7%). Immunocompromising conditions represented were hematologic malignancy treatment (89, 48.6%), solid organ transplant (47, 25.7%), autoimmune disease treatment (14, 7.7%), solid tumor treatment (3, 1.6%), HIV infection (15, 8.2%), and primary immunodeficiency (15, 8.2%). Median duration from the first to the last positive SARS-CoV-2 RT-PCR result was 56 days in upper respiratory and 60 days in lower respiratory tract specimens. Significant differences in median duration of SARS-CoV-2 RNA detection were observed between patients with and without pneumonia and for patients with hematologic malignancies compared to solid organ transplant patients. Among patients with viral culture performed, median duration of replication-competent SARS-CoV-2 was 60.5 days from symptom onset (maximum 238 days) and 59 days from first RT-PCR positive result (maximum 268 days).
CONCLUSIONS: Immunocompromised persons can have replication-competent SARS-CoV-2 in respiratory tissues for months, including while asymptomatic. Serial SARS-CoV-2 testing can inform the duration of isolation for immunocompromised patients with SARS-CoV-2 infection.}, }
@article {pmid40394536, year = {2025}, author = {Hamoud, J and Devkota, J and Regan, T and Luken, A and Waring, J and Han, JJ and Naughton, F and Vilardaga, R and Bricker, J and Latkin, C and Moran, M and Thrul, J}, title = {Smoking cessation message testing to inform app-based interventions for young adults - an online experiment.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {1852}, pmid = {40394536}, issn = {1471-2458}, support = {R01 CA246590/CA/NCI NIH HHS/United States ; T32 DA007292/DA/NIDA NIH HHS/United States ; NIDA; T32 DA007292/DA/NIDA NIH HHS/United States ; NCI; R01 CA246590/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/psychology ; Male ; Female ; Adult ; Young Adult ; *Mobile Applications ; Cognitive Behavioral Therapy ; Acceptance and Commitment Therapy ; Motivation ; }, abstract = {BACKGROUND: To improve the efficacy of digital smoking cessation interventions for young adults, intervention messages need to be acceptable and appropriate for this population. The current study compared ratings of smoking cessation and urge reduction messages based on Cognitive Behavioral Therapy (distraction themed) and Acceptance and Commitment Therapy (acceptance themed) in young adults who smoke.
METHODS: A total of 124 intervention messages were rated by an online Qualtrics panel of N = 301 diverse young adults who currently smoked tobacco cigarettes (Age M = 26.6 years; 54.8% male; 51.5% racial/ethnic minority; 16.9% sexual or gender minority (SGM); 62.5% daily smoking). Each participant rated 10 randomly selected messages (3,010 total message ratings; 24.3 ratings per message) on 5-point scales (higher scores representing more favorable ratings) evaluating quality of content, quality of design, perceived support for coping with smoking urges, and perceived support for quitting smoking. Mixed models examined associations between message category (distraction vs. acceptance), participant level predictors (sociodemographic variables, readiness and motivation to quit, daily smoking, psychological flexibility), and message ratings.
RESULTS: Overall ratings ranged from M = 3.61 (SD = 1.25) on support for coping with urges to M = 3.90 (SD = 1.03) on content, with no differences between distraction and acceptance messages. Male participants gave more favorable ratings on the dimensions of support for coping (p < 0.01) and support for quitting (p < 0.01). Participants identifying as SGM gave lower ratings for message design (p < 0.05). Participants with a graduate degree gave higher ratings on support for coping with urges and support for quitting (both p < 0.05). Higher motivation to quit was associated with more favorable scores across all dimensions (all p < 0.01). Those smoking daily rated messages as less helpful for coping with urges (p < 0.01) and quitting smoking (p < 0.05) compared to those smoking non-daily. Few interactions were found between message category distraction vs. acceptance and participant characteristics.
CONCLUSIONS: Distraction and acceptance messages received similar ratings among young adults who smoke cigarettes. Message revisions may be needed to increase appeal to women, SGM, those with lower education, and those less motivated to quit. Messages will be refined and used in an ongoing micro-randomized trial to investigate their real-time impact on smoking urges and behaviors.}, }
@article {pmid40394326, year = {2025}, author = {Flanagan, MR and van den Bruele, AMB and Downs-Canner, SM and Thomas, SM and Gallagher, KK and Jakub, JW and Tevis, SEA and Verdial, FC and Zhang, JQ and Elmore, LC and Mukhtar, RA and Brennan, M and Lillie, M and Gibson, TC and Verosky, A and Plichta, JK and Rosenberger, LH}, title = {A Multi-Institutional Analysis of Contralateral Axillary Metastases: Advanced Local-Regional Disease Divergent from Stage IV Breast Cancer.}, journal = {Annals of surgical oncology}, volume = {32}, number = {8}, pages = {5551-5562}, pmid = {40394326}, issn = {1534-4681}, support = {P30CA014236//Duke Cancer Institute/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/pathology/therapy/mortality ; Middle Aged ; Retrospective Studies ; Axilla ; Aged ; Survival Rate ; Neoplasm Staging ; Lymphatic Metastasis ; Follow-Up Studies ; Prognosis ; *Lymph Node Excision/mortality ; Neoadjuvant Therapy/mortality ; *Carcinoma, Ductal, Breast/secondary/therapy ; *Neoplasm Recurrence, Local/pathology ; }, abstract = {BACKGROUND: Contralateral axillary metastasis (CAM) is a rare event and is considered stage IV disease. We sought to evaluate outcomes in a CAM cohort treated with curative intent and contemporary systemic and locoregional therapy.
PATIENTS AND METHODS: A retrospective multi-institutional review was conducted from 2016 to 2022 of patients with CAM who underwent axillary surgery. Survival outcomes were compared with those with locally advanced breast cancer (LABC) and metastatic breast cancer (MBC).
RESULTS: In total, 754 patients were included in the study (63 CAM, 188 LABC, and 503 MBC). The median age at CAM diagnosis was 62 years [(interquartile range (IQR) 49.2-69.3)], and the majority demonstrated invasive ductal histology (74.6%). Over half of the patients with CAM received neoadjuvant chemotherapy (55.6%) followed by axillary dissection (82.5%) and adjuvant radiation (74.6%) in most cases. On unadjusted analysis, the LABC cohort demonstrated the highest 3-year unadjusted overall survival (OS) (89.4%), followed by CAM (79.7%) and MBC (53%) (p < 0.001). On multivariable analysis adjusting for age, race/ethnicity, insurance, and hormone receptor status, patients with MBC had inferior survival compared with LABC [hazard ratio (HR) 6.59, 95% confidence interval (CI) 4.22-10.28, p < 0.001], while CAM had similar survival to that seen in LABC (HR 2.13, 95% CI 0.82-5.52, p = 0.12).
CONCLUSIONS: Survival was higher for patients with CAM compared with MBC and was similar to patients with LABC. Though the LABC group demonstrated better recurrence-free survival than the CAM group, these numbers were comparable within the first 2 years of follow-up. Our data provides additional support for the consideration of curative intent management for patients with CAM.}, }
@article {pmid40392909, year = {2025}, author = {Naudin, S and Wang, M and Dimou, N and Ebrahimi, E and Genkinger, J and Adami, HO and Albanes, D and Babic, A and Barnett, M and Bogumil, D and Cai, H and Chen, C and Eliassen, AH and Freudenheim, JL and Gierach, G and Giovannucci, EL and Gunter, MJ and Håkansson, N and Hirabayashi, M and Hou, T and Huang, BZ and Huang, WY and Jayasekara, H and Jones, ME and Katzke, VA and Koh, WP and Lacey, JV and Lagerros, YT and Larsson, SC and Liao, LM and Lo, K and Loftfield, E and MacInnis, RJ and Männistö, S and McCullough, ML and Miller, A and Milne, RL and Moore, SC and Mucci, LA and Neuhouser, ML and Patel, AV and Platz, EA and Prizment, A and Robien, K and Rohan, TE and Sacerdote, C and Sandin, S and Sawada, N and Schoemaker, M and Shu, XO and Sinha, R and Snetselaar, L and Stampfer, MJ and Stolzenberg-Solomon, R and Thomson, CA and Tjønneland, A and Um, CY and van den Brandt, PA and Visvanathan, K and Wang, SS and Wang, R and Weiderpass, E and Weinstein, SJ and White, E and Willett, W and Woslk, A and Wolpin, BM and Yaun, SS and Yuan, C and Yuan, JM and Zheng, W and Brennan, P and Smith-Warner, SA and Ferrari, P}, title = {Alcohol intake and pancreatic cancer risk: An analysis from 30 prospective studies across Asia, Australia, Europe, and North America.}, journal = {PLoS medicine}, volume = {22}, number = {5}, pages = {e1004590}, pmid = {40392909}, issn = {1549-1676}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; UM1 CA173640/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 AA024770/AA/NIAAA NIH HHS/United States ; R01 CA039742/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; U01 CA199277/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; U01 HL145386/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 CA063673/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/epidemiology/etiology ; Female ; Male ; Middle Aged ; *Alcohol Drinking/adverse effects/epidemiology ; North America/epidemiology ; Europe/epidemiology ; Prospective Studies ; Australia/epidemiology ; Risk Factors ; Asia/epidemiology ; Aged ; Adult ; Incidence ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Alcohol is a known carcinogen, yet the evidence for an association with pancreatic cancer risk is considered as limited or inconclusive by international expert panels. We examined the association between alcohol intake and pancreatic cancer risk in a large consortium of prospective studies.
METHODS AND FINDINGS: Population-based individual-level data was pooled from 30 cohorts across four continents, including Asia, Australia, Europe, and North America. A total of 2,494,432 participants without cancer at baseline (62% women, 84% European ancestries, 70% alcohol drinkers [alcohol intake ≥ 0.1 g/day], 47% never smokers) were recruited between 1980 and 2013 at the median age of 57 years and 10,067 incident pancreatic cancer cases were recorded. In age- and sex-stratified Cox proportional hazards models adjusted for smoking history, diabetes status, body mass index, height, education, race and ethnicity, and physical activity, pancreatic cancer hazard ratios (HR) and 95% confidence intervals (CI) were estimated for categories of alcohol intake and in continuous for a 10 g/day increase. Potential heterogeneity by sex, smoking status, geographic regions, and type of alcoholic beverage was investigated. Alcohol intake was positively associated with pancreatic cancer risk, with HR30-to-<60 g/day and HR≥60 g/day equal to 1.12 (95% CI [1.03,1.21]) and 1.32 (95% CI [1.18,1.47]), respectively, compared to intake of 0.1 to <5 g/day. A 10 g/day increment of alcohol intake was associated with a 3% increased pancreatic cancer risk overall (HR: 1.03; 95% CI [1.02,1.04]; pvalue < 0.001) and among never smokers (HR: 1.03; 95% CI [1.01,1.06]; pvalue = 0.006), with no evidence of heterogeneity by sex (pheterogeneity = 0.274) or smoking status (pheterogeneity = 0.624). Associations were consistent in Europe-Australia (HR10 g/day = 1.03, 95% CI [1.00,1.05]; pvalue = 0.042) and North America (HR10 g/day = 1.03, 95% CI [1.02,1.05]; pvalue < 0.001), while no association was observed in cohorts from Asia (HR10 g/day = 1.00, 95% CI [0.96,1.03]; pvalue = 0.800; pheterogeneity = 0.003). Positive associations with pancreatic cancer risk were found for alcohol intake from beer (HR10 g/day = 1.02, 95% CI [1.00,1.04]; pvalue = 0.015) and spirits/liquor (HR10 g/day = 1.04, 95% CI [1.03,1.06]; pvalue < 0.001), but not wine (HR10 g/day = 1.00, 95% CI [0.98,1.03]; pvalue = 0.827). The differential associations across geographic regions and types of alcoholic beverages might reflect differences in drinking habits and deserve more investigations.
CONCLUSIONS: Findings from this large-scale pooled analysis support a modest positive association between alcohol intake and pancreatic cancer risk, irrespective of sex and smoking status. Associations were particularly evident for baseline alcohol intake of at least 15 g/day in women and 30 g/day in men.}, }
@article {pmid40392851, year = {2025}, author = {Zhu, L and Beichman, A and Harris, K}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {21}, pages = {e2423311122}, pmid = {40392851}, issn = {1091-6490}, support = {T32 AG066574/AG/NIA NIH HHS/United States ; R35GM133428//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Career Award at the Scientific Interface//Burroughs Wellcome Fund (BWF)/ ; Discovery Center for Cell Lineage Tracing//Allen Foundation (The Allen Foundation)/ ; R35 GM133428/GM/NIGMS NIH HHS/United States ; Pew Scholarship//Pew Charitable Trusts (PEW)/ ; }, mesh = {*Mutation Rate ; *Germ-Line Mutation/genetics ; Animals ; Population Density ; Male ; *Reproduction/genetics ; Female ; *Longevity/genetics ; DNA Repair ; Germ Cells ; Spermatogonia ; DNA Damage ; }, abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with fewer mutations occurring each generation in species that reproduce quickly and maintain large effective population sizes. A compelling explanation is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that modulate cell division or interfere with the molecular efficacy of DNA repair. However, while the fidelity of a single cell division largely determines microorganisms' mutation rates, the relationship of the mutation rate to the molecular determinants of DNA damage and repair is more complex in multicellular species with long generation times. Since long generations leave more time for mutations to accrue each generation, we posit that a long generation time likely amplifies the fitness consequences of any damage agent or DNA repair defect that creates extra mutations in the spermatogonia or oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for avoiding and repairing mutations in their reproductive cells. Consistent with this, we show that mutation rates in the reproductive cells are inversely correlated with generation time; in contrast, the number of germline mutations that occur during prepuberty development trends weakly upward as generation time increases. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, }
@article {pmid40392206, year = {2025}, author = {Hery, CM and Zhang, X and McLaughlin, E and Von Ah, D and Anderson, GL and Harris, HR and VoPham, T and Garcia, L and Shadyab, AH and Follis, S and Paskett, ED}, title = {Association of Cancer History with COVID-19 Risk and Outcomes Among Older Postmenopausal Women: Results from the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1682}, pmid = {40392206}, issn = {1538-7755}, abstract = {BACKGROUND: Several studies early in the COVID-19 pandemic suggested those with a cancer history had higher risk of COVID-19 infections and complications. However, few prospective studies evaluated the association of cancer with COVID-19 in older women. We aimed to examine the association of cancer history with risk of COVID-19 and various COVID-19 outcomes among older women.
METHODS: The Women's Health Initiative (WHI) is an ongoing cohort study that recruited 161,808 postmenopausal women aged 50-79 from 1993-1998. Those who completed the COVID-19 survey (2021-2022) were included (n=35,623). Multivariable linear and logistic regression were used to examine COVID-19 positivity, symptoms severity, long COVID, and COVID concerns/anxiety outcomes.
RESULTS: 28% (n=9,901) of participants had a history of cancer. Cancer history was not significantly associated with COVID-19 positivity (OR: 0.94, 95% CI: 0.81-1.08), COVID-19 hospitalization (OR: 1.21, 95% CI: 0.85-1.72), number of symptoms (LS Mean: 0.33, 95% CI: -0.20, 0.85), and long COVID (OR: 1.18, 95% CI: 0.88-1.58).
CONCLUSIONS: History of cancer was not associated with most COVID-19 outcomes. Future studies should continue to examine physiological mechanisms contributing to differences within cancer survivors and prioritize the inclusion of underserved populations to identify strategies to address the impact of COVID-19.
IMPACT: These findings may assure cancer survivors their diagnosis alone does not increase their risk of COVID-19 and suggests older women with a history of cancer may have similar risk of COVID-19 outcomes compared to their non-cancer counterparts.}, }
@article {pmid40390365, year = {2025}, author = {Arimura, Y and Konishi, HA and Funabiki, H}, title = {MagIC-Cryo-EM, structural determination on magnetic beads for scarce macromolecules in heterogeneous samples.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40390365}, issn = {2050-084X}, support = {Scholarship for Study Abroad//Osamu Hayaishi Memorial Scholarship/ ; Overseas Research Fellowships//Japan Society for the Promotion of Science/ ; R35 GM132111/GM/NIGMS NIH HHS/United States ; SNF Institute for Global Infectious Disease Research//Stavros Niarchos Foundation/ ; R35GM132111/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Histones/chemistry ; Nucleosomes/ultrastructure/chemistry ; *Cryoelectron Microscopy/methods ; Xenopus laevis ; *Macromolecular Substances/chemistry ; Nucleoplasmins/chemistry ; Nucleophosmin ; }, abstract = {Cryo-EM single-particle analyses typically require target macromolecule concentration at 0.05~5.0 mg/ml, which is often difficult to achieve. Here, we devise Magnetic Isolation and Concentration (MagIC)-cryo-EM, a technique enabling direct structural analysis of targets captured on magnetic beads, thereby reducing the targets' concentration requirement to <0.0005 mg/mL. Adapting MagIC-cryo-EM to a Chromatin Immunoprecipitation protocol, we characterized structural variations of the linker histone H1.8-associated nucleosomes that were isolated from interphase and metaphase chromosomes in Xenopus egg extract. Combining Duplicated Selection To Exclude Rubbish particles (DuSTER), a particle curation method that excludes low signal-to-noise ratio particles, we also resolved the 3D cryo-EM structures of nucleoplasmin NPM2 co-isolated with the linker histone H1.8 and revealed distinct open and closed structural variants. Our study demonstrates the utility of MagIC-cryo-EM for structural analysis of scarce macromolecules in heterogeneous samples and provides structural insights into the cell cycle-regulation of H1.8 association to nucleosomes.}, }
@article {pmid40389573, year = {2025}, author = {Khyzha, N}, title = {SLAM-RT&Tag: spatiotemporal profiling of RNA within nuclear compartments in situ.}, journal = {Nature reviews. Genetics}, volume = {26}, number = {7}, pages = {439}, pmid = {40389573}, issn = {1471-0064}, }
@article {pmid40389082, year = {2025}, author = {Yang, H and Wang, Y and Luo, K and Mossavar-Rahmani, Y and Cordero, C and Ostfeld, RJ and Martinez, C and Maldonado, L and Pirzada, A and Daviglus, M and Yu, B and Hu, FB and Kaplan, RC and Qi, Q}, title = {Dietary patterns, serum metabolites, and risk of cardiovascular disease in United States Hispanic/Latino adults: a prospective analysis of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {The American journal of clinical nutrition}, volume = {122}, number = {1}, pages = {92-100}, doi = {10.1016/j.ajcnut.2025.05.008}, pmid = {40389082}, issn = {1938-3207}, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Cardiovascular Diseases/epidemiology/blood/ethnology ; *Diet ; *Hispanic or Latino ; Prospective Studies ; Risk Factors ; United States/epidemiology ; }, abstract = {BACKGROUND: Healthy dietary patterns are recommended to prevent cardiovascular disease (CVD), yet the relationships among healthy dietary patterns, blood metabolite profile, and incident CVD are not well understood.
OBJECTIVES: This study aimed to assess the associations of healthy dietary patterns and related serum metabolite profiles with incident CVD in United States Hispanic/Latino adults.
METHODS: The study included 13,922 participants aged 18-74 y from the Hispanic Community Health Study/Study of Latinos. Dietary pattern scores, including Healthy Eating Index (HEI)-2020, healthful Plant-based Diet Index (hPDI), and alternate Mediterranean diet score (aMED), were constructed at baseline (2008-2011) based on 2 24-h dietary recalls. The primary outcome was incident CVD, encompassing myocardial infarction, heart failure, and stroke. Dietary-pattern-associated metabolites were identified in a subsample of participants free of diabetes at baseline (n = 4096). Associations of dietary pattern scores, individual metabolites, and metabolite scores with incident CVD were evaluated using multivariable Cox regression.
RESULTS: During a median 9.7-y follow-up period, 260 CVD events occurred among 13,922 participants. After adjusting for demographic, socioeconomic and behavioral factors, higher dietary pattern scores were associated with lower risk of CVD [hazard ratios (HRs) = 0.53 (95% confidence interval: 0.30, 0.92), 0.50 (0.27, 0.91) and 0.62 (0.36, 1.07) for HEI-2020, hPDI, and aMED, respectively, by comparing the highest tertile to the lowest tertile]. A total of 60 metabolites were identified to be associated with all 3 dietary pattern scores, including 45 metabolites positively and 15 metabolites negatively associated with dietary pattern scores. A total metabolite score based on these 60 dietary-pattern-associated metabolites was negatively associated with the risk of CVD after multivariable adjustment [HR = 0.57 (0.35, 0.92) by comparing the highest tertile to the lowest tertile].
CONCLUSIONS: Healthier diet patterns and related serum metabolite profiles are associated with a lower risk of CVD in United States Hispanic/Latino adults.}, }
@article {pmid40388716, year = {2025}, author = {Ashford, NK and Rane, S and Farris, KM and Miglani, J and Chu, B and Hippe, DS and Gandhi, T and Hanson, AJ}, title = {Acute cerebral blood flow response to heavy cream ingestion in older adults: A non-randomized pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {106}, number = {1}, pages = {331-341}, doi = {10.1177/13872877251340369}, pmid = {40388716}, issn = {1875-8908}, mesh = {Humans ; Male ; Female ; Aged ; Pilot Projects ; *Cerebrovascular Circulation/physiology ; Magnetic Resonance Imaging ; Middle Aged ; *Brain/diagnostic imaging/blood supply ; Blood Pressure/physiology ; Spin Labels ; }, abstract = {BackgroundHypertension and the APOE4 allele are known risk factors for Alzheimer's disease (AD) and E4 carriers show different blood pressure (BP) and cognitive responses to high fat feeding.ObjectiveWe investigated the influence of these factors on global cerebral blood flow (CBF) and four regions of interest (ROIs) (angular gyrus, hippocampus, posterior cingulate, temporal lobe) using arterial spin labeling (ASL) MRI in fasting state and after ingestion of heavy cream in older adults.Methods29 adults (age in years 66.8 ± 4.1) underwent baseline and 1, 2, 3-h ASL MRI after ingestion of 100 mL heavy cream. We used pCASL MRI with background suppression to measure CBF in ml/100 g/min. Statistical analyses included mixed-effects modeling and Pearson correlation to ascertain whether CBF changed over time and how variables influenced results.ResultsGlobal CBF decreased at 1-, 2-, and 3-h post-heavy cream, compared to time 0 (overall change 7.11%, p < 0.01); recapitulated in 3 of 4 ROIs. Mean arterial pressure emerged as a predictive variable for both baseline and post-heavy cream CBF (β = -0.25, 95% CI = -0.39, -0.10, p = 0.002). Individuals with higher BP demonstrated reduced CBF, particularly in posterior cingulate and temporal lobe (β = -5.50, 95% CI = -9.9, -1.09; β = -6.28, 95% CI = -12.35, -0.21, respectively, both p < 0.05). Examination of correlations with BP and change scores revealed that this relationship was driven largely by E4 carriers.ConclusionsCBF decreased after ingestion of heavy cream, globally and in regions known to be important in AD, and this finding was driven by E4 carriers with higher BP.}, }
@article {pmid40386555, year = {2025}, author = {Alabi, A and Ainsworth, V and Lawal, A and Kizub, D and Chin, J and Woodmark, C and Omidiji, O and Adegboyega, B and Sowunmi, A and Ogunyemi, A and Swanson, W and Joseph, A and Ngwa, W}, title = {Key stakeholders' experiences, knowledge and perspectives regarding care quality for breast cancer in South-West Nigeria.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1418649}, pmid = {40386555}, issn = {2234-943X}, abstract = {The landscape of breast cancer care in Nigeria is complex, with various structural and individual barriers impacting patient care. Breast cancer (BC) is the most common cancer and a leading cause of cancer deaths among women worldwide. In Africa, the cancer burden is expected to rise significantly, with projections estimating an increase of 50% by 2050. Rising incidence rates and barriers to care contribute to a healthcare crisis, leading to late-stage presentation and high mortality rates for women with breast cancer in Nigeria. Quality healthcare must be patient-centered, involving stakeholders - patients, clinical and community partners, and other healthcare stakeholders to achieve a desired outcome. Understanding the cancer journey from different perspectives allows for targeted approaches for increasing access to quality healthcare as well as reducing morbidity and mortality rates. To address this, healthcare provider perspectives about breast cancer care were compared with the lived experiences of breast cancer patients to emphasize the need to increase access and quality of care. A mixed method study was conducted in 2 phases: Phase I: 3 Focus group discussions (FGDs) with breast cancer patients and their care givers were conducted at the NSIA-LUTH Cancer Centre in Lagos, Nigeria. Phase II: A pre and post-survey of a continuing medical education course focused on breast cancer was delivered to healthcare providers in southwest Nigeria. Survey responses regarding causes for delays and barriers to care indicated financial strain, fear, and alternative treatments as the largest hurdles, coinciding with patient testimony from the FGD. Fear of mastectomy was a perceived barrier to care for 90% of healthcare providers while 87% and 86% of providers perceived seeking spiritual and herbal treatments as the largest delays of care. Despite this, a significant number of focus group participants (39%) presented within the first month of noticing a breast symptom to a proper healthcare provider. Data from our study reports that 70% of patients receive help from family to fund treatment highlighting why cancer can be a poverty trap for families and the need for universal health insurance. Half of the focus group participants had a positive interaction with their doctors, with the rest reporting neutral (19%) or even negative (31%) interactions. Our study also reports 42% of healthcare providers feeling only "somewhat" qualified to deal with breast cancer, highlighting the significant need for more education, with a further 14% feeling neutral or negative about their qualification, a potential contributing factor in negative interactions recalled by patients. Knowledge increase was consistent for best practice diagnostic modalities among healthcare providers (p < 0.05). At the same time, items related to symptoms and risks of breast cancer had inconsistent knowledge increases, indicating why further courses like these should be pursued. With the success of the course and the inspiration of breast cancer survivors, a proposed expansion into community awareness is discussed along with enlisting local practitioners in the fight against breast cancer in hopes of lowering the barriers to and delays of care in Nigeria.}, }
@article {pmid40384944, year = {2025}, author = {Halloran, ME}, title = {Designs for Vaccine Studies.}, journal = {Annual review of statistics and its application}, volume = {12}, number = {}, pages = {1-18}, pmid = {40384944}, issn = {2326-8298}, support = {R01 AI085073/AI/NIAID NIH HHS/United States ; }, abstract = {Due to dependent happenings, vaccines can have different effects in populations. In addition to direct protective effects in the vaccinated, vaccination in a population can have indirect effects in the unvaccinated individuals. Vaccination can also reduce person-to-person transmission to vaccinated individuals or from vaccinated individuals compared with unvaccinated individuals. Design of vaccine studies has a history extending back over a century. Emerging infectious diseases, such as the SARS-CoV-2 pandemic and the Ebola outbreak in West Africa, have stimulated new interest in vaccine studies. We focus on some recent developments, such as target trial emulation, test-negative design, and regression discontinuity design. Methods for evaluating durability of vaccine effects were developed in the context of both blinded and unblinded placebo crossover studies. The case-ascertained design is used to assess the transmission effects of vaccines. The novel ring vaccination trial design was first used in the Ebola outbreak in West Africa.}, }
@article {pmid40384751, year = {2025}, author = {Sanchez-Youngman, S and Jacquez, B and Adsul, P and Dickson, E and Akintobi, TH and Hoffman, L and Rosas, LG and Gay, S and Mendoza, JA and Mapes, D and Oetzel, J and Nease, D and Wallerstein, N}, title = {Engage for equity plus: Transforming academic health centers to sustain patient/community engaged research structures, policies, and practices.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e80}, pmid = {40384751}, issn = {2059-8661}, abstract = {INTRODUCTION: Community-based participatory research (CBPR) and patient/ community engaged research (P/CEnR) are shown to be effective approaches that improve health inequities, particularly among disadvantaged populations. While the science of CBPR demonstrates promising partnering practices that lead to effective interventions, there are institutional and structural barriers to creating and sustaining patient/community research within academic health centers (AHCs). As the field matures, there is a growing need to enhance patient/community leadership so that communities can set their own research agendas and priorities.
METHODS: Engage for Equity PLUS sought to address these challenges by implementing an engagement intervention aimed at transforming AHCs through supporting champion teams of academic, community, and patient partners to strengthen research infrastructures for P/CEnR. This paper uses a qualitative, case study analysis to describe how E2PLUS enabled champion teams at Stanford School of Medicine, Fred Hutchinson/University of Washington Cancer Consortium, and Morehouse School of Medicine to pursue institutional change strategies through coaching, workshops, contextual data analysis, and a community of practice.
RESULTS: This paper describes key themes of how E2Plus helped identify targets of change by a) using institutional data collection as core to generating critical consciousness of contextual conditions; b) implementing feasible E2PLUS strategies to leverage conditions for catalyzing a champion team for advocacy and achievable actions; c) identifying the critical role of patients/community members in stimulating change; and d) the role of continual collective reflection.
CONCLUSION: We discuss the overall implications for E2 PLUS for other AHCs working toward sustainable community/patient engaged research policies and practices.}, }
@article {pmid40384469, year = {2025}, author = {Bell-Brown, A and Tawfik, B and Segarra-Vazquez, B and Hopkins, T and Watabayashi, K and O'Kane, P and Carlos, RC and Langer, SL and Unger, JM and Darke, AK and Hershman, DL and Ramsey, SD and Shankaran, V}, title = {Addressing Challenges in Research Aimed at Reducing Financial Toxicity Among Cancer Patients and Caregivers: An Example From the CREDIT Study (SWOG S1912CD).}, journal = {Cancer control : journal of the Moffitt Cancer Center}, volume = {32}, number = {}, pages = {10732748251344469}, pmid = {40384469}, issn = {1526-2359}, support = {R01 CA248656/CA/NCI NIH HHS/United States ; UG1 CA189856/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/economics/psychology ; *Neoplasms/economics/therapy ; *Financial Stress/prevention & control ; Female ; Male ; }, abstract = {IntroductionCancer-related financial hardship is pervasive, impacting both patients and caregivers, making it crucial to address financial hardship at the household level. The CREDIT (S1912CD) study was designed to enroll and randomize cancer patients and spousal caregivers as dyads to proactive financial navigation compared to usual care. The study faced several challenges to recruitment. This paper discusses the changes made to successfully complete the study.MethodsThe study took place among NCI Community Oncology Research Program (NCORP) sites and allowed several venues for protocol feedback, including SWOG group meetings, NCORP administrator meetings, and individual calls with recruiting sites. A patient advocate worked with the study team to review and update documents to ensure the study was relevant and accessible to potential participants.ResultsSeveral barriers were identified including sites facing challenges in enrolling patient-spouse dyads, multiple financial navigation partners causing confusion and delays in delivery of the intervention, eligibility criteria concerns, and participant discomfort with providing social security numbers. Several modifications were made to address these obstacles during a study restructure, including making caregiver participation optional, streamlining intervention delivery, and modifying eligibility criteria to allow more time between diagnosis and enrollment. Changes from the restructure resulted, on average, in a 9.5 patient per month increase in accrual (4.1 to 13.6) and has enabled the study to reach overall accrual within the study timeline. Importantly, the study maintained diverse accrual and continued to accrue willing caregivers to enable exploratory analysis of caregiver outcomes.ConclusionInterventions examining how to mitigate financial hardship for cancer patients and those affected by cancer, must be pragmatic in order to be translated into sustainable programs in real world settings. Providing recruiting sites an avenue for feedback ensured that the study team could adjust the protocol to meet site needs and successfully complete this financial navigation study.}, }
@article {pmid40384398, year = {2025}, author = {Moore, M and Glidden, D and Anderson, P and Hendrix, C and Dimitrov, D}, title = {Dosing forgiveness of oral PrEP for cisgender women remains uncertain.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {5}, pages = {e26496}, pmid = {40384398}, issn = {1758-2652}, support = {5UM1AI068617-20/DA/NIDA NIH HHS/United States ; 5UM1AI068617-20//National Institute of Allergy and Infectious Diseases/ ; 1R01AI179417-01A1//National Institute of Allergy and Infectious Diseases/ ; R01AI170298//National Institute of Allergy and Infectious Diseases/ ; }, }
@article {pmid40383922, year = {2025}, author = {Dashevsky, BZ and Fish, LJ and Breit, S and Waheed, U and Coffey, K and Parikh, JR and Mullen, LA and Reig, B and Dontchos, BN and Dodelzon, K and Grimm, LJ}, title = {Contrast-Enhanced Mammography Implementation: Early Struggles and Successes.}, journal = {Journal of breast imaging}, volume = {7}, number = {3}, pages = {345-354}, doi = {10.1093/jbi/wbaf018}, pmid = {40383922}, issn = {2631-6129}, mesh = {Humans ; *Mammography/methods/economics ; *Contrast Media ; Female ; *Breast Neoplasms/diagnostic imaging ; United States ; Workflow ; Focus Groups ; Patient Selection ; *Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {We used focus groups of radiologists who led the implementation of contrast-enhanced mammography (CEM) in their practice to identify barriers and strategies for adoption. Members of the Society of Breast Imaging in the United States who served as lead on CEM implementation were invited to participate in 2 separate focus groups. Ten breast imaging radiologists with varied geographic and practice type (60% academic, 30% private, and 10% community practice) participated. There were 4 major themes identified: patient selection, workflow, contrast, and billing. Patient selection varied widely among practices, with some limiting CEM to patients unable to obtain MRI and others routinely using CEM for diagnostic workup. Lack of Food and Drug Administration approval limited screening applications in some practices. Workflow challenges were numerous, and site-specific solutions were developed for ordering, scheduling, staffing, and intravenous access. There were universal concerns regarding contrast, including safe administration, response to reactions, and biopsy planning for findings only visible on CEM. Contrast reaction training, including conducting mock codes at some practices, helped alleviate concerns of the radiologists and technologists. Finally, billing was an administrative hurdle that influenced patient selection. Ample preparation is needed to successfully start a CEM program with particular attention to patient selection, workflow, contrast administration/reactions, and billing.}, }
@article {pmid40383778, year = {2025}, author = {Kim, S and Radford, CE and Xu, D and Zhong, J and Do, J and Pham, DM and Travisano, KA and Filsinger Interrante, MV and Bruun, TUJ and Rezek, V and Wilder, B and Palomares, M and Seaman, MS and Kitchen, SG and Bloom, JD and Kim, PS}, title = {A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4617}, pmid = {40383778}, issn = {2041-1723}, support = {DP1 AI158125/AI/NIAID NIH HHS/United States ; 5DP1AI158125//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*HIV-1/immunology/genetics/drug effects ; *Antibodies, Bispecific/immunology/pharmacology/genetics ; Humans ; Animals ; *HIV Infections/immunology/virology ; Mice ; Male ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology ; HIV Envelope Protein gp41/immunology/genetics ; Viral Load/drug effects ; HEK293 Cells ; Receptors, IgG/genetics/immunology/metabolism ; Neutralization Tests ; CD4 Antigens/immunology ; Broadly Neutralizing Antibodies/immunology ; }, abstract = {Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.}, }
@article {pmid40383698, year = {2025}, author = {Hill, M and Garcia, LR and Nguyen, E and Korolkova, A and Cohn, L and Rodriguez, A and Hoh, R and Deeks, SG and Peluso, MJ and Sauceda, JA and Dubé, K}, title = {Corrigendum to 'Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States' [Soc. Sci. Med. Volume 366, February 2025, 117644].}, journal = {Social science & medicine (1982)}, volume = {}, number = {}, pages = {118161}, doi = {10.1016/j.socscimed.2025.118161}, pmid = {40383698}, issn = {1873-5347}, }
@article {pmid40382524, year = {2025}, author = {Yap, TA and LoRusso, P and Miller, RE and Kristeleit, R and Paulovich, AG and McMorn, S and Oplustil O'Connor, L and Lombardi, B and Marco-Casanova, P and Gangl, ET and Patel, B and O'Connor, MJ and Dean, E and Zviezdin, R and Plummer, R}, title = {The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {40382524}, issn = {1532-1827}, abstract = {BACKGROUND: Upregulation of DNA-dependent protein kinase (DNA-PK) is associated with poor prognosis and decreased response to DNA-damaging agents across cancer types. A Phase I/IIa study (NCT03907969) investigated the highly potent, selective DNA-PK inhibitor AZD7648 as monotherapy or combined with pegylated liposomal doxorubicin (PLD) in patients with advanced cancer.
METHODS: Thirty patients received escalating doses of AZD7648 as monotherapy (n = 14), starting at 5 mg QD, or with PLD 40 mg/m[2] (n = 16). The primary objective was safety and tolerability.
RESULTS: AZD7648 monotherapy was administered at 5-160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1-7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response.
DISCUSSION: Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.}, }
@article {pmid40381914, year = {2025}, author = {Yeung, CCS and Narava, SK and Chang, TC and Saeed, M and Aicher, L and Beppu, LW and Majano, MS and Taylor, EM and Camalier, CE and Sandhuria, P and Sala-Torra, O and Li, J and Yee, LM and McShane, LM and Karlovich, C and Little, RF and Harris, L and Doroshow, JH and Williams, PM and Radich, JP and Jiwani, S}, title = {Analytical Performance of the NCI-myeloMATCH Assay: A Rapid Turnaround Genomic Profiling Assay for Myeloid Disorders.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmoldx.2025.05.001}, pmid = {40381914}, issn = {1943-7811}, abstract = {myeloMATCH is a National Cancer Institute (NCI) precision medicine clinical trial initiative to evaluate treatments for acute myeloid leukemia and myelodysplastic syndrome based on a leukemia's diagnostic molecular-genetic profile. The NCI myeloid assay version 2 (NMAv2) uses the Genexus System, an automated platform with <48-hour turnaround from specimen receipt to reporting, to provide harmonized regulatory-compliant use for myeloMATCH across two independent clinical laboratories. Using clinical specimens, cell lines, and contrived reference materials, NMAv2 exhibited 99% sensitivity for 291 known mutations and 100% specificity. High reproducibility detecting all reportable variants was observed, with >98% mean positive percentage agreement and 100% negative percent agreement across six reproducibility assessments. Reproducibility experiments of companion diagnostic biomarkers (1 to 1.5× clinical limit of reporting) showed 100% positive percentage agreement and negative percent agreement. The limit of detection was 0.06% for hotspot single-nucleotide variants, 0.16% for non-hotspot single-nucleotide variants, 0.51% for hotspot insertion/deletions, approximately 1% for non-hotspot insertion/deletions, 0.23% for FLT3-internal tandem duplications, and ≤40 reads at 0.1% tumor content for fusions. Concordance of 99.39% was observed in orthogonal assays testing 76 blinded myeloid specimens in the sensitivity study, and 100% concordance was observed in testing 54 FLT3-internal tandem duplication specimens. The results show that NMAv2 has high specificity, sensitivity, accuracy, and reproducibility, and can rapidly characterize genomic alterations in acute myeloid leukemia and myelodysplastic syndrome.}, }
@article {pmid40379905, year = {2025}, author = {Krakow, EF and Lee, N and Jenkins, I and Sala-Torra, O and Beppu, L and Radich, JP and Fukuda, B and Sandmaier, BM and Yeung, CC and Bozic, I}, title = {A clinical solution for tracking clonal evolution of acute myeloid leukemia after allogeneic transplantation using bulk next generation sequencing.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40379905}, issn = {1476-5365}, abstract = {Clinical next generation sequencing (NGS) typically relies on limited gene panels run on bulk marrow or blood. Current computational tools for inferring clonal relationships is generally limited by the use of a small panel of pathogenic mutations to define clones. We developed an online software (CloneTracker) that uses 'incidentally-sequenced' single nucleotide polymorphisms (SNPs) in the regions of recurrent somatic mutations in addition to conventional mutation data from bulk NGS gene panels to provide detailed visualizations of clonal evolution during cancer treatment, alongside clinical data. Tested on 29 patients who underwent non-myeloablative transplantation for AML, CloneTracker successfully reconstructed the evolutionary dynamics of donor engraftment from bulk NGS and rendered intuitive visualizations of residual patient-derived hematopoiesis and relapsing malignant clones. The software does not require sequencing donor samples, as donor-derived clones are identifiable from post-HCT SNP data. This manuscript aims to introduce CloneTracker to the BMT community and make it available for those who would ascertain its clinical utility, e.g, in BMT trials leveraging molecular minimal residual disease (MRD) monitoring and targeted interventions to pre-empt relapse.}, }
@article {pmid40379049, year = {2025}, author = {Mehta, RS and Aljawai, YM and Al-Juhaishi, T and Saultz, J and Milano, F and Kanakry, JA and Kanakry, CG and Lazaryan, A}, title = {Role of Donor Cytomegalovirus Serostatus in Cytomegalovirus-Seronegative Recipients of Unrelated Donor Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Prophylaxis.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.005}, pmid = {40379049}, issn = {2666-6367}, abstract = {While donor age significantly impacts allogeneic hematopoietic cell transplantation (HCT) outcomes, the effect of donor cytomegalovirus (CMV) serostatus, particularly in CMV-seronegative recipients, remains a critical consideration. Donor CMV seropositivity is linked to increased CMV viremia and non-relapse mortality (NRM) in these recipients. Given the limited scope of novel antiviral prophylaxis drugs, eg, letermovir solely for CMV-seropositive recipients and the association of post-transplant cyclophosphamide (PTCy) with increased CMV reactivation, this study investigates the impact of donor CMV serostatus on outcomes in CMV-seronegative acute myeloid leukemia (AML) patients undergoing HLA-matched or mismatched unrelated donor HCT with PTCy. We retrospectively analyzed data from the Center for International Blood and Marrow Transplant Research, including adult CMV-seronegative AML patients who underwent unrelated donor HCT with PTCy between 2017 and 2021. Primary outcome was overall survival (OS). Secondary outcomes included relapse, NRM, and acute/chronic graft-versus-host disease. Donor age was dichotomized at ≤32 and >32 years. Multivariable Cox proportional hazards models, stratified by donor age, and Restricted Mean Survival Time (RMST) and Restricted Mean Time Lost (RMTL) analyses were performed. Of 408 CMV-seronegative recipients, 127 received transplants from CMV-seropositive donors. Baseline characteristics were well-balanced between groups. Multivariable analysis demonstrated that recipients of CMV-seropositive donors had a significantly higher hazard of mortality (hazard ratios [HR] 1.51, 95% confidence interval [CI] 1.07 to 2.14, P = .019). Donor age and donor type did not significantly impact OS in this CMV seronegative patient population. RMST analysis showed that recipients with CMV-seronegative donors lived on average 2.95 months longer (P = .045), while RMTL ratio was 1.34 (P = .037), indicating that recipients of CMV-seropositive donors experienced a 34% higher risk of loss of survival time. The difference in OS was primarily driven by a trend toward increased relapse risk in the CMV-seropositive donor group (HR 1.42, 95% CI: 0.95 to 2.08, P = .06) rather than NRM (HR 1.19, 95% CI: 0.66 to 2.13, P = .56). In CMV-seronegative adult AML patients undergoing unrelated donor HCT with PTCy, CMV-seropositive donors are associated with worse OS than CMV-seronegative donors, likely linked to higher relapse risk. These findings underscore the importance of considering donor CMV serostatus in donor selection for CMV-seronegative recipients undergoing HCT with PTCy. Further investigation is necessary to optimize donor selection strategies and improve outcomes in this patient population.}, }
@article {pmid40379030, year = {2025}, author = {Verwimp, S and Wagoner, J and Arenas, EG and De Coninck, L and Abdelnabi, R and Hyde, JL and Schiffer, JT and White, JM and Matthijnssens, J and Neyts, J and Polyak, SJ and Delang, L}, title = {Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo.}, journal = {Antiviral research}, volume = {239}, number = {}, pages = {106186}, doi = {10.1016/j.antiviral.2025.106186}, pmid = {40379030}, issn = {1872-9096}, mesh = {Animals ; *Antiviral Agents/pharmacology/administration & dosage/therapeutic use ; Mice ; Humans ; *Alphavirus/drug effects ; Sofosbuvir/pharmacology/administration & dosage/therapeutic use ; Chikungunya virus/drug effects ; *Alphavirus Infections/drug therapy/virology ; Amides/pharmacology/administration & dosage/therapeutic use ; Pyrazines/pharmacology/administration & dosage/therapeutic use ; Disease Models, Animal ; Administration, Oral ; Chikungunya Fever/drug therapy/virology ; Encephalitis Virus, Venezuelan Equine/drug effects ; Sindbis Virus/drug effects ; *Nucleosides/pharmacology/administration & dosage ; Semliki forest virus/drug effects ; Drug Synergism ; Drug Therapy, Combination ; Cytidine/analogs & derivatives/pharmacology/administration & dosage ; Fibroblasts/virology/drug effects ; Cell Line ; Hydroxylamines ; }, abstract = {Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable. We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis. In human skin fibroblasts, synergistic antiviral effects were observed for combinations of MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver cells, FAV + MPV conferred additive to synergistic activity against VEEV and SINV, while SOF synergized with FAV against SINV. In mice, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titres. Combination treatment with MPV and SOF significantly reduced swelling and infectious titres compared to monotherapies of each drug. Sequencing of CHIKV RNA from joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to monotherapy with several higher doses of MPV. Combining these approved oral nucleoside analogues confers potent suppression of multiple alphaviruses in vitro and in vivo with enhanced control of viral genetic evolution in face of antiviral pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.}, }
@article {pmid40378930, year = {2025}, author = {Jreij, G and Canton, G and Hippe, DS and Balu, N and Yuan, C and Cebral, J and Crone, C and Sikdar, S and Hatsukami, T and Gray, V and Desikan, S and Beach, K and Lal, BK}, title = {Systematic review of biomechanical forces associated with carotid plaque disruption and stroke.}, journal = {Journal of vascular surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvs.2025.05.014}, pmid = {40378930}, issn = {1097-6809}, abstract = {OBJECTIVE: Carotid plaque disruption with release of atheroembolic debris and consequent brain infarction is the primary mechanism for brain injury in patients with carotid stenosis. Disease severity is quantified traditionally by the degree of stenosis, although it is not an accurate marker of stroke risk. It has been proposed that biomechanical forces acting on a carotid plaque may render it vulnerable to rupture by causing adverse remodeling of its morphology or by direct disruption. We conducted a systematic review to assess the forces acting on carotid plaques and their relationship to adverse plaque outcomes.
METHODS: A literature search for studies reporting measurements of flow-related biomechanical forces acting on carotid atherosclerotic plaques was conducted using PubMed, Embase, and Web of Science. Studies were included if they reported on human carotid plaques, used patient-specific geometry, measured forces on or in the atherosclerotic lesions, and reported on carotid plaque-related adverse outcomes.
RESULTS: Of 5635 articles screened, 154 met eligibility criteria. Forces were computed using patient-specific arterial geometry derived from multiple imaging modalities, mainly magnetic resonance imaging (58.4%) and ultrasound examination (25.3%). Methodologies used to quantify the forces included computational fluid dynamics (31.8%), finite element analysis (10.4%), fluid-structure interaction models (27.3%), in vivo measurements (29.9%), and in vitro assessments (0.6%). Wall shear stress (WSS) and plaque wall stress (PWS) were the most frequently measured forces, in 72.1% and 45.5% of studies, respectively. Principal PWS (n = 15 studies) and WSS (n = 21 studies) were elevated in patients with adverse outcomes. PWS levels of >160 kPa had a sensitivity of >80% and specificity of >75% in identifying patients with adverse events. Increasing PWS was associated with subsequent ischemic cerebrovascular events (HR=hazard ratio, 12.98 per 1 kPa increase; P = .02). WSS levels of >50 dyn/cm[2] had a sensitivity of 100% and specificity of 67% in differentiating patients with adverse events (plaque rupture, cerebral infarction, stroke, or transient ischemic attack) compared with those without.
CONCLUSIONS: There is heterogeneity in sample size, study design, imaging protocols, image processing methodology, forces assessed, and adverse carotid plaque-related outcomes measured in the literature. Despite these limitations, increasing PWS and WSS were associated with adverse plaque outcomes consistently and predicted adverse outcomes with moderate to high degrees of sensitivity and specificity. Because the information available is heterogenous, these relationships need to be confirmed in larger prospective studies.}, }
@article {pmid40378608, year = {2025}, author = {Ahmad, K and Henikoff, S}, title = {Profiling regulatory elements in vivo by genome-wide methods.}, journal = {Current opinion in structural biology}, volume = {92}, number = {}, pages = {103064}, doi = {10.1016/j.sbi.2025.103064}, pmid = {40378608}, issn = {1879-033X}, mesh = {Chromatin/metabolism/genetics ; Humans ; Animals ; *Regulatory Sequences, Nucleic Acid/genetics ; *Genome ; DNA/metabolism/genetics ; *Genomics/methods ; }, abstract = {The biology of gene regulation in eukaryotic genomes is a mature field. The biochemical principles of factor binding to DNA are well-known from in vitro studies, as are the structural interactions in which specific domains of these proteins interface across a short stretch of DNA to confer sequence-specific recognition. Whereas the basic principles of binding and dissociation defined in vitro apply in vivo, the living nucleus is a dynamic compartment crowded with molecules, including motors that drive chromatin movements critical for the regulation of gene expression. Understanding these dynamics in vivo has spurred the development of cutting-edge technologies to observe factor-DNA interactions. The biological significance of chromatin dynamics is now revealed by a wide variety of high-resolution chromatin profiling methods.}, }
@article {pmid40378559, year = {2025}, author = {Bakaloudi, DR and Talukder, R and Enright, T and Leary, JB and Makrakis, D and Diamantopoulos, LN and Hobeika, C and Thomas, VM and Swami, U and Zakopoulou, R and Bamias, A and Brown, JR and Pinato, DJ and Latchford, C and Jindal, T and Koshkin, VS and Murgić, J and Miletić, M and Frobe, A and Johnson, J and Zakharia, Y and Alva, A and Nguyen, CB and Hui, G and Drakaki, A and Rodriguez-Vida, A and Rey-Cárdenas, M and Castellano, D and Buznego, LA and Duran, I and Barrera, RM and Marmolejo, D and McKay, RR and Stewart, TF and Barata, P and Epstein, IB and Bellmunt, J and Yu, EY and Raychaudhuri, R and Nadal, R and Vakar-Lopez, F and Gupta, S and Wright, JL and Khaki, AR and Grivas, P}, title = {Response and Survival With Immune Checkpoint Inhibitor in Patients With Advanced Urothelial Carcinoma and Histology Subtypes.}, journal = {Clinical genitourinary cancer}, volume = {23}, number = {4}, pages = {102356}, doi = {10.1016/j.clgc.2025.102356}, pmid = {40378559}, issn = {1938-0682}, abstract = {BACKGROUND: Immune Checkpoint Inhibitors (ICIs) are used for advanced urothelial carcinoma (aUC) in different settings. Most patients have pure UC (PUC) but about one-third have UC mixed with histology subtypes (HS). We examined outcomes in patients with HS aUC treated with ICI.
MATERIALS AND METHODS: We included patients from 26 centers with PUC and any HS treated with ICI as 1st line (1L) upfront, maintenance avelumab (mAV), and ≥2nd line [2+L] therapy. We calculated overall and progression-free survival (OS, PFS) and observed response rate (ORR) from ICI start.
RESULTS: We included 1511 patients; 752 1L, 609 2+L, 150 mAV. 1L: median OS was 15 (95% CI, 12-17) months for patients with PUC (n = 518), 15 (95% CI, 8-23) months for squamous UC (n = 85) (HR = 1.2, [95% CI, 0.8-1.6]), 11 (95% CI, 6-17) months for micropapillary UC (n = 46) (HR = 1.2, [95% 0.8-1.8]), and 21 (95% CI, 12-30) months in patients with UC mixed with ≥2 HS (n = 30), (HR = 0.9, [95% CI, 0.5-1.4]). 2+L: median OS was 9 (95% CI, 8-10) months for patients with PUC (n = 441), 9 (95% CI, 1-12) months for squamous UC (n = 60) (HR = 1.1, (95% CI, 0.8-1.6]), 6 (95% CI, 1-11) months for micropapillary UC (n = 37) (HR = 1.1, [95% 0.7-1.6]), and 7 (95% CI, 4-10) months in patients with UC mixed with ≥2 HS (n = 17), (HR = 1.6, [95% CI, 0.9-3.1]).
CONCLUSION: We found no significant OS difference between PUC and HS in patients with aUC treated with ICI monotherapy. Limitations include retrospective design, small sample size in several subsets, lack of randomization, no central imaging or pathology review, selection and confounding biases. Results are hypothesis-generating and need prospective validation.}, }
@article {pmid40377378, year = {2025}, author = {Subramanian, NG and Guffey, D and Avery, J and Garcia, D and Basom, R and Lee, SJ and Klein, K and Kebriaei, P and Rondon, G and Shpall, E and Jin, S and Young, E and Rojas Hernandez, CM and Li, A}, title = {Clinical Factors Associated With Catheter-Related VTE in Patients Undergoing Hematopoietic Cell Transplantation: A Multi-Center Study.}, journal = {American journal of hematology}, volume = {100}, number = {8}, pages = {1463-1466}, pmid = {40377378}, issn = {1096-8652}, support = {K23 HL159271/HL/NHLBI NIH HHS/United States ; //Conquer Cancer Foundation/ ; 3OT2OD032581-01S1//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; RR190104//Cancer Prevention and Research Institute of Texas/ ; //American Society of Hematology/ ; K23 HL159271/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid40377211, year = {2025}, author = {Dadafarin, S and Alvi, MA and Massa, ST and Veatch, J and Rizvi, ZH}, title = {Survival Correlates With Adjuvant Choice in Sentinel Node Positive Head and Neck Cutaneous Melanoma.}, journal = {The Laryngoscope}, volume = {}, number = {}, pages = {}, doi = {10.1002/lary.32269}, pmid = {40377211}, issn = {1531-4995}, support = {1R25DC021791-01/DC/NIDCD NIH HHS/United States ; }, abstract = {OBJECTIVE(S): The objective of this study is to evaluate the utilization and outcomes of completion lymph node dissection (CLND) and immunotherapy for sentinel lymph node biopsy (SLNB) positive head and neck cutaneous melanoma (HNCM).
METHODS: Patients with primary HNCM and positive SLNB in the 2020 National Cancer Database (NCDB) Melanoma file were reviewed. The frequency of CLND and immunotherapy was tracked from 2012 to 2019. Clinicodemographic features of patients were evaluated with respect to their post-SLNB treatment choice. Overall survival (OS) was calculated from the time of diagnosis, and the association of therapy choice with survival was determined using a multivariate Cox regression analysis.
RESULTS: The rates of CLND declined from 66% to 18% while adjuvant immunotherapy increased to a peak of approximately 40%, with an inflection point occurring in 2016. Multivariate survival analysis indicated that immunotherapy use alone, though not CLND, was associated with improved prognosis (hazard ratio 0.65, 95% confidence interval 0.45-0.93). Patient characteristics associated with immunotherapy administration included age (p < 0.01), insurance type (p = 0.002), income (p < 0.001), and healthcare facility type (p = 0.005).
CONCLUSION: In this retrospective NCDB-based study, we find that the modern management of SLNB-positive patients has shifted towards greater use of adjuvant immunotherapy and a decline in CLND; the use of immunotherapy is associated with improved OS. Patients treated with immunotherapy were more likely to be younger, of higher income, and with private health insurance.}, }
@article {pmid40376505, year = {2025}, author = {Li, Y and Zheng, J and Mlacha, YP and Lu, S and Abdulla, S and Li, Q and Yan, G and Zhou, X and Xiao, N and Githu, V and Gavana, T and Chaki, P and Bi, P and Sui, Y and Wang, Y and Wang, D}, title = {Impact of Implementation Interruptions of 1,7-Malaria Reactive Community-Based Testing and Response Approach on Malaria Control Efforts - Southern Tanzania.}, journal = {China CDC weekly}, volume = {7}, number = {18}, pages = {628-634}, pmid = {40376505}, issn = {2096-7071}, abstract = {INTRODUCTION: Surveys from the China-Tanzania Malaria Control Project demonstrated that the 1,7-malaria Reactive Community-Based Testing and Response (1,7-mRCTR) approach significantly reduced malaria incidence rates. However, implementation was disrupted by security concerns, infectious disease outbreaks, and supply shortages. This study evaluates how these interruptions affected intervention effectiveness to inform future malaria control strategies.
METHODS: The study employed a two-phased design: Phase I (2016-2018) and Phase II (2019-2021). Weekly malaria incidence rates per 100 people were calculated from cases reported by local health facilities in the intervention areas during both phases. Seasonal and trend decomposition using loess (STL) and interrupted time series modeling with piecewise linear regression were used to evaluate the impact of disruptions on 1,7-mRCTR implementation effectiveness.
RESULTS: In Tanzania's 1,7-mRCTR areas, malaria incidence peaked during November-December and June-July. Phase I's 8-month interruption reversed the weekly trend from a 0.17% decline to a 0.58% increase (P=0.001). After resumption, incidence dropped 8.96% (P=0.039) and maintained a 0.39% long-term decline (P=0.003). Even with seasonal adjustment, the interruption slowed the weekly decline from 0.08% to 0.07% (P=0.003). Phase II showed a similar pattern: a one-week interruption caused a 0.70% drop (P=0.007) but shifted the trend from a 0.02% decline to a 0.08% increase (P=0.001). After resumption, interventions stabilized the decline at 0.11% weekly (P=0.001).
CONCLUSIONS: This research demonstrates that Tanzania's malaria incidence is closely linked to seasonal patterns and consistent intervention efforts. Phase I's 8-month security-related interruption reduced 1,7-mRCTR effectiveness by 12.5%, while Phase II's 3-month pandemic-induced interruption caused only short-term fluctuations with minimal long-term impact. Rapid resumption of interventions after disruptions allowed for prompt recovery, highlighting the importance of adaptive strategies to maintain progress toward malaria control goals.}, }
@article {pmid40376501, year = {2025}, author = {Wang, S and Ding, W and Lu, S and Li, L and Qian, F and Chen, C and Liu, L and Cai, Y and Liu, X and Perez, S and Frutos, R and Yao, H and Zhou, Y and Ye, C and Wu, D and Li, S and Kwete, XJ and Sui, Y and Wang, D}, title = {China's Malaria R&D Innovations: A Scoping Review from 2013-2023.}, journal = {China CDC weekly}, volume = {7}, number = {18}, pages = {635-643}, pmid = {40376501}, issn = {2096-7071}, abstract = {Malaria remains a major global health challenge. Understanding the research progress of the potential innovative tools is important for malaria elimination. This scoping review aims to explore China's research and development (R&D) advances from 2013-2023 in addressing the current challenges and contributing to global malaria elimination. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), this review searched the English and Simplified Chinese data sources from five databases. A total of 11,112 English articles and 2,944 Chinese articles were retrieved. After screening, 44 English and 13 Chinese articles were included. Key advancements were identified in three domains: vector control, pathogen screening and diagnosis, and prevention and treatment. Innovations in vector control include studies such as the use of Serratia strains and symbiont-mediated RNAi approaches to block malaria transmission. Advances in pathogen screening and diagnosis feature biosensor development, AI monitoring technologies, and novel amplification gene and nucleic acid detection technologies. In prevention and treatment, artemisinin-based combination therapies (ACTs) remain a cornerstone, with additional progress in industrial pharmaceuticals and technologies already in field and semi-field-testing stages. This review underscores the importance of leveraging China's R&D capacity to meet global challenges. To maximize impact, we call for global attention to strengthening international collaboration with China in malaria R&D to accelerate the commercialization, regulatory approval, and large-scale deployment of innovations.}, }
@article {pmid40374764, year = {2025}, author = {Kwak, JW and Houghton, AM}, title = {Targeting neutrophils for cancer therapy.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, pmid = {40374764}, issn = {1474-1784}, abstract = {Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes - including those with antitumour activity - and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.}, }
@article {pmid40373766, year = {2025}, author = {Sajadi, MM and Abbasi, A and Tehrani, ZR and Siska, C and Clark, R and Chi, W and Seaman, MS and Mielke, D and Wagh, K and Liu, Q and Jumpa, T and Ketchem, RR and Nguyen, DN and Tolbert, WD and Pierce, BG and Atkinson, B and Deming, D and Sprague, M and Asakawa, A and Ferrer, D and Dunn, Y and Calvillo, S and Yin, R and Guest, JD and Korber, B and Mayer, BT and Sato, AH and Ouyang, X and Foulke, S and Habibzadeh, P and Karimi, M and Aslanabadi, A and Hojabri, M and Saadat, S and Zareidoodeji, R and Kędzior, M and Pozharski, E and Heredia, A and Chen, H and Montefiori, D and Ferrari, G and Pazgier, M and Lewis, GK and Jardine, JG and Lusso, P and DeVico, A}, title = {A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {7}, pages = {1150-1164.e8}, pmid = {40373766}, issn = {1878-4186}, support = {I01 BX004525/BX/BLRD VA/United States ; INV-036842/GATES/Gates Foundation/United States ; R01 AI155150/AI/NIAID NIH HHS/United States ; R01 AI147870/AI/NIAID NIH HHS/United States ; P01 AI162242/AI/NIAID NIH HHS/United States ; R01 AI174908/AI/NIAID NIH HHS/United States ; INV-005284/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *HIV Antibodies/chemistry/immunology/genetics/pharmacology ; *Antibodies, Neutralizing/chemistry/immunology/genetics/pharmacology ; *Protein Engineering ; *HIV-1/immunology ; HIV Infections/immunology ; CD4 Antigens/immunology/metabolism ; Animals ; Broadly Neutralizing Antibodies/chemistry ; }, abstract = {Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.}, }
@article {pmid40373748, year = {2025}, author = {Kublin, JG}, title = {Antibiotics fire up inflammation to cool vaccine responsiveness.}, journal = {Cell host & microbe}, volume = {33}, number = {5}, pages = {618-620}, doi = {10.1016/j.chom.2025.04.015}, pmid = {40373748}, issn = {1934-6069}, mesh = {Humans ; *Anti-Bacterial Agents/adverse effects ; *Inflammation/chemically induced/immunology ; *Rabies Vaccines/immunology/administration & dosage ; *Gastrointestinal Microbiome/drug effects/immunology ; Vaccination ; Animals ; }, abstract = {In this issue of Cell Host & Microbe, Feng et al. find that broad-spectrum antibiotics perturbed the ecology of the gut microbiome in individuals receiving a rabies vaccine, resulting in systemic inflammatory responses. Such inflammation is hypothesized to alter immune homeostasis with consequences for immunological responsiveness to vaccination.}, }
@article {pmid40373198, year = {2025}, author = {Davis, MR and Kufel, JE and Kufel, WD and McCreary, EK and Oleksiuk, LM and Ours, R and Pham, CU and Ross, JK and Smith, EA and Trisler, MJ and Tverdek, F}, title = {You've Got a Friend in Me: Curbside Questions Infectious Diseases Clinicians Ask Infectious Diseases Pharmacists.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf250}, pmid = {40373198}, issn = {1537-6591}, abstract = {This multicenter study highlights the critical role of ID pharmacists in supporting ID consult services, with 89% of 1,518 curbside inquiries from ID clinicians resulting in clinical management changes as recommended by the pharmacist. These findings emphasize the necessity of ID pharmacists in optimizing multidisciplinary patient care.}, }
@article {pmid40373114, year = {2025}, author = {Caniels, TG and Prabhakaran, M and Ozorowski, G and MacPhee, KJ and Wu, W and van der Straten, K and Agrawal, S and Derking, R and Reiss, EIMM and Millard, K and Turroja, M and Desrosiers, A and Bethony, J and Malkin, E and Liesdek, MH and van der Veen, A and Klouwens, M and Snitselaar, JL and Bouhuijs, JH and Bronson, R and Jean-Baptiste, J and Gajjala, S and Rikhtegaran Tehrani, Z and Benner, A and Ramaswami, M and Duff, MO and Liu, YW and Sato, AH and Kim, JY and Baken, IJL and Mendes Silva, C and Bijl, TPL and van Rijswijk, J and Burger, JA and Cupo, A and Yasmeen, A and Phulera, S and Lee, WH and Randall, KN and Zhang, S and Corcoran, MM and Regadas, I and Sullivan, AC and Brown, DM and Bohl, JA and Greene, KM and Gao, H and Yates, NL and Sawant, S and Prins, JM and Kootstra, NA and Kaminsky, SM and Barin, B and Rahaman, F and Meller, M and Philiponis, V and Laufer, DS and Lombardo, A and Mwoga, L and Shotorbani, S and Holman, D and Koup, RA and Klasse, PJ and Karlsson Hedestam, GB and Tomaras, GD and van Gils, MJ and Montefiori, DC and McDermott, AB and Hyrien, O and Moore, JP and Wilson, IA and Ward, AB and Diemert, DJ and de Bree, GJ and Andrews, SF and Caskey, M and Sanders, RW}, title = {Precise targeting of HIV broadly neutralizing antibody precursors in humans.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eadv5572}, doi = {10.1126/science.adv5572}, pmid = {40373114}, issn = {1095-9203}, abstract = {A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, that target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.}, }
@article {pmid40373112, year = {2025}, author = {Willis, JR and Prabhakaran, M and Muthui, M and Naidoo, A and Sincomb, T and Wu, W and Cottrell, CA and Landais, E and deCamp, AC and Keshavarzi, NR and Kalyuzhniy, O and Lee, JH and Murungi, LM and Ogonda, WA and Yates, NL and Corcoran, MM and Phulera, S and Musando, J and Tsai, A and Lemire, G and Sein, Y and Muteti, M and Alamuri, P and Bohl, JA and Holman, D and Himansu, S and Leav, B and Reuter, C and Lin, LA and Ding, B and He, C and Straus, WL and MacPhee, KJ and Regadas, I and Nyabundi, DV and Chirchir, R and Anzala, A and Kimotho, JN and Kibet, C and Greene, K and Gao, H and Beatman, E and Benson, K and Laddy, D and Brown, DM and Bronson, R and Baptiste, J and Gajjala, S and Rikhtegaran-Tehrani, Z and Benner, A and Ramaswami, M and Lu, D and Alavi, N and Amirzehni, S and Kubitz, M and Tingle, R and Georgeson, E and Phelps, N and Adachi, Y and Liguori, A and Flynn, C and McKenney, K and Zhou, X and Owuor, DC and Owuor, S and Kim, SY and Duff, M and Kim, JY and Gibson, G and Baboo, S and Diedrich, J and Schiffner, T and Shields, M and Matsoso, M and Santos, J and Syvertsen, K and Kennedy, A and Schroeter, M and Vekemans, J and Yates, J and Paulson, JC and Hyrien, O and McDermott, AB and Maenetje, P and Nyombayire, J and Karita, E and Ingabire, R and Edward, V and Muturi-Kioi, V and Maenza, J and Shapiro, AE and McElrath, MJ and Edupuganti, S and Taylor, BS and Diemert, D and Ozorowski, G and Koup, RA and Montefiori, D and Ward, AB and Hedestam, GK and Tomaras, G and Hunt, DJ and Muema, D and Sok, D and Laufer, DS and Andrews, SF and Nduati, EW and Schief, WR}, title = {Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eadr8382}, doi = {10.1126/science.adr8382}, pmid = {40373112}, issn = {1095-9203}, abstract = {A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI-G002 in the United States and IAVI-G003 in Rwanda and South Africa, we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI-G002). The vaccines were generally safe and well tolerated, except 18% of IAVI-G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM, and heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development. The results establish clinical proof of concept that heterologous boosting can advance bnAb-precursor maturation and demonstrate bnAb priming in Africa where the HIV burden is highest.}, }
@article {pmid40372917, year = {2025}, author = {Alassaf, M and Madan, A and Ranganathan, S and Marschall, S and Wong, JJ and Goldberg, ZH and Brent, AE and Rajan, A}, title = {Adipocyte metabolic state regulates glial phagocytic function.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115704}, pmid = {40372917}, issn = {2211-1247}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, mesh = {Animals ; *Neuroglia/metabolism ; *Adipocytes/metabolism ; *Phagocytosis ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Mitochondria/metabolism ; Glycolysis ; Apolipoproteins B/metabolism ; Lipid Metabolism ; Brain/metabolism ; Membrane Proteins/metabolism ; }, abstract = {Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.}, }
@article {pmid40372253, year = {2025}, author = {Elkholi, IE and Robert, A and Malouf, C and Wu, JL and Kuasne, H and Drapela, S and Macleod, G and Hébert, S and Pacis, A and Calderon, V and Kleinman, CL and Gomes, AP and Alvarez, JV and Aguirre-Ghiso, JA and Park, M and Angers, S and Côté, JF}, title = {Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation.}, journal = {Cancer research}, volume = {85}, number = {12}, pages = {2179-2198}, pmid = {40372253}, issn = {1538-7445}, support = {//U.S. Department of Defense (DOD)/ ; P30CA013330//National Cancer Institute (NCI)/ ; //Miles for Moffit/ ; R01 CA292658/CA/NCI NIH HHS/United States ; R01 CA109182/CA/NCI NIH HHS/United States ; //The Gurwin Foundation/ ; //Melanoma Research Alliance (MRA)/ ; //Quebec Breast Cancer Foundation/ ; //Samuel Waxman Cancer Research Foundation (SWCRF)/ ; CA253977//National Cancer Institute (NCI)/ ; //Diane and Sal Guerrera Chair in Cancer Genetics/ ; U01 CA284085/CA/NCI NIH HHS/United States ; RSG-22-164-01-MM//American Cancer Society (ACS)/ ; //Institut de Recherche Clinique De Montréal Foundation/ ; //Calcul Quebec/ ; CA284085//National Cancer Institute (NCI)/ ; FDN-143281//Canadian Institutes of Health Research (CIHR)/ ; //Fonds de Recherche du Québec - Santé (FRQS)/ ; CA109182//National Cancer Institute (NCI)/ ; //Compute Canada (Calcul Canada)/ ; PJT-156086//Canadian Institutes of Health Research (CIHR)/ ; //Canada Research Chairs (Chaires de recherche du Canada)/ ; 25244//Cancer Research Society (CRS)/ ; R01CA292658//National Cancer Institute (NCI)/ ; //Peter Quinlan Postdoctoral research Fellowship in Oncology/ ; R01 CA253977/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; //The Mark Foundation Aspire Program/ ; //Rose C. Falkenstein Chair in Cancer Research/ ; //Canadian Cancer Society (CCS)/ ; }, mesh = {*Mechanistic Target of Rapamycin Complex 1/metabolism/antagonists & inhibitors/genetics ; Animals ; Humans ; Female ; *Breast Neoplasms/pathology/metabolism/genetics/drug therapy ; Mice ; Signal Transduction/drug effects ; *Class III Phosphatidylinositol 3-Kinases/metabolism/antagonists & inhibitors/genetics ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Neoplasm Metastasis ; Mice, Inbred BALB C ; }, abstract = {UNLABELLED: Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07 cells displayed a unique dependency on class III PI3K (PIK3C3). Unexpectedly, 4T07 cells exhibited higher mechanistic target of rapamycin complex 1 (mTORC1) activity than 4T1 cells due to lysosome-dependent signaling occurring at the cell periphery. Pharmacologic inhibition of PIK3C3 suppressed this phenotype in the 4T1-4T07 models as well as in human breast cancer cell lines and a breast cancer patient-derived xenograft. Furthermore, inhibiting PIK3C3 selectively reduced metastasis burden in the 4T07 model and eliminated dormant cells in a HER2-dependent murine breast cancer dormancy model. These findings suggest that PIK3C3-peripheral lysosomal signaling to mTORC1 may represent a targetable axis for preventing dormant cancer cell-initiated metastasis in patients with breast cancer.
SIGNIFICANCE: Dormancy-prone breast cancer cells depend on the class III PI3K to mediate peripheral lysosomal positioning and mTORC1 hyperactivity, which can be targeted to blunt breast cancer metastasis.}, }
@article {pmid40372237, year = {2025}, author = {Hullar, MA and Kahsai, OJ and Hill, C and Levy, L and Malen, RC and Curtis, KR and Ammar, H and Sillah, A and Reedy, AM and Lampe, JW and Ogino, S and Potter, JD and Newcomb, PA and Phipps, AI}, title = {Highly sensitive DNA testing of Fusobacterium nucleatum (Fn) in colorectal tumors.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1020}, pmid = {40372237}, issn = {1538-7755}, abstract = {BACKGROUND: Fusobacterium nucleatum (Fn) has been associated with risk of colorectal cancer (CRC), poorer CRC survival, and tumor attributes. Accurate and sensitive detection of Fn in tumor tissue is critical to evaluating their role in CRC.
METHODS: We developed a droplet digital PCR (ddPCR) assay for detecting Fn, using the transcription termination/anti-termination gene (nusG) normalized for host tissue (solute carrier organic anion transporter family member 2A1, SLCO2A1). We assayed Fn(nusG), in matched tumor and normal tissue, for 613 participants in the Seattle site of the Colon Cancer Family Registry (SCCFR). We used logistic regression to determine the odds of Fn enrichment in tumor tissue according to tumor site and stage, adjusting for age, sex, and body mass index.
RESULTS: The limit of quantitation for Fn(nusG) was 4.1 copies/10 ng host tissue. Detection of Fn was quenched and more poorly detected at low levels in FFPE tissues using qPCR. There was low agreement between qPCR and ddPCR (Cohen's kappa = 0.46). Fn(nusG) was detected in tumor (21%) and normal (10%) tissue and enriched in 19% of tumors. Individuals with tumors enriched in Fn were more likely to be female (59% vs. 48%, respectively, p=0.04) with proximal colon tumors (57% vs 43%, p=0.026). In multivariable-adjusted analyses, proximal colon tumors were significantly associated with Fn enrichment (odds ratio vs. rectal tumors: 1.86; 95% CI: 1.11 to 3.24).
CONCLUSIONS: We established a sensitive and specific method to detect Fn enrichment in human tissues.
IMPACT: ddPCR enhanced detection of Fn(nusG) for studies targeting tumor-associated bacteria.}, }
@article {pmid40371912, year = {2025}, author = {Wesselink, E and Thomas, CE and Takashima, Y and Mizuno, H and Buchanan, DD and Qu, C and Hsu, L and Dias Costa, A and Ugai, S and Zhong, Y and Huyghe, JR and Thomas, S and Gallinger, S and Grant, RC and Le Marchand, L and Masugi, Y and van Duijnhoven, FJ and Ugai, T and Ogino, S and Nowak, JA and Peters, U and Phipps, AI}, title = {Associations between calcium intake and T cell infiltration in colorectal tumours.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-25-0023}, pmid = {40371912}, issn = {1940-6215}, abstract = {Higher T cell infiltration in colorectal tumours has been associated with better prognosis. Evidence indicates that calcium signalling is essential for T cells functioning. However, as it is unknown whether calcium intake influences T cell infiltration, we investigated the association of calcium intake with T cell subsets in the tumour microenvironment of colorectal cancer. In total, 943 participants from three cohort studies, for which data on tumour infiltrating T cells and calcium intake was available, were included for these analyses. Immune cell infiltration was quantified by digital image analyses with machine learning algorithms using a customized 9-plex multispectral immunofluorescence assay (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, DAPI). Associations between pre-diagnostic calcium intake and densities of non-overlapping subsets of epithelial and stromal tissue area T cells were assessed using multivariable binary or ordinal logistic regression analyses. A higher dietary calcium intake was positively associated with CD3+CD4-CD8- double negative T cells density in the epithelial (OR 1.57; 95% CI 1.13-2.24) and stromal (OR 1.24; 95%CI 1.06-1.45) tumour tissue area. No other statistically significant associations were observed after correcting for multiple testing. In conclusion, dietary calcium intake was associated with a higher density of CD4-CD8- double negative T cells in the epithelial and stromal tumour tissue area, but not with infiltration of CD4+ or CD8+ T cells. More research is needed to further unravel the role of calcium in tumour immune profiles and associations with clinical outcomes. Our findings offer a promising basis for further research.}, }
@article {pmid40369385, year = {2025}, author = {Manohar, PM and Peterson, LM and Jenkins, IC and Wu, QV and Kurland, BF and Novakova-Jiresova, A and Muzi, M and Chen, DL and Specht, JM and Dintzis, S and Kinahan, PE and Mankoff, DA and Linden, HM}, title = {[18 F]-Fluoroestradiol PET (FES-PET) and [18 F] Flurodeoxyglucose PET (FDG-PET) Imaging May Aid in Managing Therapy in Patients with Metastatic Lobular Breast Cancer.}, journal = {Molecular imaging and biology}, volume = {27}, number = {3}, pages = {410-420}, pmid = {40369385}, issn = {1860-2002}, support = {R50 CA211270/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fluorodeoxyglucose F18/chemistry ; Female ; *Breast Neoplasms/diagnostic imaging/pathology/therapy ; Middle Aged ; *Positron-Emission Tomography/methods ; Aged ; Adult ; *Estradiol/analogs & derivatives/chemistry ; Neoplasm Metastasis ; *Carcinoma, Lobular/diagnostic imaging/therapy/pathology ; Retrospective Studies ; Aged, 80 and over ; }, abstract = {AIM: This study examines the combination of FES-PET and FDG-PET as complementary imaging for detection of metastatic ILC.
METHODS: We retrospectively evaluated FES and FDG uptake in patients with metastatic ILC from an estrogen receptor (ER) positive primary tumor. We classified lesions into three categories (FES high/FDG low, FES high/FDG high, FES low/FDG low) using SUVmax cut-off values of 1.5 for FES and 5.0 for FDG. Qualitative evaluation included examination of the difference in the extent of disease between FES and FDG.
RESULTS: Of the 38 patients, 82% had FES uptake in all tumor sites identified by FDG, with 18% lacking FES uptake in at least one lesion. Mean (range) SUVmax for FES and FDG was 4.0 (0.67-10.6) and 4.6 (1.3-12.5), respectively. The majority of ILC patients (25/38), had lesions with FES high/FDG low uptake, consistent with the strongly ER + indolent nature of ILC. Patients with disease classified as FES high/FDG low had longer median overall survival (OS) (3.2 years) and progression-free survival (PFS) (1.5 years) than FES high/FDG high (OS = 2.1 years and PFS = 0.46 years). The median overall OS for all patients was 3.0 years (95% CI 2.5, 4.8) and PFS of 1.3 years (95% CI 0.6, 2.5). 8 patients (21%) had qualitatively more extensive disease by FES-PET.
CONCLUSIONS: Our findings suggest that both FES-PET and FDG-PET can identify metastatic ILC and be useful in detecting the pattern and extent of disease. The imaging combination provides additional information for prognosis and clinical decision making, balancing suitability for endocrine therapy and aggressiveness/indolence of disease.}, }
@article {pmid40368142, year = {2025}, author = {Friedman, RK and Heath, AS and Huffman, JE and Baker, JT and Hasbani, NR and Gagliano Taliun, SA and Chen, MH and Howard, TE and Lewis, JP and Pankratz, N and Patil, S and Reiner, AP and Thibord, F and Yanek, LR and Yao, J and Chen, HH and Curran, JE and Faraday, N and Guo, X and Wheeler, MM and Ryan, KA and Zhou, X and Cho, K and Almasy, L and Auer, PL and Becker, LC and Wilson, PWF and Boerwinkle, E and O'Connell, JR and Rich, SS and Samuels, DC and , and , and , and Blangero, J and Fornage, M and Kooperberg, C and Mathias, RA and Mitchell, BD and Rotter, JI and Johnson, AD and Smith, NL and Coban-Akdemir, ZH and Below, JE and Morrison, AC and Johnsen, JM and de Vries, PS}, title = {Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtha.2025.04.029}, pmid = {40368142}, issn = {1538-7836}, abstract = {BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored.
OBJECTIVES: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL.
METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels ≤ 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen.
RESULTS: Variants at 2 loci were associated (P < 5 × 10[-9]) with VWF:Ag levels ≤ 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels ≤ 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54).
CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤ 50 IU/dL, bleeding, and VWD.}, }
@article {pmid40368025, year = {2025}, author = {Park, ER and Kirchhoff, AC and Mitchell, CO and Durieux, N and Foor, A and Kuhlthau, K and Perez, GK and Ards, L and Alston, S and Armstrong, GT and Vaca Lopez, PL and McDonald, A and Nolan, VG and Levy, DE and Leisenring, WM and Galbraith, AA and Nathan, PC and Vukadinovich, C and Cooper, CL and Donelan, K}, title = {Assessing the effect of virtual navigation interventions to improve health insurance literacy and decrease financial burden in cancer survivors: The HINT II study protocol.}, journal = {Contemporary clinical trials}, volume = {154}, number = {}, pages = {107952}, pmid = {40368025}, issn = {1559-2030}, support = {R01 CA271380/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors ; *Health Literacy/organization & administration/methods ; *Insurance, Health ; *Patient Navigation/organization & administration ; Health Expenditures/statistics & numerical data ; Randomized Controlled Trials as Topic ; *Neoplasms/economics/therapy ; Adult ; Patient Acceptance of Health Care/statistics & numerical data ; Cost of Illness ; Male ; }, abstract = {BACKGROUND: Childhood cancer survivors often face high healthcare costs to monitor and manage new or lasting effects of their treatment. Enhancing survivors' health insurance literacy (HIL) - the knowledge, ability, and confidence in enrolling in and navigating health plans - is vital for minimizing financial burden. Few studies have assessed the effect of a health insurance navigation program on improving HIL among survivors. We present the protocol for an ongoing randomized controlled trial (RCT) assessing the effectiveness of two health insurance navigation programs (HINT-S and HINT-A) on improving HIL, financial burden, out-of-pocket costs, and healthcare utilization for adult survivors of childhood cancer.
METHODS: This three-arm RCT assesses the effectiveness of two digitally delivered health insurance navigation interventions and enhanced usual care (EUC) on improving HIL at six and 12 months in a national cohort of childhood cancer survivors. While HINT-S is composed of five synchronous, navigator-led sessions, HINT-A is an asynchronous, prerecorded set of five videos. EUC participants receive only a health insurance informational booklet. Financial burden, medical out-of-pocket costs, and healthcare utilization (receipt of preventive care, recommended screenings/vaccinations, and acute care) are assessed at 12 months. Moderators to the interventions' effectiveness will be investigated, as well as implementation outcomes (feasibility, acceptability, appropriateness, fidelity, and cost-effectiveness).
CONCLUSIONS: There is a strong need for interventions to improve cancer survivors' HIL, helping them navigate the complexity of the U.S. healthcare system. This trial will elucidate the potential effectiveness and implementation of health insurance navigation programs that may benefit many cancer survivors.
TRIAL REGISTRATION: NCT05527392.}, }
@article {pmid40367160, year = {2025}, author = {Stepanov, I and Gottshall, NR and Ahmadianyazdi, A and Sinha, D and Lockhart, EJ and Nguyen, TNH and Hassan, S and Horowitz, LF and Yeung, RS and Gujral, TS and Folch, A}, title = {Low-cost robotic manipulation of live microtissues for cancer drug testing.}, journal = {Science advances}, volume = {11}, number = {20}, pages = {eads1631}, pmid = {40367160}, issn = {2375-2548}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Robotics/economics/instrumentation ; Drug Screening Assays, Antitumor/methods/economics/instrumentation ; *Antineoplastic Agents/pharmacology ; *Neoplasms/drug therapy/pathology ; Lab-On-A-Chip Devices ; }, abstract = {The scarcity of human biopsies available for drug testing is a paramount challenge for developing therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective, and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.}, }
@article {pmid40366394, year = {2025}, author = {Hardy, S and Chhan, CB and Davis, AR and McGuire, AT}, title = {Viral Entry.}, journal = {Current topics in microbiology and immunology}, volume = {}, number = {}, pages = {}, doi = {10.1007/82_2025_300}, pmid = {40366394}, issn = {0070-217X}, abstract = {Epstein-Barr virus chiefly infects B cells and epithelial cells but is capable of infecting other cell types in the human host. Host cell entry is a complex process mediated by several viral glycoproteins that define tropism and mediate membrane fusion. This chapter will review what is known about the function of viral glycoproteins in the entry process, explore the nature of interactions between viral glycoproteins and host cell receptors, and highlight gaps in knowledge about the entry process that remain to be filled.}, }
@article {pmid40365909, year = {2025}, author = {Levy, JA and Kazemian, E and Ramin, C and Loroña, NC and Nadri, M and Gasho, JO and Silos, KD and Nikolova, AP and Dey, D and Siegel, EM and Gigic, B and Hardikar, S and Byrd, DA and Toriola, AT and Ose, J and Li, CI and Shibata, D and Ulrich, CM and Tamarappoo, BK and Atkins, KM and Figueiredo, JC}, title = {Subclinical Atherosclerosis and Cardiovascular Events Among Patients With Colorectal Cancer.}, journal = {Cancer medicine}, volume = {14}, number = {10}, pages = {e70938}, pmid = {40365909}, issn = {2045-7634}, support = {P30CA042014//National Cancer Institute of the National Institutes of Health/ ; R01CA160684//National Cancer Institute of the National Institutes of Health/ ; R01CA189184//National Cancer Institute of the National Institutes of Health/ ; R01CA207371//National Cancer Institute of the National Institutes of Health/ ; R01CA215134//National Cancer Institute of the National Institutes of Health/ ; R01CA254108//National Cancer Institute of the National Institutes of Health/ ; R03CA270473//National Cancer Institute of the National Institutes of Health/ ; U01CA206110//National Cancer Institute of the National Institutes of Health/ ; U01CA246659//National Cancer Institute of the National Institutes of Health/ ; }, mesh = {Humans ; Male ; Female ; *Colorectal Neoplasms/complications/epidemiology/therapy ; Middle Aged ; Aged ; Prospective Studies ; *Atherosclerosis/epidemiology/etiology ; *Cardiovascular Diseases/epidemiology/etiology ; Risk Factors ; Positron Emission Tomography Computed Tomography ; Coronary Vessels/diagnostic imaging ; }, abstract = {BACKGROUND: Prior studies have documented that patients with colorectal cancer (CRC) are at an increased risk of cardiovascular disease (CVD).
OBJECTIVES: To examine coronary artery calcium (CAC) as a marker of subclinical atherosclerosis and its association with major adverse cardiovascular events (MACE) in patients with CRC across the cancer treatment trajectory.
METHODS: Adults with newly diagnosed CRC were enrolled in the prospective ColoCare study from 2017 to 2024. CAC was measured from routine diagnostic computed tomography (CT) and positron emission tomography-CT scans at CRC diagnosis until 5 years post-diagnosis. Atherosclerosis was defined as the presence of CAC. We used multivariable-adjusted Fine and Gray models to assess the association between CAC and MACE risk, accounting for competing risks.
RESULTS: Among 300 CRC patients, the most common CVD risk factors at cancer diagnosis were hypertension (37%), hyperlipidemia (24%), and diabetes (14%). During follow-up (median = 5.3 years), 75 (25%) individuals experienced MACE: stroke (3%), new/worsening HF (9%), HF exacerbation requiring hospitalization (2%), coronary revascularization (3%), and death (19%). Among individuals with imaging at baseline (n = 101), 37 (36.6%) had CAC, and statins were not prescribed in 11 (55.0%) patients with moderate/high CAC. For those with serial imaging (n = 61), 31.1% showed worsening CAC and 3% developed new CAC. Baseline CAC conferred a higher risk of MACE (HR = 4.79; 95% CI: 1.05-21.75, p = 0.04) after accounting for cancer-related deaths as a competing risk.
CONCLUSIONS: Subclinical atherosclerosis and MACE are common among patients with CRC. Integrating CAC from routine cancer imaging can identify patients who may benefit from cardio-preventive treatment.}, }
@article {pmid40365115, year = {2025}, author = {Restar, AJ and Lucas, R and Nfn, S and Alpert, AB and Phipps, A and Wang, G and Operario, D and Radix, A and van der Merwe, LA and Lindström, S and Everhart, A and Gamarel, KE and Streed, CG}, title = {Underinvested, Under-Referred, and Underserved: Applying a Gender Equity Continuum Framework in Cancer Control Continuum Programs and Policies to Expand to Transgender and Nonbinary Populations.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2400023}, pmid = {40365115}, issn = {2994-9750}, abstract = {Gender-inclusive and gender-specific approaches are critically needed in cancer control continuum services to recognize and meet the needs of transgender and nonbinary (trans) populations. Current research, programs, and policies largely cater to cisgender populations and subscribe to a binary, gendered cisnormative ideology, both within health care systems and insurance policies, leaving trans people's cancer prevention and treatment needs neglected. Such disparities can be attributed to the significant gap in funding and research to address trans cancer prevention and treatment. We discuss the research, program, and policy implications of cisnormative practices and provide recommendations for promoting gender-inclusive and specific services across the cancer control continuum with the goal of eliminating cancer disparities and improving cancer outcomes for people of all gender groups, including trans populations.}, }
@article {pmid40364978, year = {2025}, author = {Alavattam, KG and Dickson, BM and Hirano, R and Dell, R and Tsukiyama, T}, title = {ChIP-seq Data Processing and Relative and Quantitative Signal Normalization for Saccharomyces cerevisiae.}, journal = {Bio-protocol}, volume = {15}, number = {9}, pages = {e5299}, pmid = {40364978}, issn = {2331-8325}, abstract = {Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) is a widely used technique for genome-wide analyses of protein-DNA interactions. This protocol provides a guide to ChIP-seq data processing in Saccharomyces cerevisiae, with a focus on signal normalization to address data biases and enable meaningful comparisons within and between samples. Designed for researchers with minimal bioinformatics experience, it includes practical overviews and refers to scripting examples for key tasks, such as configuring computational environments, trimming and aligning reads, processing alignments, and visualizing signals. This protocol employs the sans-spike-in method for quantitative ChIP-seq (siQ-ChIP) and normalized coverage for absolute and relative comparisons of ChIP-seq data, respectively. While spike-in normalization, which is semiquantitative, is addressed for context, siQ-ChIP and normalized coverage are recommended as mathematically rigorous and reliable alternatives. Key features • ChIP-seq data processing workflow for Linux and macOS integrating data acquisition, trimming, alignment, processing, and multiple forms of signal computation, with a focus on reproducibility. • ChIP-seq signal generation using siQ-ChIP to quantify absolute IP efficiency-providing a rigorous alternative to spike-in normalization-and normalized coverage for relative comparisons. • Broad applicability demonstrated with Saccharomyces cerevisiae (experimental) and Schizosaccharomyces pombe (spike-in) data but suitable for ChIP-seq in any species. • In-depth notes and troubleshooting guide users through setup challenges and key concepts in basic bioinformatics, data processing, and signal computation. Graphical overview Flowchart depicting ChIP-seq data processing steps covered in this protocol.}, }
@article {pmid40364850, year = {2025}, author = {Rubinstein, S and Mohsin, A and Banerjee, R and Ma, W and Mishra, S and Kwok, M and Yang, P and Warner, JL and Cowan, AJ}, title = {Summarizing clinical evidence utilizing large language models for cancer treatments: a blinded comparative analysis.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1569554}, pmid = {40364850}, issn = {2673-253X}, abstract = {BACKGROUND: Concise synopses of clinical evidence support treatment decision-making but are time-consuming to curate. Large language models (LLMs) offer potential but they may provide inaccurate information. We objectively assessed the abilities of four commercially available LLMs to generate synopses for six treatment regimens in multiple myeloma and amyloid light chain (AL) amyloidosis.
METHODS: We compared the performance of four LLMs: Claude 3.5, ChatGPT 4.0; Gemini 1.0 and Llama-3.1. Each LLM was prompted to write synopses for six regimens. Two hematologists independently assessed accuracy, completeness, relevance, clarity, coherence, and hallucinations using Likert scales. Mean scores with 95% confidence intervals (CI) were calculated across all domains and inter-rater reliability was evaluated using Cohen's quadratic weighted kappa.
RESULTS: Claude demonstrated the highest performance in all domains, outperforming the other LLMs in accuracy: mean Likert score 3.92 (95% CI 3.54-4.29); ChatGPT 3.25 (2.76-3.74); Gemini 3.17 (2.54-3.80); Llama 1.92 (1.41-2.43);completeness: mean Likert score 4.00 (3.66-4.34); GPT 2.58 (2.02-3.15); Gemini 2.58 (2.02-3.15); Llama 1.67 (1.39-1.95); and extentofhallucinations: mean Likert score 4.00 (4.00-4.00); ChatGPT 2.75 (2.06-3.44); Gemini 3.25 (2.65-3.85); Llama 1.92 (1.26-2.57). Llama performed considerably poorer across all the studied domains. ChatGPT and Gemini had intermediate performance. Notably, none of the LLMs registered perfect accuracy, completeness, or relevance.
CONCLUSION: Claude performed at a consistently higher level than other LLMs, all tested LLMs required careful editing from a domain expert to become usable. More time will be needed to determine the suitability of LLMsto independently generate clinical synopses.}, }
@article {pmid40364846, year = {2025}, author = {Battisti, P and Ykema, MR and Kasal, DN and Jennewein, MF and Beaver, S and Weight, AE and Hanson, D and Singh, J and Bakken, J and Cross, N and Fusco, P and Archer, J and Reed, S and Gerhardt, A and Julander, JG and Casper, C and Voigt, EA}, title = {A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1569454}, pmid = {40364846}, issn = {1664-3224}, support = {75N93019C00059/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Zika Virus/immunology ; *Zika Virus Infection/prevention & control/immunology ; Antibodies, Neutralizing/immunology/blood ; Mice ; *Yellow fever virus/immunology ; Antibodies, Viral/immunology/blood ; *Yellow Fever/prevention & control/immunology ; Mice, Inbred C57BL ; Cricetinae ; *Viral Vaccines/immunology ; Female ; Mesocricetus ; CD8-Positive T-Lymphocytes/immunology ; *Yellow Fever Vaccine/immunology ; Immunogenicity, Vaccine ; }, abstract = {INTRODUCTION: Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases.
METHODS: YFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized.
RESULTS AND DISCUSSION: Monovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4[+] and CD8[+] T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases.}, }
@article {pmid40360879, year = {2025}, author = {Wang'ondu, RW and Ashcraft, E and Chang, TC and Roberts, KG and Brady, SW and Fan, Y and Evans, W and Relling, MV and Crews, KR and Yang, J and Yang, W and Pounds, S and Wu, G and Devidas, M and Maloney, K and Mattano, L and Schore, RJ and Angiolillo, A and Larsen, E and Salzer, W and Burke, MJ and Loh, ML and Jeha, S and Pui, CH and Inaba, H and Cheng, C and Mullighan, CG}, title = {Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia.}, journal = {Leukemia}, volume = {39}, number = {7}, pages = {1595-1606}, pmid = {40360879}, issn = {1476-5551}, support = {P30 CA021765 and R35 CA197695//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA98543, U10 CA180886, U10 CA98413, U10 CA180899, U24 CA114766, U24-CA196173//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; American Society of Hematology Minority Hematology Fellow award//American Society of Hematology (ASH)/ ; }, mesh = {Humans ; *Ikaros Transcription Factor/genetics ; Child ; Female ; Male ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology/mortality ; Child, Preschool ; Adolescent ; Prognosis ; Infant ; Recurrence ; *Neoplasm Recurrence, Local/genetics/pathology ; *Biomarkers, Tumor/genetics ; Genomics ; Polymorphism, Single Nucleotide ; }, abstract = {Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1[plus] with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adverse prognostic factors. Associations of genomic IKZF1[plus] and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and to predict response in patients with B-ALL.}, }
@article {pmid40359708, year = {2025}, author = {Gouda, MA and Voss, MH and Tawbi, H and Gordon, M and Tykodi, SS and Lam, ET and Vaishampayan, U and Tannir, NM and Chaves, J and Nikolinakos, P and Fan, A and Lee, R and McDermott, D and Shapiro, GI and Gandhi, L and Bhatia, S and Katragadda, V and Meric-Bernstam, F}, title = {A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.}, journal = {ESMO open}, volume = {10}, number = {5}, pages = {104536}, pmid = {40359708}, issn = {2059-7029}, mesh = {Humans ; *Nivolumab/administration & dosage/therapeutic use/adverse effects/pharmacology ; Male ; Female ; Middle Aged ; Aged ; *Melanoma/drug therapy/pathology ; *Lung Neoplasms/drug therapy/pathology ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; *Carcinoma, Renal Cell/drug therapy/pathology ; *Kidney Neoplasms/drug therapy/pathology ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.
PATIENTS AND METHODS: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.
RESULTS: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-naïve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.
CONCLUSIONS: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.}, }
@article {pmid40359110, year = {2025}, author = {Gen, R and Addetia, A and Asarnow, D and Park, YJ and Quispe, J and Chan, MC and Brown, JT and Lee, J and Campbell, MG and Lapointe, CP and Veesler, D}, title = {SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115696}, doi = {10.1016/j.celrep.2025.115696}, pmid = {40359110}, issn = {2211-1247}, mesh = {*Viral Nonstructural Proteins/metabolism/chemistry/genetics ; Animals ; *SARS-CoV-2/metabolism ; Humans ; Chiroptera/virology ; *Protein Biosynthesis ; Cryoelectron Microscopy ; COVID-19/virology ; Mammals ; Ribosome Subunits, Small, Eukaryotic/metabolism ; HEK293 Cells ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats-natural reservoirs of sarbecoviruses with a markedly different innate immune system than humans. We reveal that nsp1 potently inhibits translation in Rhinolophus lepidus bat cells, which belong to the same genus as known sarbecovirus reservoir hosts. We determined a cryoelectron microscopy structure of nsp1 bound to the R. lepidus 40S ribosomal subunit, showing that it blocks the mRNA entry channel by targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cells from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity, providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillover.}, }
@article {pmid40358923, year = {2025}, author = {Yorke, AA and Schandorf, MT and Quaye, ANM and Twum, PT and Sengupta, B and Nkansah-Poku, K and Kplorfia, JA and Fagestrom, J}, title = {Empowering young minds through STEM education: Engaging high schoolers in Ghana through medical physics.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {6}, pages = {e70126}, pmid = {40358923}, issn = {1526-9914}, mesh = {Humans ; Ghana ; Female ; Adolescent ; *Health Physics/education ; *Students/psychology ; *Mathematics/education ; *Engineering/education ; *Career Choice ; *Science/education ; *Radiation Oncology/education ; *Empowerment ; *Technology/education ; Schools ; Surveys and Questionnaires ; }, abstract = {PURPOSE: To promote diversity in Science, Technology, Engineering, and Mathematics (STEM), an educational presentation and hands-on session was organised to raise awareness of STEM career opportunities among high school girls to introduce the students to the field of medical physics.
MATERIALS AND METHODS: The study involved 65 first-year Senior High School girls, aged 13-16, pursuing general science in Accra, Ghana. This initiative, organised by the Girls Excellence Movement (GEM) in collaboration with a United States (US) institution, implemented the "heroes in radiation oncology" program, which included a relatable presentation and hands-on experience in simulation to treatment planning activities. The program's effectiveness was assessed through pre-and post-assessment surveys, and a thematic analysis of student feedback.
RESULTS: Participants' awareness of career fields showed an interest in traditional healthcare professions (92%) and engineering (73.8%), with minimal medical physics awareness (12.3%). Post-presentation survey showed a significant change in participants' perception of medical physics 87.3%. Thematic analysis revealed increased awareness, understanding, and interest, dispelled misconceptions about radiation safety, and highlighted the interdisciplinary nature and career opportunities. The presentation was successful in inspiring participants and expanding their perspectives on medical physics.
CONCLUSION: The program raised awareness of medical physics among participants, many of whom were previously unfamiliar with the field. Participants reported a newfound understanding of the interdisciplinary nature of medical physics, its connections to biology, mathematics, and engineering.This program can easily be reproduced in community and school outreaches.}, }
@article {pmid40358803, year = {2025}, author = {Krisch, JM and Ermoian, RP and Indelicato, DJ and Lee, JY and Perentesis, JP and Perkins, SM and Laack, NN and Chang, JH and MacEwan, IJ and Wolden, SL and Wang, D and Yock, TI and Aridgides, PD}, title = {Outcomes following radiation therapy for embryonal tumor with multilayered rosettes (ETMR): results from the Pediatric Proton/Photon Consortium Registry (PPCR).}, journal = {Journal of neuro-oncology}, volume = {174}, number = {2}, pages = {369-380}, pmid = {40358803}, issn = {1573-7373}, mesh = {Humans ; Child ; Female ; Male ; *Proton Therapy/mortality ; Child, Preschool ; Registries ; Infant ; *Neoplasms, Germ Cell and Embryonal/radiotherapy/pathology/mortality ; Follow-Up Studies ; *Brain Neoplasms/radiotherapy/pathology/mortality ; Survival Rate ; Treatment Outcome ; Prognosis ; }, abstract = {PURPOSE: Embryonal tumor with multilayered rosettes (ETMR) is a rare pediatric CNS embryonal tumor with poor survival. The Pediatric Proton/Photon Consortium Registry (PPCR) was queried for outcomes data from prospectively consenting pediatric patients with ETMR treated with proton radiation therapy (RT).
METHODS: 20 patients (2013-2021) at 9 institutions had ETMR; 2 with prior RT were excluded from statistical analyses (PPCR ETMR, N = 18). Overall Survival (OS) and Event Free Survival (EFS) analyses were performed using the Kaplan-Meier method and log-rank values. Median follow-up was calculated using the reverse Kaplan-Meier method.
RESULTS: Median age at RT was 3.0 years (1.7-12.2); median follow-up was 55.5 months (2.6-119.4). 8 patients (44%) expired and 6 patients (33%) are surviving ≥ 55 months. 11 (61%) patients received systemic therapy with stem cell support. The majority (89%) had focal RT (median dose 54 Gy), while 2 patients received craniospinal irradiation (CSI, 30.6-36 Gy). 4-year OS and EFS were 59.6% and 54.2%, respectively. Local control (LC) at 4 years was 81%. No differences in OS or EFS were observed for receipt of systemic therapy with stem cell support (p = 0.361, p = 0.57), progression prior to RT (p = 0.127, p = 0.18), or surgery to RT ≥ 200 days (p = 0.35, p = 0.254). Symptomatic radionecrosis was not reported.
CONCLUSION: Focal proton RT provided effective local control as part of multimodality therapy for ETMR, with encouraging survival for this rare and often infant age tumor. Outcomes for CSI were limited to 2 patients treated upfront, and 1 patient receiving salvage CSI for disseminated relapse after focal RT who is surviving > 1 year.
TRIAL REGISTRATION: DFCI protocol 12-103, clinicaltrials.gov NCT01696721, date of registration 9/27/2012.}, }
@article {pmid40357548, year = {2025}, author = {Blair, KM and Bohinc, DJ and Bane, KL and Warnock, M and Abuaita, B and Gura, C and Grinsztejn, E and Marshall, SH and Wilson, BM and Bonomo, RA and Tambralli, A and Knight, JS and O'Riordan, MX and Lawrence, DA and Stavrou, EX and Sandkvist, M}, title = {Acinetobacter Baumannii Secreted Protease CpaA Inhibits Factor XII-Mediated Bradykinin Generation and Neutrophil Activation.}, journal = {Circulation research}, volume = {137}, number = {1}, pages = {e1-e15}, pmid = {40357548}, issn = {1524-4571}, support = {I01 BX003851/BX/BLRD VA/United States ; R01 AI072219/AI/NIAID NIH HHS/United States ; R01 HL137695/HL/NHLBI NIH HHS/United States ; U2C DK129440/DK/NIDDK NIH HHS/United States ; }, mesh = {*Bradykinin/metabolism/biosynthesis ; Humans ; *Neutrophil Activation ; *Acinetobacter baumannii/enzymology ; *Factor XII/metabolism ; *Neutrophils/metabolism/immunology ; Factor XIIa/metabolism ; *Bacterial Proteins/metabolism/genetics ; Animals ; Prekallikrein/metabolism ; Mice ; Kallikrein-Kinin System ; }, abstract = {BACKGROUND: FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to FXIIa (activated factor XII) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKS (kallikrein-kinin system) and to determine the downstream consequences on thromboinflammatory responses.
METHODS: The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA.
RESULTS: We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture.
CONCLUSIONS: These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and kallikrein-kinin pathways and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.}, }
@article {pmid40357217, year = {2025}, author = {Kuczmarski, TM and Lynch, RC}, title = {Optimizing therapy for relapsed/refractory classic Hodgkin lymphoma in the era of PD-1 blockade.}, journal = {HemaSphere}, volume = {9}, number = {5}, pages = {e70110}, pmid = {40357217}, issn = {2572-9241}, }
@article {pmid40355027, year = {2025}, author = {Phelan, R and Rotz, S and Dandoy, CE and Auletta, JJ and Badia, P and Bhatt, NS and Ballard, SA and Blacken, R and Daraiseh, NM and Desmond, C and Dunseath, C and Epling, P and Flesch, L and Huber, J and Jenssen, K and Kapadia, M and Kent, G and Klunk, A and Kusnier, K and Lehmann, L and Liberio, N and Maier, S and Myers, KC and O'Connor, G and Pai, A and Tarquini, S and Fitch, TJ and Hartley, D}, title = {Multicenter Study on Caregiver Experiences in Pediatric Hematopoietic Stem Cell Transplantation: Part II. Treatment Challenges, Communication Barriers, and Caregiver-Driven Approaches to Mitigation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.04.012}, pmid = {40355027}, issn = {2666-6367}, abstract = {Hematopoietic stem cell transplantation (HSCT) is a life-saving yet complex treatment for pediatric patients that introduces significant physical, emotional, and logistical challenges for caregivers. This multicenter, prospective qualitative longitudinal study explored caregiver experiences across 4 time points: pre-transplant (n = 47), 30 d post-transplant (n = 43), 100 d post-transplant (n=34), and 6 months post-transplant (n=26). Forty-nine caregivers participated in semi-structured interviews, which were transcribed and thematically analyzed. This manuscript encompasses the following themes that emerged from the interviews: treatment-related side effects and complications, communication gaps, and the impact of the COVID-19 pandemic. Caregiver priorities evolved over time, shifting from managing acute complications such as pain, infections, mucositis, and medication administration to addressing longer-term concerns like developmental delays, nutritional rehabilitation, and psychosocial adaptation. Caregivers reported challenges such as information overload, inconsistent messaging, and limited preparation for transitions in care. They employed various strategies to cope, including advocacy, peer support, and the use of healthcare team resources. These findings highlight the importance of stage-specific, tailored interventions to support caregivers throughout the HSCT journey. Clear communication, accessible education, and coordinated multidisciplinary care are essential to fostering caregiver resilience and improving patient and family-centered outcomes.}, }
@article {pmid40350587, year = {2025}, author = {Sala, M and Roos, CR and Kober, H and Bricker, JB and Stern, CM and Plutchik, J and John, M and Haeny, AM and Feldman, JM and Aslan, M and Hay, JL and Forman, EM}, title = {Combining Cognitive-Behaviour Therapy With Mindfulness Training in a Digital Intervention for Binge Eating Disorder: A Single-Session Pilot Trial.}, journal = {European eating disorders review : the journal of the Eating Disorders Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/erv.3204}, pmid = {40350587}, issn = {1099-0968}, support = {K23AT012126/AT/NCCIH NIH HHS/United States ; }, abstract = {OBJECTIVE: Delivering a single-session treatment digitally can offer increased accessibility. We developed and tested a single-session digital intervention for binge-eating disorder (BED) combining cognitive behavioural therapy (CBT) and mindfulness training.
METHOD: English-speaking adults who met criteria for BED were recruited nationally. Participants completed a 60-min digital single-session intervention for BED. Our primary outcome was to evaluate initial acceptability (usability, overall satisfaction, engagement, visual appeal of content, understandability of programme material, desire to continue the programme, and overall helpfulness) and feasibility (intervention completion). We also evaluated changes in binge eating episodes, assessed via the Eating Disorder Examination Questionnaire (EDE-Q) objective binge eating episodes question, and eating disorder symptoms, assessed via the EDE-Q and Binge Eating Scale (BES). Acceptability measures were administered immediately after the completion of the digital module, while the BES and EDE-Q were administered at pre-treatment and at 1-month follow-up.
RESULTS: All participants (N = 21) completed the intervention. Ratings for acceptability were excellent, with averages above a four on a five-point Likert scale on ratings for all dimensions. Participants reported large and significant decreases in binge eating episodes (d = 0.86) and BES scores (d = 0.91) as well as medium and significant decreases in global eating disorder symptoms at 1-month follow-up (d = 0.55).
DISCUSSION: Results from this pilot suggest promising acceptability and feasibility for a single session of Mindful Courage for BED. This single session also appears to be preliminarily efficacious in reducing binge eating.}, }
@article {pmid40349288, year = {2025}, author = {Mauro, M and Radich, J and Jain, P and Sequeira, D and Bellanti, F and Douer, D}, title = {Pharmacokinetic profile of novel reduced-dose Danziten[™] (nilotinib tablets) versus Tasigna[®] (nilotinib capsules): in vivo bioequivalence and population pharmacokinetic analysis.}, journal = {Cancer chemotherapy and pharmacology}, volume = {95}, number = {1}, pages = {56}, pmid = {40349288}, issn = {1432-0843}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; Biological Availability ; Capsules ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Fasting ; Food-Drug Interactions ; Models, Biological ; *Pyrimidines/pharmacokinetics/administration & dosage ; Tablets ; Therapeutic Equivalency ; }, abstract = {PURPOSE: To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten[™] (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna[®] (nilotinib capsules) and investigate food effects on PK of both formulations.
METHODS: A population PK model evaluating nilotinib capsules (300 or 400 mg) or tablets (142 or 190 mg) was developed using data from 14 single dose studies and > 30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration-time profiles following twice daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects.
RESULTS: PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets ~ 50% lower than that for capsules resulted in bioequivalent nilotinib exposures. Administration with a low-fat meal under modified fasting conditions increased the bioavailability (BA) of 142 mg and 190 mg nilotinib tablets by 26.0% and 29.3%, respectively, vs. fasting; values for 300 mg and 400 mg capsules were 56.8% and 60.7%. Administration with a high-fat meal under modified fasting conditions increased the BA of 142 and 190 mg nilotinib tablets by 48.6% and 52.2%, respectively; values for 300 and 400 mg capsules were 180.6% and 183.3%.
CONCLUSION: Nilotinib tablets 142 and 190 mg provide bioequivalent exposures to 300 mg and 400 mg capsules under fasted conditions and substantially smaller effects of food on exposure.}, }
@article {pmid40347455, year = {2025}, author = {Schenk, JM and Gulati, R and Beatty, SJ and Plymate, S and Lin, DW and Dash, A and Porter, MP and Vandoren, M and Wright, JL and Neuhouser, ML}, title = {Reduced adipose tissue with limited loss of lean mass after weight loss: results from the Prostate Active Lifestyle Study.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf113}, pmid = {40347455}, issn = {1460-2105}, abstract = {Adiposity reduction has both cancer-specific and overall health benefits for patients with overweight or obesity. However, the indiscriminate loss of lean mass accompanying weight loss remains a concern for older cancer patients. Body composition was evaluated in the Prostate Active Lifestyle Study, a randomized controlled weight loss trial targeting caloric restriction and increased physical activity among patients with prostate cancer (PCa) and overweight or obesity on active surveillance. Compared to control, the intervention statistically significantly decreased total fat (-3.4%; 95%CI: -5.3%, -1.5%), android fat (-2.0%; 95%CI: -3.6%, -0.4%), and visceral adipose tissue mass (-613 g; 95%CI: -894 g, -331 g) (all 2-sided p < .001) with no difference in lean mass (p = .70) and a statistically significant increase in lean-to-fat ratio (0.40; 95%CI: 0.06, 0.73; 2-sided p = .02). Weight loss interventions incorporating diet and physical activity among patients with PCa and overweight or obesity can yield statistically significant reductions in adiposity while limiting lean mass loss.}, }
@article {pmid40346049, year = {2025}, author = {Pasvolsky, O and Dima, D and Feng, L and Dong, W and Richards, T and Davis, JA and Afrough, A and Vazquez-Martinez, M and Sannareddy, A and Goel, U and Banerjee, R and Khouri, J and Cervoni, F and Gaballa, MR and Lieberman-Cribbin, A and Rana, MS and Julian, K and Ferreri, CJ and Shune, L and DeJarnette, S and Bhurtel, E and Susanibar Adaniya, S and Portuguese, A and Hosoya, H and Mikkilineni, L and Kaur, G and Rossi, A and Herr, MM and Schrum, D and Lin, C and Raza, S and Lin, Y and Midha, S and Omar, N and Atarsh, S and McGuirk, J and Sborov, D and Voorhees, P and Anwer, F and Alsina, M and Freeman, C and Garfall, AL and Razzo, BM and Sidana, S and Cowan, AJ and Anderson, LD and Hansen, DK and Richard, S and Patel, KK and Lee, HC and Grajales-Cruz, A}, title = {Outcomes of elderly patients with relapsed refractory multiple myeloma (RRMM) treated with teclistamab: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {92}, pmid = {40346049}, issn = {2044-5385}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA281756/CA/NCI NIH HHS/United States ; NCI Grant P30 CA016672//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; NCI (R01CA281756-01A1)//U.S. Department of Health & Human Services | NIH | NIH Clinical Center (Clinical Center)/ ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; Aged ; Male ; Female ; Aged, 80 and over ; Middle Aged ; Retrospective Studies ; *Antibodies, Bispecific/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; United States ; Adult ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Age Factors ; }, abstract = {Teclistamab, a BCMA-directed bispecific antibody, received regulatory approval for relapsed/refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. Despite the fact that myeloma is primarily a cancer of elderly adults, only 15% of MajesTEC-1 participants (n = 24) were ≥75 years old. In this multicenter retrospective study, we report real-world outcomes of a large cohort of older RRMM patients treated with teclistamab. Of 385 analyzed patients, 83 (22%) were in the older group (age ≥75) and 302 (78%) in the younger group (age <75). Compared to the younger group, the older group had less adverse baseline disease characteristics, including a lower incidence of high-risk cytogenetics (44.6% vs. 57.9%, p = 0.03) and extramedullary disease (22% vs. 40%, p = 0.02). There were no significant differences in rates of any-grade CRS (52% vs. 59%, p = 0.27), any-grade ICANS (19% vs. 13%, p = 0.12), and overall response rate (62% vs. 53%, p = 0.17) between the older and younger groups. In multivariable analysis, age was not significantly associated with survival outcomes. Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration.}, }
@article {pmid40346033, year = {2025}, author = {Mihalas, AB and Arora, S and O'Connor, SA and Feldman, HM and Cucinotta, CE and Mitchell, K and Bassett, J and Kim, D and Jin, K and Hoellerbauer, P and Delegard, J and Ling, M and Jenkins, W and Kufeld, M and Corrin, P and Carter, L and Tsukiyama, T and Aronow, B and Plaisier, CL and Patel, AP and Paddison, PJ}, title = {KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4327}, pmid = {40346033}, issn = {2041-1723}, support = {R01 CA295090/CA/NCI NIH HHS/United States ; R01 CA190957/CA/NCI NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; R01CA190957//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01NS119650//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM139429/GM/NIGMS NIH HHS/United States ; T32CA080416//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R21 CA232244/CA/NCI NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; P30CA15704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {*Glioblastoma/pathology/genetics/metabolism ; Humans ; *Histone Acetyltransferases/metabolism/genetics ; *Brain Neoplasms/pathology/genetics/metabolism ; Cell Line, Tumor ; Neoplastic Stem Cells/metabolism/pathology ; Animals ; Gene Expression Regulation, Neoplastic ; Neural Stem Cells/metabolism ; Mice ; Cell Proliferation ; Proto-Oncogene Proteins c-myc/metabolism/genetics ; }, abstract = {Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.}, }
@article {pmid40344957, year = {2025}, author = {Rugo, HS and Bardia, A and Gradishar, WJ and Hamilton, EP and Hurvitz, SA and Jhaveri, K and Mahtani, R and Tolaney, SM}, title = {Expert consensus on treating HR+/HER2- metastatic breast cancer based on real-world practice patterns observed in the RETRACT survey of US oncologists.}, journal = {Breast (Edinburgh, Scotland)}, volume = {82}, number = {}, pages = {104485}, pmid = {40344957}, issn = {1532-3080}, abstract = {Hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2-mBC) is incurable, but recent progress has been made in developing new treatment options and the treatment landscape is rapidly shifting. There are published recommendations for treatment choices and sequencing to help guide oncologists in treating HR+/HER2-mBC, but little evidence has been published regarding real-world practice patterns. The REal-world TReatment patterns And Considerations of Toxicity in HR+/HER2-mBC (RETRACT) survey was designed to evaluate real-world practice patterns in the testing and management of this disease by US oncologists. The survey questions were answered via an online platform and the data were anonymized before analysis. A total of 150 oncologists practicing at academic and community centers completed the survey. The results showed this sample of oncologists largely followed recommended best practices for testing biomarkers, selecting treatments, and managing adverse events. However, several items did show substantial minorities of oncologists not in alignment with recommendations in areas including the definition and treatment of visceral crisis, ideal treatment for patients with endocrine resistance, the routine use of next-generation sequencing for biomarker testing, and the use of prophylactic measures for treatment-related adverse events in patients receiving alpelisib.}, }
@article {pmid40344546, year = {2025}, author = {Check, DK and Li, Z and Shibeika, S and Sloan, CE and Sitlinger, A and Zullig, LL and Graf, SA and Blalock, DV}, title = {Receipt of Alcohol Screening, Brief Intervention, and Treatment Among US Adults With and Without a History of Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2401030}, doi = {10.1200/OP-24-01030}, pmid = {40344546}, issn = {2688-1535}, abstract = {PURPOSE: Many cancer survivors consume alcohol above recommended limits, increasing their risk of recurrence, second cancers, and cancer-related mortality. Alcohol screening, brief intervention, and referral to treatment (SBIRT) is a guideline-recommended strategy for reducing unhealthy alcohol consumption among adult primary care patients. To our knowledge, no prior studies have evaluated SBIRT's reach among cancer survivors.
METHODS: We conducted a cross-sectional study of adults who completed the National Survey on Drug Use and Health from 2015 to 2022. We examined past-year receipt of alcohol screening and-among respondents who endorsed unhealthy alcohol use-brief intervention and treatment. All outcomes were examined among cancer survivors and those with no cancer history. We used modified Poisson regression to assess the associations of cancer history with each outcome, adjusting for sociodemographic characteristics.
RESULTS: The cohort included 86,410 respondents with no history of cancer and 9,963 cancer survivors. The percentages of respondents endorsing past-year receipt of alcohol screening (approximately 40%), brief intervention (approximately 8%), and treatment (approximately 2%) were similarly low in both groups. After adjustment, there was a small but statistically significant difference in alcohol screening, with cancer survivors more likely than people without a history of cancer to receive alcohol screening (adjusted risk ratio [aRR], 1.07; 95% CI, 1.02 to 1.13). Among those with unhealthy alcohol use, cancer survivors were no more or less likely than people without a history of cancer to receive brief alcohol intervention (aRR, 1.00; 95% CI, 0.93 to 1.07) or alcohol treatment (aRR, 0.92; 95% CI, 0.47 to 1.69).
CONCLUSION: Results reveal an important opportunity to improve SBIRT uptake across the board and especially for cancer survivors, who are at increased risk of alcohol-related adverse health effects and, potentially, more motivated to change cancer-related health behaviors.}, }
@article {pmid40343485, year = {2025}, author = {Yang, H and Luo, K and Peters, BA and Wang, Y and Zhang, Y and Daviglus, M and Pirzada, A and Cordero, C and Yu, B and Burk, RD and Kaplan, R and Qi, Q}, title = {Diet, Gut Microbiota, and Histidine Metabolism Toward Imidazole Propionate Production in Relation to Type 2 Diabetes.}, journal = {Diabetes care}, volume = {48}, number = {7}, pages = {1225-1232}, pmid = {40343485}, issn = {1935-5548}, support = {R01HL140976/HL/NHLBI NIH HHS/United States ; R01 DK120870/DK/NIDDK NIH HHS/United States ; N01 HC065236/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; R01 HL141824/HL/NHLBI NIH HHS/United States ; R01 HL148094/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; R01 MD011389/MD/NIMHD NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; K01 HL150406/HL/NHLBI NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; R01 DK134672/DK/NIDDK NIH HHS/United States ; R01 AG085320/AG/NIA NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; R01HL140976/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; R01HL148094/HL/NHLBI NIH HHS/United States ; R01DK126698/DK/NIDDK NIH HHS/United States ; R01 DK137968/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism/blood/epidemiology/microbiology ; *Gastrointestinal Microbiome/physiology ; *Histidine/metabolism/blood ; Female ; Male ; Middle Aged ; *Imidazoles/blood/metabolism ; *Diet ; *Propionates/metabolism/blood ; Adult ; Cross-Sectional Studies ; Prospective Studies ; Aged ; Hispanic or Latino ; White ; }, abstract = {OBJECTIVE: To examine associations of serum imidazole propionate (ImP), histidine, and their ratio with incident type 2 diabetes (T2D) and related dietary and gut microbial factors in U.S. Hispanic/Latino people.
RESEARCH DESIGN AND METHODS: In the Hispanic Community Health Study/Study of Latinos, we evaluated serum ImP, histidine, and ImP-to-histidine ratio at baseline (2008-2011) and their cross-sectional associations with dietary intake and prospective associations with incident T2D over ∼12 years (n = 4,632). In a subsample with gut microbiota data during a follow-up visit (2016-2018), we examined gut microbial species associated with serum ImP and their potential interactions with dietary intake.
RESULTS: Serum ImP and ImP-to-histidine ratio were positively associated with incident T2D (hazard ratio [95% CI] 1.17 [1.00-1.36] and 1.33 [1.14-1.55], respectively, comparing highest and lowest tertiles), whereas histidine was inversely associated with incident T2D (hazard ratio 0.75 [95% CI 0.64-0.86]). A higher amount of fiber intake was associated with lower serum ImP level and ImP-to-histidine ratio, whereas histidine intake was not associated with serum ImP level in the overall sample. Fifty-three bacterial species, including 19 putative ImP producers, were associated with serum ImP. Histidine intake was positively associated with serum ImP and ImP-to-histidine ratio only in participants with a high ImP-associated gut microbiota score (P = 0.03 and 0.02, respectively, for interaction). The associations of fiber intake with serum ImP and ImP-to-histidine ratio were partly mediated by ImP-associated gut microbiota (proportion mediated = 31.4% and 19.8%, respectively).
CONCLUSIONS: This study suggested an unfavorable relationship between histidine metabolism toward ImP production, potentially regulated by dietary intake and gut microbiota, and risk of T2D in U.S. Hispanic/Latino people.}, }
@article {pmid40342410, year = {2025}, author = {Zhang, T and Gentry, CA and Kuderer, NM and Lyman, GH and Ng, B and Michailidou, D}, title = {Association of SSRI and SNRI use with incidence of cardiovascular events in veterans with giant cell arteritis and polymyalgia rheumatica.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1509941}, pmid = {40342410}, issn = {1664-3224}, mesh = {Humans ; *Polymyalgia Rheumatica/drug therapy/epidemiology/complications ; Male ; Female ; Aged ; *Giant Cell Arteritis/drug therapy/epidemiology/complications ; *Selective Serotonin Reuptake Inhibitors/therapeutic use/adverse effects ; Incidence ; Veterans ; *Serotonin and Noradrenaline Reuptake Inhibitors/therapeutic use/adverse effects ; *Cardiovascular Diseases/epidemiology/etiology ; Aged, 80 and over ; Middle Aged ; United States/epidemiology ; }, abstract = {The leading cause of death in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) is cardiovascular disease. The objective of this study was to determine whether the use of selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) in veterans with GCA and PMR could have a cardio-modulatory effect as compared to nonuse. Patients with GCA and PMR were identified through the Veterans Affairs Informatics and Computing Infrastructure. After a 2:1 propensity score matching for SSRI or SNRI users, we identified nonusers with similar covariates. We then applied a multivariate logistic regression (MLR), to calculate the odds ratio (OR) for cardiovascular event (CVE) outcomes within 5 years after the index date. Related hazard ratios (HR) were also calculated to validate the discovery of our findings. We identified 2249 patients with GCA and 3906 patients with PMR. Among patients with GCA, 174 (27%) SSRI users had incident cardiovascular disease as compared to 47 (28%) SNRI users and 277 (19%) nonusers; in the PMR cohort, 108 (13%) were SSRI users compared to 71 (15%) SNRI users and 255 (11%) nonusers. The adjusted ORs of the CVE outcome associated with venlafaxine (2.44, p=0.01) and sertraline (1.45, p=0.04) were significantly greater than 1 in GCA, with similar results observed in the PMR cohort (2.01, p=0.02, and 1.45, p=0.04, respectively). Cox-regression analysis was also conducted, and the hazard ratios were qualitatively consistent with the MLR analysis. In conclusion, the adjusted risk of CVE in patients with GCA or PMR using either venlafaxine or sertraline was higher than that in the non-exposed groups.}, }
@article {pmid40341939, year = {2025}, author = {Byun, J and Han, Y and Choi, J and Sun, R and Shaw, VR and Zhu, C and Xiao, X and Lusk, C and Badr, H and Lee, HS and Jang, HJ and Li, Y and Lim, H and Long, E and Liu, Y and Kachuri, L and Walsh, KM and Wiencke, JK and Albanes, D and Lam, S and Tardon, A and Neuhouser, ML and Barnett, MJ and Chen, C and Bojesen, S and Brenner, H and Landi, MT and Johansson, M and Risch, A and Wichmann, HE and Bickeböller, H and Christiani, DC and Rennert, G and Arnold, S and Field, JK and Shete, S and Le Marchand, L and Liu, G and Andrew, AS and Zienolddiny, S and Grankvist, K and Johansson, M and Caporaso, N and Taylor, F and Lazarus, P and Schabath, MB and Aldrich, MC and Patel, A and Lin, X and Zanetti, KA and Harris, CC and Chanock, S and McKay, J and Schwartz, AG and Hung, RJ and Amos, CI and , }, title = {Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci.}, journal = {Human molecular genetics}, volume = {34}, number = {14}, pages = {1227-1237}, doi = {10.1093/hmg/ddaf059}, pmid = {40341939}, issn = {1460-2083}, support = {R03CA282953 (YLiu)//the National Institutes of Health (NIH)/ ; R01CA141769 (AGS)//the National Institutes of Health (NIH)/ ; U01CA063673//the National Institutes of Health (NIH)/ ; UM1CA167462//the National Institutes of Health (NIH)/ ; R03CA277197 (JB)//the National Institutes of Health (NIH)/ ; U19CA203654//the National Institutes of Health (NIH)/ ; R01CA243483 (CIA)//the National Institutes of Health (NIH)/ ; U01CA253560 (MCA)//the National Institutes of Health (NIH)/ ; U01CA167462//the National Institutes of Health (NIH)/ ; N01PC35142 (MN)//the National Institutes of Health (NIH)/ ; 001/WHO_/World Health Organization/International ; RR170048//Cancer Prevention Research Interest of Texas (CPRIT)/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Adenocarcinoma of Lung/genetics ; *Black or African American/genetics ; *Carcinoma, Squamous Cell/genetics ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Lung Neoplasms/genetics/pathology/epidemiology/ethnology ; Polymorphism, Single Nucleotide/genetics ; United States/epidemiology ; }, abstract = {Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer focused on studying African Americans, comprising 2267 lung cancer cases and 4264 controls. We identified three loci associated with lung cancer, one with lung adenocarcinoma, and four with lung squamous cell carcinoma in this population at the genomic-wide significance level. Among them, three novel loci were identified near VWF at 12p13.31 for overall lung cancer and GACAT3 at 2p24.3 and LMAN1L at 15q24.1 for lung squamous cell carcinoma. In addition, we confirmed previously reported risk loci with known or new lead variants near CHRNA5 at 15q25.1 and CYP2A6 at 19q13.2 associated with lung cancer and TRIP13 at 5p15.33 and ERC1 at 12p13.33 associated with lung squamous cell carcinoma. Further multi-step functional analyses shed light on biological mechanisms underlying these associations of lung cancer in this population. Our study highlights the importance of ancestry-specific studies for the potential alleviation of lung cancer burden in African Americans.}, }
@article {pmid40341199, year = {2025}, author = {Ajani, JA and D'Amico, TA and Bentrem, DJ and Corvera, CU and Das, P and Enzinger, PC and Enzler, T and Gerdes, H and Gibson, MK and Grierson, P and Gupta, G and Hofstetter, WL and Ilson, DH and Jalal, S and Kim, S and Kleinberg, LR and Klempner, S and Lacy, J and Lee, B and Licciardi, F and Lloyd, S and Ly, QP and Matsukuma, K and McNamara, M and Merkow, RP and Miller, AM and Mukherjee, S and Mulcahy, MF and Perry, KA and Pimiento, JM and Reddi, DM and Reznik, S and Roses, RE and Strong, VE and Su, S and Uboha, N and Wainberg, ZA and Willett, CG and Woo, Y and Yoon, HH and McMillian, NR and Stein, M}, title = {Gastric Cancer, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {5}, pages = {169-191}, doi = {10.6004/jnccn.2025.0022}, pmid = {40341199}, issn = {1540-1413}, mesh = {Humans ; *Stomach Neoplasms/therapy/diagnosis/pathology/mortality ; *Medical Oncology/standards/methods ; Biomarkers, Tumor/analysis ; Prognosis ; Neoplasm Staging ; }, abstract = {Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.}, }
@article {pmid40341193, year = {2025}, author = {Tsang, TK and Rojas, DP and Xu, F and Xu, Y and Zhu, X and Halloran, ME and Longini, IM and Yang, Y}, title = {Estimating transmissibility of Zika virus in Colombia in the presence of surveillance bias.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4299}, pmid = {40341193}, issn = {2041-1723}, mesh = {Humans ; *Zika Virus Infection/transmission/epidemiology/virology ; Colombia/epidemiology ; Female ; Adolescent ; Male ; Adult ; *Zika Virus/physiology ; Young Adult ; Bayes Theorem ; Disease Outbreaks ; Middle Aged ; Child ; Population Surveillance ; Bias ; Microcephaly/epidemiology/virology ; }, abstract = {The 2015-2016 Zika virus outbreak in the Americas presented significant challenges in understanding the transmission dynamics due to substantial reporting biases, as women of reproductive age (15-39 years) were disproportionately represented in the surveillance data when public awareness of relationship between Zika and microcephaly increased. Using national surveillance data from Colombia during July 27, 2015-November 21, 2016, we developed a Bayesian hierarchical modeling framework to reconstruct the true numbers of symptomatic cases and estimate transmission parameters while accounting for differential reporting across age-sex groups. Our model revealed that the detection rate of symptomatic cases among women of reproductive age was 99% (95% CI: 98.7-100), compared to 85.4% (95% CI: 84.7-86.1) in other demographic groups. After correcting for these biases, our results showed that females aged 15-39 years remained 82.8% (95% CI: 80.2-85.2%) more susceptible to Zika symptomatic infection than males of the same age, independent of differential reporting areas. Departments with medium-high altitude, medium-high population density, low coverage of forest, or high dengue incidence from 2011-2015 exhibited greater Zika risk. This study underscores the importance of accounting for surveillance biases in epidemiological studies to better understand factors influencing Zika transmission and to inform disease control and prevention.}, }
@article {pmid40340857, year = {2025}, author = {Kumar, SK and Callander, NS and Adekola, K and Anderson, LD and Baljevic, M and Baz, R and Campagnaro, E and Costello, C and D'Angelo, C and Derman, B and Devarakonda, S and Elsedawy, N and Godara, A and Godby, K and Hillengass, J and Holmberg, L and Htut, M and Huff, CA and Hultcrantz, M and Kang, Y and Larson, S and Lee, HC and Liedtke, M and Martin, T and Omel, J and Robinson, T and Rosenberg, A and Schroeder, MA and Sherbenou, D and Suvannasankha, A and Valent, J and Varshavsky-Yanovsky, AN and Vogl, D and Kovach, E and Kumar, R}, title = {NCCN Guidelines® Insights: Multiple Myeloma, Version 1.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {5}, pages = {132-140}, doi = {10.6004/jnccn.2025.0023}, pmid = {40340857}, issn = {1540-1413}, mesh = {Humans ; *Multiple Myeloma/diagnosis/therapy ; *Medical Oncology/standards ; }, abstract = {The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.}, }
@article {pmid40340130, year = {2025}, author = {Ujjani, C and Wang, H and Broome, C and Gopal, AK and Smith, SD and Lai, C and Shadman, M and Leslie, L and Warren, EH and Lynch, R and Swanson, N and Grossfeld, T and Cheson, BD and Dunleavy, K}, title = {Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.04.004}, pmid = {40340130}, issn = {2152-2669}, abstract = {BACKGROUND: Bruton tyrosine kinase (BTK) inhibitors are approved in several B-cell malignancies, including the recent authorization of zanubrutinib for relapsed or refractory follicular lymphoma (FL).
METHODS: Based on preclinical studies demonstrating synergy with ibrutinib and the B-cell lymphoma (BCL)-2 inhibitor, venetoclax, in FL cell lines, we conducted a multicenter phase Ib/II study evaluating this combination in relapsed or refractory FL.
RESULTS: The recommended phase 2 dose was ibrutinib 560 mg and venetoclax 600 mg. There was no evidence of clinical tumor lysis syndrome, despite the omission of a venetoclax ramp up. At a median duration of therapy of 6 months, the most common adverse events were low grade diarrhea (83%), infection (75%), and rash (58%). Amongst the 24 patients enrolled, the overall and complete response (CR) rates were 63% and 21%. At a median follow up of 6.9 months, the median progression-free survival was 8.2 months, and the median duration of CR (n = 5) was 38 months.
CONCLUSION: The combination of a BTK and BCL2 inhibitor is efficacious in relapsed/refractory FL and represents a unique dual-targeted approach warranting further investigation.}, }
@article {pmid40339678, year = {2025}, author = {Dontchos, BN and Dodelzon, K and Bhole, S and Edmonds, CE and Mullen, LA and Parikh, JR and Daly, CP and Epling, JA and Christensen, S and Grimm, LJ}, title = {Opinions and Preferences Regarding Artificial Intelligence Use in Health Care Delivery: Results From a National Multisite Survey of Breast Imaging Patients.}, journal = {Journal of the American College of Radiology : JACR}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacr.2025.05.001}, pmid = {40339678}, issn = {1558-349X}, abstract = {OBJECTIVE: Artificial intelligence (AI) utilization is growing, but patient perceptions of AI are unclear. Our objective was to understand patient perceptions of AI through a multisite survey of breast imaging patients.
METHODS: A 36-question survey was distributed to eight US practices (six academic, two nonacademic) from October 2023 through October 2024. This article analyzes a subset of questions from the survey addressing digital health literacy and attitudes toward AI in medicine and breast imaging specifically. Multivariable analysis compared responses by respondent demographics.
RESULTS: A total of 3,532 surveys were collected (response rate: 69.9%, 3,532 of 5,053). Median respondent age was 55 years (interquartile range 20). Most respondents were White (73.0%, 2,579 of 3,532) and had completed college (77.3%, 2,732 of 3,532). Overall, respondents were undecided (range: 43.2%-50.8%) regarding questions about general perceptions of AI in health care. Respondents with higher electronic health literacy, more education, and younger age were significantly more likely to consider it useful to use AI for aiding medical tasks (all P < .001). In contrast, respondents with lower electronic health literacy and less education were significantly more likely to indicate it was a bad idea for AI to perform medical tasks (P < .001). Non-White patients were more likely to express concerns that AI will not work as well for some groups compared with others (P < .05). Overall, favorable opinions of AI use for medical tasks were associated with younger age, more education, and higher electronic health literacy.
DISCUSSION: As AI is increasingly implemented into clinical workflows, it is important to educate patients and provide transparency to build patient understanding and trust.}, }
@article {pmid40339592, year = {2025}, author = {Escrivá-de-Romani, S and Cejalvo, JM and Alba, E and Friedmann, J and Rodríguez-Lescure, Á and Savard, MF and Pezo, RC and Gion, M and Ruiz-Borrego, M and Hamilton, E and Pluard, T and Webster, M and Beeram, M and Linden, H and Saura, C and Shpektor, D and Salim, B and Harvey, P and Hurvitz, SA}, title = {Zanidatamab plus palbociclib and fulvestrant in previously treated patients with hormone receptor-positive, HER2-positive metastatic breast cancer: primary results from a two-part, multicentre, single-arm, phase 2a study.}, journal = {The Lancet. Oncology}, volume = {26}, number = {6}, pages = {745-758}, doi = {10.1016/S1470-2045(25)00140-8}, pmid = {40339592}, issn = {1474-5488}, mesh = {Humans ; Female ; Fulvestrant/administration & dosage/adverse effects ; Pyridines/administration & dosage/adverse effects ; Piperazines/administration & dosage/adverse effects ; *Receptor, ErbB-2/metabolism ; *Breast Neoplasms/drug therapy/pathology/mortality ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Adult ; Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; Progression-Free Survival ; Aged, 80 and over ; Neoplasm Metastasis ; Antibodies, Bispecific ; }, abstract = {BACKGROUND: New HER2-targeted regimens, including chemotherapy-free options, are needed for metastatic breast cancer. In an ongoing, two-part, phase 2a study, we assessed the safety and antitumour activity of zanidatamab, a HER2-targeted bispecific antibody, plus palbociclib and fulvestrant, in heavily pretreated patients with hormone receptor-positive, HER2-positive advanced or metastatic breast cancer.
METHODS: This multicentre, single-arm, two-part, phase 2a study is being conducted at 13 university hospitals, cancer centres, or research institutes in Spain, Canada, and the USA. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, and with pathologically confirmed unresectable or metastatic breast cancer, assessed locally to be hormone receptor-positive and HER2-positive, with disease progression during or after previous HER2-targeted therapies. Patients were enrolled in part 1, part 2, or part 1 followed by part 2. In part 1, patients received starting doses of zanidatamab (20 mg/kg intravenously once every 2 weeks on days 1 and 15 of a 28-day cycle) with palbociclib (125 mg orally once a day on days 1-21 of each cycle) and fulvestrant (500 mg intramuscular injection once every 2 weeks for the first three doses [cycle 1: days 1 and 15, cycle 2: day 1], then once every 4 weeks [all subsequent cycles: day 1]). In part 1, primary endpoints were safety of the triplet combination and confirmation of recommended doses for part 2. In part 2, patients received the recommended doses confirmed in part 1, and the primary endpoint was progression-free survival at 6 months. Safety and progression-free survival were assessed in all enrolled patients who received any dose of zanidatamab, palbociclib, or fulvestrant. Patients in part 1 who were treated at the recommended doses were analysed together with the patients in part 2. This study is registered with ClinicalTrials.gov, NCT04224272, and is active with recruitment completed.
FINDINGS: Overall, 51 patients (49 [96%] female and two [4%] male; median age 54·0 [46·0-62·0] years; 42 [82%] White) were enrolled: eight in part 1 (June 10, 2020-Feb 7, 2021) and 43 in part 2 (Feb 8, 2021-Oct 31, 2022). All 51 patients had received study treatment at the data cutoff (Aug 3, 2023); median follow-up was 16·1 months (IQR 9·9-23·4) and the median duration of triplet regimen treatment was 7·4 months (3·4-14·8). The median number of previous HER2-targeted therapies was 4 (IQR 3-4). 12 (24%) of 51 patients had previously received trastuzumab deruxtecan. The planned starting drug doses administered in part 1 of the study were confirmed as the recommended doses for part 2. All 51 patients were treated at the recommended doses. All 51 patients had at least one treatment-related adverse event of any grade, with diarrhoea being the most common (41 [80%] patients, with 34 [67%] having grade 1-2 events). Grade 3 or 4 treatment-related adverse events occurred in 34 (67%) patients, with neutropenia being the most common (26 [51%] patients). One (2%) patient had a serious grade 3 treatment-related adverse event of increased transaminases. No treatment-related deaths occurred. In the overall sample (N=51), progression-free survival at 6 months was 66·7% (95% CI 52·1-79·2).
INTERPRETATION: Zanidatamab plus palbociclib and fulvestrant was generally safe and showed promising antitumour activity, supporting further evaluation of this chemotherapy-free triplet regimen.
FUNDING: Zymeworks, Jazz Pharmaceuticals, and Pfizer.}, }
@article {pmid40339051, year = {2025}, author = {Burger, R and Bell-Mandla, N and Harper, A and Richardson, S and Kanema, S and Thomas, R and Mwenge, L and Wilson, E and Floyd, S and Bock, P and Ayles, H and Fidler, S and Hayes, R and Hauck, K and , }, title = {Does enhanced HIV prevention, diagnosis, and linkage to care reduce hospitalisation in high HIV-burden communities in Zambia and South Africa? findings from the HPTN 071 (PopART) randomised trial.}, journal = {PLOS global public health}, volume = {5}, number = {5}, pages = {e0004373}, pmid = {40339051}, issn = {2767-3375}, abstract = {ClinicalTrials.gov NCT01900977.}, }
@article {pmid40339010, year = {2025}, author = {Ely, ZA and Kulstad, ZJ and Gunaydin, G and Addepalli, S and Verzani, EK and Casarrubios, M and Clauser, KR and Wang, X and Lippincott, IE and Louvet, C and Schmitt, T and Kapner, KS and Agus, MP and Hennessey, CJ and Cleary, JM and Hadrup, SR and Klaeger, S and Su, J and Jaeger, AM and Wolpin, BM and Raghavan, S and Smith, EL and Greenberg, PD and Aguirre, AJ and Abelin, JG and Carr, SA and Jacks, T and Freed-Pastor, WA}, title = {Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition.}, journal = {Science (New York, N.Y.)}, volume = {388}, number = {6747}, pages = {eadk3487}, pmid = {40339010}, issn = {1095-9203}, support = {T32 GM007287/GM/NIGMS NIH HHS/United States ; P30 CA014051/CA/NCI NIH HHS/United States ; U24 CA270823/CA/NCI NIH HHS/United States ; P01 CA206978/CA/NCI NIH HHS/United States ; K08 CA260442/CA/NCI NIH HHS/United States ; U01 CA271402/CA/NCI NIH HHS/United States ; K08 CA259621/CA/NCI NIH HHS/United States ; F31 CA268835/CA/NCI NIH HHS/United States ; R35 CA274464/CA/NCI NIH HHS/United States ; }, mesh = {*Pancreatic Neoplasms/immunology/therapy/genetics ; Humans ; *Antigens, Neoplasm/immunology/genetics ; *Histocompatibility Antigens Class I/immunology ; *T-Lymphocytes, Cytotoxic/immunology ; *Peptides/immunology ; Organoids/immunology ; Receptors, Antigen, T-Cell/immunology ; Antigen Presentation ; Cell Line, Tumor ; }, abstract = {Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.}, }
@article {pmid40338545, year = {2025}, author = {Schoen, MW and Doherty, J and Eaton, D and Khan, S and Candelieri, D and Fedele, N and Baxi, P and Wynveen, M and Pickett, C and Wilson, RJ and Stackable, K and Ingram, K and Karunanandaa, K and Agarwal, R and Rajasekhar, A and Riekhof, F and Govindan, S and Cheranda, N and Knoche, EM and Etzioni, RD and Montgomery, RB}, title = {Treatment Patterns and Survival Among Veterans With De Novo Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JAMA network open}, volume = {8}, number = {5}, pages = {e259433}, pmid = {40338545}, issn = {2574-3805}, mesh = {Humans ; Male ; Aged ; Retrospective Studies ; Cross-Sectional Studies ; *Veterans/statistics & numerical data ; *Prostatic Neoplasms/mortality/drug therapy/pathology ; Docetaxel/therapeutic use ; *Androgen Antagonists/therapeutic use ; Middle Aged ; United States/epidemiology ; Aged, 80 and over ; *Androgen Receptor Antagonists/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {IMPORTANCE: Combination therapy for metastatic hormone-sensitive prostate cancer (mHSPC) has been widely adopted, yet clinical use and outcomes are unknown. Furthermore, optimal therapy is uncertain due to lack of direct comparison of androgen receptor pathway inhibitors (ARPIs) and docetaxel in high-volume disease.
OBJECTIVE: To evaluate the use of combination therapy and its association with overall survival among patients with mHSPC and to compare ARPIs vs docetaxel doublet therapy by volume of disease.
This retrospective cross-sectional study was conducted in the US Veterans Health Administration among 6216 US veterans with de novo mHSPC from January 1, 2013, to December 31, 2022, treated with androgen deprivation therapy (ADT) within 3 months of diagnosis. Treatments for mHSPC were collected within 4 months of ADT. Volume of disease was assessed from radiology report review. Data were analyzed from July 2023 to October 2024.
MAIN OUTCOMES AND MEASURES: Overall survival (OS) and clinical progression-free survival (PFS), indicated by time to castration resistance or death.
RESULTS: Among 6216 male veterans with mHSPC (mean [SD] age, 73.9 [9.7] years), use of combination therapy increased from 344 of 637 veterans (54.0%) in 2020 to 465 of 737 veterans (63.1%) in 2022. Among 4106 veterans treated from 2017 to 2022, combination therapy was associated with longer OS (40.3 [95% CI, 38.0-42.1] months vs 33.0 [95% CI, 31.2-35.1] months; hazard ratio [HR], 0.80 [95% CI, 0.74-0.87]) and was used more frequently among younger veterans with fewer comorbidities. Among 1174 veterans with high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (32.3 [95% CI, 29.5-35.3] months vs 34.7 [95% CI, 31.7-37.1] months; HR, 1.06 [95% CI, 0.91-1.23]); however, ARPIs were associated with longer PFS (18.7 [95% CI, 17.1-20.9] months vs 16.0 [95% CI, 14.0-17.7] months; HR, 0.80 [95% CI, 0.70-0.91]; P = .001). In a multivariable model of high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (adjusted HR, 0.89 [95% CI, 0.76-1.05]). Among 366 veterans with low-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (68.4 [95% CI, 52.6 months to not reached] months vs 55.3 [95% CI, 41.7-78.9] months; HR, 0.81 [95% CI, 0.58-1.13]), but ARPIs were associated with longer PFS (39.7 [95% CI, 34.3-52.9] months vs 24.0 [95% CI, 20.3-32.9] months; HR, 0.57 [95% CI, 0.43-0.76]).
CONCLUSIONS AND RELEVANCE: In this cross-sectional study of veterans with de novo mHSPC, use of combination therapies increased over time and were associated with longer survival compared with ADT monotherapy. In both high- and low-volume mHSPC, no differences in OS were observed between ARPI and docetaxel combinations; however, ARPIs had longer PFS. Future research into the role of docetaxel is needed to elucidate the benefit of chemotherapy in mHSPC.}, }
@article {pmid40337764, year = {2025}, author = {Damle, SR and Pillarisetty, VG and Safyan, RA and Chiorean, EG}, title = {A new dawn in cancer immunotherapy: the promise of mutant KRAS-specific vaccines.}, journal = {Translational gastroenterology and hepatology}, volume = {10}, number = {}, pages = {20}, pmid = {40337764}, issn = {2415-1289}, }
@article {pmid40337301, year = {2025}, author = {Eckardt, JN and Hahn, W and Ries, RE and Chrost, SD and Winter, S and Stasik, S and Röllig, C and Platzbecker, U and Müller-Tidow, C and Serve, H and Baldus, CD and Schliemann, C and Schäfer-Eckart, K and Hanoun, M and Kaufmann, M and Burchert, A and Schetelig, J and Bornhäuser, M and Wolfien, M and Meshinchi, S and Thiede, C and Middeke, JM}, title = {Age-stratified machine learning identifies divergent prognostic significance of molecular alterations in AML.}, journal = {HemaSphere}, volume = {9}, number = {5}, pages = {e70132}, pmid = {40337301}, issn = {2572-9241}, abstract = {Risk stratification in acute myeloid leukemia (AML) is driven by genetics, yet patient age substantially influences therapeutic decisions. To evaluate how age alters the prognostic impact of genetic mutations, we pooled data from 3062 pediatric and adult AML patients from multiple cohorts. Signaling pathway mutations dominated in younger patients, while mutations in epigenetic regulators, spliceosome genes, and TP53 alterations became more frequent with increasing age. Machine learning models were trained to identify prognostic variables and predict complete remission and 2-year overall survival, achieving area-under-the-curve scores of 0.801 and 0.791, respectively. Using Shapley (SHAP) values, we quantified the contribution of each variable to model decisions and traced their impact across six age groups: infants, children, adolescents/young adults, adults, seniors, and elderly. The highest contributions to model decisions among genetic variables were found for alterations of NPM1, CEBPA, inv(16), and t(8;21) conferring favorable risk and alterations of TP53, RUNX1, ASXL1, del(5q), -7, and -17 conferring adverse risk, while FLT3-ITD had an ambiguous role conferring favorable treatment responses yet poor overall survival. Age significantly modified the prognostic value of genetic alterations, with no single alteration consistently predicting outcomes across all age groups. Specific alterations associated with aging such as TP53, ASXL1, or del(5q) posed a disproportionately higher risk in younger patients. These results challenge uniform risk stratification models and highlight the need for context-sensitive AML treatment strategies.}, }
@article {pmid40335656, year = {2025}, author = {Harris, K}, title = {An uneasy truce between population health and the gene pools within our bodies.}, journal = {Nature reviews. Genetics}, volume = {26}, number = {7}, pages = {441}, pmid = {40335656}, issn = {1471-0064}, }
@article {pmid40334068, year = {2025}, author = {Muhsen, IN and Roloff, GW and Faramand, RG and Othman, T and Valtis, YK and Kopmar, NE and Dekker, SE and Connor, M and Mercadal, S and O'Connor, TE and Dykes, KC and Ahmed, M and Jeyakumar, N and Zhang, A and Miller, K and Sutherland, KC and Guzowski, C and Gupta, VK and Majhail, NS and Battiwalla, M and Solh, MM and Malik, SA and Mathews, J and Oliai, C and Shaughnessy, PJ and Mountjoy, L and Lee, CJ and Logan, AC and Tsai, SB and Leonard, JT and Schwartz, MS and Sasine, JP and Kumaran, M and Frey, NV and Park, JH and Koura, D and Cassaday, RD and Shah, BD and Aldoss, I and Muffly, LS and Hill, LC}, title = {Outcomes of Brexucabtagene Autoleucel in Relapsed/Refractory Acute Lymphoblastic Leukemia Patients with CNS Involvement.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015779}, pmid = {40334068}, issn = {2473-9537}, abstract = {Relapsed/Refractory (r/r) B-cell acute lymphoblastic leukemia patients with central nervous system involvement (CNS B-ALL) have poor outcomes and were frequently excluded from CD19-targeting chimeric antigen receptor T-cell (CAR T-cell) clinical trials. The efficacy and safety of brexucabtagene autoleucel (brexu-cel) in adults with r/r B-ALL was established by the ZUMA-3 trial, which excluded patients with advanced or symptomatic CNS involvement. In this retrospective multicenter analysis, we investigated the safety and efficacy of brexu-cel in CNS B-ALL patients utilizing data from the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) consortium. Of 189 patients infused, 31 had CNS-2 (presence of blasts in CSF with < 5 WBC/uL) or CNS-3 (presence of blasts with >5 WBC/uL and/or clinical signs/symptoms) disease pre-apheresis and are the focus of this report. The median age was 46.5 years (range, 24-76), and 58.1% were males. Most (87.1%) received bridging therapy. Following brexu-cel, 21 of 24 with CNS restaging (87.5%) achieved CNS-1. Additionally, 28 of 30 evaluable patients achieved marrow complete remission (CR); 25 were MRD-negative. No statistically significant differences were seen in progression-free survival (PFS) or overall survival (OS) following brexu-cel among patients with or without CNS involvement. Similarly, grade 3-4 immune effector cell associated neurotoxicity syndrome (ICANS) occurred similarly in patients with (35.5%) and without CNS disease (30%). In conclusion, our data suggest that brexu-cel results in high response rates in CNS B-ALL patients with toxicity comparable to patients without CNS involvement.}, }
@article {pmid40334067, year = {2025}, author = {Shadman, M and Burke, JM and Cultrera, J and Yimer, HA and Zafar, SF and Misleh, J and Rao, SS and Farber, CM and Cohen, AC and Yao, H and Idoine, A and An, Q and Flinn, IW and Sharman, JP}, title = {Zanubrutinib is well tolerated and effective in CLL/SLL patients intolerant of ibrutinib/acalabrutinib: Updated results.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015493}, pmid = {40334067}, issn = {2473-9537}, abstract = {Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib revolutionized chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment, although treatment-related toxicities limit the use of some BTK inhibitors. Zanubrutinib, a potent next-generation BTK inhibitor, has higher selectivity than ibrutinib or acalabrutinib. The ongoing phase 2, single-arm BGB-3111-215 study investigates the safety and efficacy of zanubrutinib in patients with B-cell malignancies who are intolerant of ibrutinib and/or acalabrutinib. Here, results in patients with CLL/SLL are presented. Patients received zanubrutinib 160 mg BID or 320 mg QD. With a 34.5-month median follow-up, 71 patients (ibrutinib intolerant only, n=44; acalabrutinib intolerant only, n=17; ibrutinib and acalabrutinib intolerant, n=10) received ≥1 zanubrutinib dose. On zanubrutinib, 54% (28/52) of ibrutinib-intolerant patients and 70% (19/27) of acalabrutinib-intolerant patients experienced no recurrence of intolerance AEs; 60% and 72% of intolerance AEs did not recur, respectively. Of recurrent ibrutinib-intolerance AEs, 64% were lower grade; 44% of acalabrutinib-intolerance AEs were lower grade. No intolerance AEs recurred at a higher grade with zanubrutinib. The most common recurrent ibrutinib-intolerance and acalabrutinib-intolerance AEs were fatigue and diarrhea, respectively. The most common TEAEs with zanubrutinib were fatigue (32%), COVID-19 (28%), and diarrhea and contusion (each 24%). Grade ≥3 TEAEs occurred in 61%, serious TEAEs in 32%, and TEAEs leading to discontinuation in 11%. Of 67 efficacy-evaluable patients, 94% experienced disease control: 30% had a best response of stable disease and 64% had a partial or complete response. These data demonstrate that patients intolerant of ibrutinib/acalabrutinib may benefit from switching to zanubrutinib therapy. ClinicalTrials.gov: NCT04116437.}, }
@article {pmid40333962, year = {2025}, author = {Zheng, D and van den Heuvel, A and Balog, J and Willemsen, IM and Kloet, S and Tapscott, SJ and Mahfouz, A and van der Maarel, SM}, title = {DUX4 activates common and context-specific intergenic transcripts and isoforms.}, journal = {Science advances}, volume = {11}, number = {19}, pages = {eadt5356}, pmid = {40333962}, issn = {2375-2548}, mesh = {*Homeodomain Proteins/genetics/metabolism ; Muscular Dystrophy, Facioscapulohumeral/genetics/metabolism/pathology ; Animals ; Protein Isoforms/genetics/metabolism ; Mice ; *DNA, Intergenic/genetics ; Transcriptome ; Humans ; Myoblasts/metabolism ; Gene Expression Regulation, Developmental ; Muscle, Skeletal/metabolism ; }, abstract = {DUX4 regulates the expression of genic and nongenic elements and modulates chromatin accessibility during zygotic genome activation in cleavage stage embryos. Its misexpression in skeletal muscle causes facioscapulohumeral dystrophy (FSHD). By leveraging full-length RNA isoform sequencing with short-read RNA sequencing of DUX4-inducible myoblasts, we elucidate an isoform-resolved transcriptome featuring numerous unannotated isoforms from known loci and novel intergenic loci. While DUX4 activates similar programs in early embryos and FSHD muscle, the isoform usage of known DUX4 targets is notably distinct between the two contexts. DUX4 also activates hundreds of previously unannotated intergenic loci dominated by repetitive elements. The transcriptional and epigenetic profiles of these loci in myogenic and embryonic contexts indicate that the usage of DUX4-binding sites at these intergenic loci is influenced by the cellular environment. These findings demonstrate that DUX4 induces context-specific transcriptomic programs, enriching our understanding of DUX4-induced muscle pathology.}, }
@article {pmid40333666, year = {2025}, author = {Olivieri, DJ and Eastment, MC and Mugisha, N and Menon, MP}, title = {Correlates of cervical cancer awareness among women aged 30-49 in five sub-Saharan African nations: Evidence from the Demographic and Health Survey (DHS)-2017-2023.}, journal = {PLOS global public health}, volume = {5}, number = {5}, pages = {e0003344}, pmid = {40333666}, issn = {2767-3375}, abstract = {Cervical cancer is the leading cause of cancer-related mortality in low- and middle-income countries (LMICs). Prior studies associate high cervical cancer awareness with reductions in cervical cancer incidence. In this study, we utilize nationally representative Demographic and Health Surveys Program (DHS) to analyze correlates of cervical cancer awareness to inform global strategies. All DHS surveys between 2017-2023 were queried for questions on cervical cancer awareness. Socio-demographic variables (e.g., age, marital status), socioeconomic variables (e.g., education, wealth, literacy) and variables pertaining to healthcare decision making, distance traveled, intimate partner violence (IPV), and female genital mutilation/circumcision (FGC/M)) were extracted. Sample weights were applied, and logistic regressions were performed. Variables with p < 0.20 were included in multivariate analysis. Data was obtained from 30,214 women aged 30-49 years old living in Benin, Cameroon, Madagascar, Mauritania, and Mozambique, 19,403 of whom were asked questions on cervical cancer awareness. Cervical cancer awareness varied from 53% in Cameroon to 12% in Benin. Literacy, frequency of watching television, mobile telephone ownership, visiting a local healthcare facility and hormonal contraceptive use were associated with increased cervical cancer awareness, while lack of healthcare decision making independence was associated with decreased awareness after multivariate adjustment. Women who experienced emotional IPV were associated with increased awareness in Cameroon. Less than 4% of all women were screened for cervical cancer. Given the known association between awareness and screening, targeted efforts to increase awareness among women without communication modalities has the potential to reduce global cervical cancer disparities. Potential strategies include co-locating cervical cancer awareness programs with public health programs and implementing large-scale telecommunication outreach programs to improve awareness.}, }
@article {pmid40329475, year = {2025}, author = {Sullivan, SD and Grueger, J and Sullivan, AP and Ramsey, SD}, title = {The consequences of pharmaceutical tariffs in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {31}, number = {6}, pages = {533-536}, pmid = {40329475}, issn = {2376-1032}, mesh = {United States ; Humans ; Biosimilar Pharmaceuticals/economics ; *Drug Industry/economics/legislation & jurisprudence ; *Drug Costs/legislation & jurisprudence ; Drugs, Generic/economics ; }, abstract = {The Trump Administration has threatened to impose tariffs on imported branded, generic, and biosimilar pharmaceutical products. Although specific details regarding the exact rates and implementation timeline remain unclear, the administration has indicated that these tariffs will be substantial. Tariffs can create supply chain disruptions, increase costs, limit patient access to essential medications, and negatively impact research and innovation. Rather than punitive tariffs, industrial policy options and collaborative international treaties may better serve US economic and public health interests and lead to a more secure and consistent domestic supply of critical medicines.}, }
@article {pmid40329098, year = {2025}, author = {Bulteel, AJB and Barnum, K and Datta, S and Dodge, LE and Lake, L and Elavalakanar, P and Lam, BD and Patell, R}, title = {Clinician characteristics associated with use of risk assessment models for venous thromboembolism and bleeding in hospitalized patients.}, journal = {Annals of hematology}, volume = {}, number = {}, pages = {}, pmid = {40329098}, issn = {1432-0584}, support = {DD20-2002/CC/CDC HHS/United States ; }, }
@article {pmid40328984, year = {2025}, author = {Abernethy, NF and McCloskey, K and Trahey, M and Rinn, L and Broder, G and Andrasik, M and Laborde, R and McGhan, D and Spendolini, S and Marimuthu, S and Kanzmeier, A and Hanes, J and Kublin, JG}, title = {Rapid development of a registry to accelerate COVID-19 vaccine clinical trials.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {251}, pmid = {40328984}, issn = {2398-6352}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1AI068635//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068614//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, abstract = {Response to the SARS-Cov-2 pandemic required the unprecedented, rapid activation of the COVID-19 Prevention Network (CoVPN) representing hundreds of sites conducting vaccine clinical trials. The CoVPN Volunteer Screening Registry (VSR) collected participant information, distributed qualified candidates across sites, and monitored enrollment progress. The system consisted of three web-based interfaces. The Volunteer Questionnaire flowed into a secure database. The Site Portal supported volunteer selection, analytics, and enrollment. The Administrative Portal enabled dynamic analytic reports by geography, clinical trial, and site, including volunteering rates over time. The VSR collected over 650,000 volunteers, serving a key role in the recruitment of diverse participants for multiple Phase 3 clinical trials. Over 47% of the 166,729 volunteers selected for screening represented prioritized groups. The success of the VSR demonstrates how digital tools can be rapidly yet safely integrated into an accelerated clinical trial setting. We summarize the development of the system and lessons learned for pandemic preparedness.}, }
@article {pmid40328898, year = {2025}, author = {Zamora, D and Xie, H and Wong, E and Santiano, C and Vivas-Jimenez, A and Sadowska-Klasa, A and Kampouri, E and Stevens-Ayers, T and Ueda Oshima, M and Leisenring, WM and Hill, JA and Boeckh, M}, title = {ELISPOT as a predictor of clinically significant cytomegalovirus infection after hematopoietic cell transplantation in letermovir recipients.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40328898}, issn = {1476-5365}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; K23AI163343//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; K23AI163343//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; K23AI163343//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, abstract = {We examined cytomegalovirus-specific cell-mediated immunity (CMV-CMI) to pp65 and IE-1 at 100 days after hematopoietic cell transplantation (HCT) following discontinuation of letermovir prophylaxis using ELISPOT (T-SPOT®.CMV, Oxford-Immunotec, Abingdon, UK). We compared ELISPOT results to a laboratory-developed intracellular cytokine staining (ICS) assay and characterized thresholds for the prediction of late clinically significant (cs)CMV infection using receiver operating characteristic analysis. We identified factors associated with high (i.e., at or above threshold) CMV-CMI to both antigens. ELISPOT correlated well with polyfunctional CMV-specific T-cell immunity by ICS. We defined thresholds of 67 and 4 spots per 250,000 cells for pp65 and IE-1, respectively, for predicting late csCMV infection. PBSC graft source, CMV seropositive donor, and/or CMV reactivation in the first 100 days post-HCT were associated with high CMV-CMI to pp65 and/or IE-1. Patients with high CMV-CMI to both antigens at day 100 had a lower incidence of late csCMV infection, however, late changes in immunosuppression affected risk prediction. Clinical risk factors (e.g., early CMV infection, acute graft-versus-host disease) predicted late csCMV and improved the predictive value of CMV-CMI testing. Thus, standardized CMV-CMI, after HCT, combined with clinical factors can be used to accurately stratify the risk of late csCMV infection after letermovir prophylaxis.}, }
@article {pmid40328734, year = {2025}, author = {Chehayeb, RJ and Odzer, N and Albany, RA and Ferrucci, L and Sarpong, D and Perez-Escamilla, R and Lewis, JB and Phipps, AI and Meisner, A and Pusztai, L}, title = {Breastfeeding attributable fraction of triple negative breast cancer in the US.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {40}, pmid = {40328734}, issn = {2374-4677}, abstract = {Rates of triple negative breast cancer (TNBC) are higher in Black women than in non-Hispanic White women. Breastfeeding duration and younger age at first birth are known risk factors for TNBC and vary by race. To quantify the contribution of these risk factors to disparities in TNBC, we calculated the population-attributable fraction (PAF). A PubMed search was performed to identify relevant studies and pooled odds ratios for breastfeeding for < 6 months and age at first birth < 25 years were calculated. PAF was calculated using the Levin formula. PAF of breastfeeding for < 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95%CI 3-26%) among Black women. We estimate that up to 15% of annual new TNBC in Black women and 12% in White women might be avoided by supporting breastfeeding. Policies supporting breastfeeding could hence reduce TNBC incidence and lessen racial disparities.}, }
@article {pmid40328293, year = {2025}, author = {Davis, CP and Fest, S and Cushing-Haugen, K and Kensler, TW and Chavarro, JE and Harris, HR}, title = {Dietary patterns and age at menarche in a prospective study of girls in the USA.}, journal = {Human reproduction (Oxford, England)}, volume = {40}, number = {6}, pages = {1087-1093}, pmid = {40328293}, issn = {1460-2350}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; T32 CA094880/NH/NIH HHS/United States ; //Breast Cancer Research Foundation/ ; U01 HL145386/NH/NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Menarche/physiology ; Female ; Child ; Prospective Studies ; Adolescent ; United States ; *Diet ; Body Mass Index ; *Feeding Behavior ; Age Factors ; Proportional Hazards Models ; Diet, Healthy ; }, abstract = {STUDY QUESTION: Are dietary patterns associated with age at menarche after accounting for BMI-for-age (BMIz) and height?
SUMMARY ANSWER: We observed associations between both the Alternative Healthy Eating Index (AHEI) and the Empirical Dietary Inflammatory Pattern (EDIP) and age at menarche.
WHAT IS KNOWN ALREADY: Dietary patterns have been sparsely examined in relation to age at menarche and no studies have examined the association between the AHEI, a healthier diet, and EDIP, a pro-inflammatory diet, and menarche.
STUDY DESIGN, SIZE, DURATION: The Growing Up Today Study (GUTS) is a prospective cohort of children ages 9-14 years at study enrollment. GUTS enrolled in two waves with enrollment beginning in 1996 (GUTS1) and 2004 (GUTS2). For this analysis, GUTS1 and GUTS2 participants were followed through 2001 and 2008, respectively.
We included 7530 participants who completed food frequency questionnaire(s) (FFQ) prior to menarche who then self-reported age at menarche during study follow-up. Cox proportional hazard models were used to calculate multivariable hazard ratios (HRs) and 95% CIs for the associations between two dietary patterns, the AHEI and EDIP, and age at menarche, with and without adjustment for time-varying BMIz and height.
Six thousand nine hundred ninety-two participants (93%) reported menarche during the study period. On average, participants completed the baseline FFQ 1.75 years prior to menarche. Participants in the highest quintile of AHEI diet score (indicating a healthier diet) were 8% less likely to attain menarche within the next month compared to those in the lowest quintile (95% CI = 0.85-0.99; Ptrend = 0.03). This association remained after adjustment for BMIz and height (corresponding HR = 0.93; 95% CI = 0.86-1.00; Ptrend = 0.04). Participants in the highest quintile of the EDIP score (i.e. most inflammatory diet), were 15% more likely to attain menarche in the next month relative to those in the lowest quintile (95% CI = 1.06-1.25; Ptrend = 0.0004), and the association remained following adjustment for BMIz and height (corresponding HR = 1.15; 95% CI = 1.06-1.25; Ptrend = 0.0004).
Self-reported questionnaires are subject to some error; however, given our prospective study design it is likely this error is non-differential with respect to the outcome.
Our findings of an association between both the AHEI and EDIP and age at menarche indicate that diet quality may play a role in age at menarche independent of BMI or height.
This work was supported by the Breast Cancer Research Foundation. The GUTS is supported by the National Institutes of Health U01 HL145386. C.P.D. was supported by National Institutes of Health T32 CA094880. The authors have no conflicts of interest to disclose.
TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid40327712, year = {2025}, author = {Jia, C and Peters, BA and Usyk, M and Wang, Z and Hanna, DB and Sharma, A and Anastos, K and Kaplan, R and Burk, R and Qi, Q}, title = {Associations of fecal and blood microbiota-related metabolites with gut microbiota and type 2 diabetes in HIV infection.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000004231}, pmid = {40327712}, issn = {1473-5571}, abstract = {OBJECTIVES: Assess the relationships of gut microbiota (GMB)-related metabolites in feces and blood with GMB and type 2 diabetes (T2D) in the context of HIV infection, the presence of which could disrupt host metabolism.
DESIGN: We conducted a cross-sectional study among 111 women with HIV (WWH) and 56 women without HIV (WWOH) in the MACS/WIHS Combined Cohort Study.
METHODS: We measured 62 targeted metabolites in both feces and plasma and examined their associations with GMB composition (243 species) and prevalent T2D.
RESULTS: We observed 44 metabolites with detection rates ≥25% in both feces and plasma. Correlations between fecal and plasma metabolites were stronger in WWOH than in WWH (median r: 0.13 vs. 0.04). Fecal metabolites showed stronger correlations with GMB than plasma metabolites among all participants (median r [IQR] of measured vs. GMB-predicted metabolites: 0.24 [0.11, 0.33] vs. 0.08 [-0.03, 0.24]; P = 0.002), and the difference in this comparison was more pronounced in WWOH compared to WWH. We found a moderate consistency for the associations of fecal and plasma metabolites with T2D in WWH (r for effect sizes of fecal and plasma metabolites on T2D = 0.36; P = 0.03), but not in WWOH (r = 0.13; P = 0.45). Fecal and plasma kynurenate, a tryptophan catabolism metabolite, showed opposite associations with T2D, with a positive association for plasma (OR: 2.54, 95% CI: [1.28-5.76]; P = 0.01) and an inverse association for feces (0.59 [0.27-1.23]; P = 0.18) in WWH.
CONCLUSIONS: Fecal metabolites are more strongly associated with GMB than plasma metabolites, especially among WWOH. HIV infection might also influence associations of fecal and plasma metabolites with T2D.}, }
@article {pmid40327300, year = {2025}, author = {Hamilton, EP and Jeselsohn, RM and Vahdat, LT and Hurvitz, SA}, title = {PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor Degraders for Treatment of Estrogen Receptor-Positive Advanced Breast Cancer.}, journal = {Targeted oncology}, volume = {20}, number = {3}, pages = {431-444}, pmid = {40327300}, issn = {1776-260X}, mesh = {Humans ; *Breast Neoplasms/drug therapy/pathology/metabolism ; Female ; Proteolysis/drug effects ; *Receptors, Estrogen/metabolism ; Animals ; Proteolysis Targeting Chimera ; }, abstract = {The estrogen receptor (ER) signaling pathway is a key driver of breast cancer, primarily through the activation of genes that promote tumor cell survival and growth. The recommended first-line treatment for ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer is endocrine therapy plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. However, most patients experience disease progression, and there is no clear standard of care in the second-line setting. Thus, novel treatments in the advanced setting are needed. In this narrative review, we describe the unique mechanisms of action of a new class of drugs called PROteolysis TArgeting Chimera (PROTAC) ER degraders. Unlike other ER-targeted therapies, these small molecules harness the body's primary intracellular natural protein disposal machinery, the ubiquitin-proteasome system, to directly induce ER degradation. Vepdegestrant (ARV-471) is the furthest advanced PROTAC ER degrader currently in clinical development. Preclinical data demonstrate increased tumor growth inhibition with vepdegestrant alone or in combination with CDK4/6 inhibitors compared with the selective ER degrader fulvestrant. In a first-in-human phase 1/2 clinical study, vepdegestrant administered orally as monotherapy or in combination with palbociclib showed promising clinical activity and a favorable safety profile in patients with heavily pretreated ER+/HER2- advanced breast cancer. Several other PROTAC ER degraders (AC699, ERD-3111, ERD-4001, and HP568) are in early development and have demonstrated activity in preclinical breast cancer models, with some recently entering clinical trials. The data highlight the potential for PROTAC ER degraders to be a new backbone therapy in breast cancer.}, }
@article {pmid40325041, year = {2025}, author = {Langowski, MD and Francica, JR and Roederer, AL and Hurlburt, NK and Rodarte, JV and Da Silva Pereira, L and Flynn, BJ and Bonilla, B and Dillon, M and Kiyuka, P and Ravichandran, R and Weidle, C and Carter, L and Rao, M and Matyas, GR and Pepper, M and Idris, AH and Seder, RA and Pancera, M and King, NP}, title = {Elicitation of liver-stage immunity by nanoparticle immunogens displaying P. falciparum CSP-derived antigens.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {87}, pmid = {40325041}, issn = {2059-0105}, support = {INV-009411/GATES/Gates Foundation/United States ; INV-010680/GATES/Gates Foundation/United States ; DGE-1762114//National Science Foundation/ ; INV-010680/GATES/Gates Foundation/United States ; }, abstract = {A vaccine that provides robust, durable protection against malaria remains a global health priority. Although a breakthrough in the fight against malaria has recently been achieved by the licensure of two vaccines based on the circumsporozoite protein (CSP), the effectiveness and durability of protection can still be improved. Both vaccines contain a portion of CSP that does not include epitopes targeted by recently identified, potently protective monoclonal antibodies, suggesting that newer immunogens can expand the breadth of immunity and potentially increase protection. Here we explored >100 alternative CSP-based immunogens and evaluated the immunogenicity and protection of a large number of candidates, comparing several to the licensed R21 vaccine. The data highlight several general features that improve the stability and immunogenicity of CSP-based vaccines, such as inclusion of the C-terminal domain and high-density display on protein nanoparticle scaffolds. We also identify antigen design strategies that do not warrant further exploration, such as synthetic repeat regions that include non-native repeat cadences. The benchmark R21 vaccine outperformed our best immunogen for immunogenicity and protection. Overall, our data provide valuable insights on the inclusion of junctional region epitopes that will guide the development of potent and durable vaccines against malaria.}, }
@article {pmid40323670, year = {2025}, author = {Rodríguez-Díaz, CE and Zangeneh, SZ and Chen, YO and Guo, X and Tsuyuki, K and Ransome, Y and Friedman, RK and Srithanaviboonchai, K and Roberts, ST and Mimiaga, MJ and Mayer, KH and Safren, SA}, title = {The Longitudinal Impact of Psychosocial Syndemic Variables on Adherence to Antiretroviral Therapy Among People With HIV in Brazil, Thailand, and Zambia: An Analysis by HIV Transmission Groups in HPTN 063.}, journal = {AIDS education and prevention : official publication of the International Society for AIDS Education}, volume = {37}, number = {2}, pages = {89-106}, doi = {10.1521/aeap.2025.37.2.89}, pmid = {40323670}, issn = {1943-2755}, mesh = {Humans ; Male ; *HIV Infections/drug therapy/psychology/epidemiology/transmission ; Thailand/epidemiology ; Zambia/epidemiology ; Female ; Adult ; Longitudinal Studies ; Brazil/epidemiology ; *Medication Adherence/psychology ; *Syndemic ; *Anti-HIV Agents/therapeutic use ; Homosexuality, Male/psychology/statistics & numerical data ; Middle Aged ; Substance-Related Disorders/psychology/epidemiology ; Heterosexuality/psychology/statistics & numerical data ; Cross-Sectional Studies ; Young Adult ; }, abstract = {In the field of HIV prevention and care, most studies of HIV syndemic problems are cross-sectional, few differentiate by HIV transmission groups, and few focus on people living with HIV (PWH). We analyzed one-year longitudinal data of 692 sexually active PWH (heterosexual men [HM], heterosexual women [HW], and men who have sex with men [MSM]) in care from Brazil, Thailand, and Zambia. Syndemic scores (0-3+) included stimulant use, polydrug use, depression, alcohol use, and fear of discrimination. Overall, syndemic scores were associated with lower ART adherence over time, but this differed across sexual transmission categories. For HM and HW, those with 2 or 3+ syndemic problems had lower odds of ART adherence than those with none. However, for MSM, the association between syndemic scores and ART adherence was not significant. While syndemic problems generally predicted suboptimal ART adherence among PWH, the association appears nuanced across subgroups.}, }
@article {pmid40323243, year = {2025}, author = {Yu, JB and Grew, D and Sculley, E and Siva, S and Hardcastle, N and Tang, C and Yang, J and Kim, M and Lo, SS}, title = {Practical Considerations for the Treatment of Primary Renal Cell Carcinoma With SABR.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2025.03.007}, pmid = {40323243}, issn = {1879-8519}, }
@article {pmid40323013, year = {2025}, author = {Garcia, NMG and Becerra, JN and Srinivasan, S and McKinney, BJ and DiMarco, AV and Wu, F and Fitzgibbon, M and Alvarez, JV}, title = {APOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer.}, journal = {Cancer research communications}, volume = {5}, number = {5}, pages = {825-840}, pmid = {40323013}, issn = {2767-9764}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA208042/CA/NCI NIH HHS/United States ; R01 CA285322/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Drug Resistance, Neoplasm/genetics ; *Lung Neoplasms/drug therapy/genetics/pathology/metabolism ; ErbB Receptors/antagonists & inhibitors/genetics ; Cell Line, Tumor ; Gefitinib/pharmacology ; *Cytidine Deaminase/metabolism/genetics ; *Protein Kinase Inhibitors/pharmacology ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/metabolism ; Mutation ; *Minor Histocompatibility Antigens/metabolism/genetics ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic ; APOBEC Deaminases ; }, abstract = {UNLABELLED: APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTP) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the ΔNp63 target genes IL-1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs and that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
SIGNIFICANCE: APOBEC mutagenesis is a common source of genetic heterogeneity in cancer, and APOBEC mutational signatures are enriched in metastatic and drug-resistant tumors. However, the mechanisms through which APOBEC3 enzymes promote tumor evolution remain unknown. In this study, we show that APOBEC3 activity contributes to the development of therapy-resistant cancer cells by promoting evolution of DTP cells. These findings offer insights into the role of APOBEC mutagenesis in cancer progression.}, }
@article {pmid40321654, year = {2025}, author = {Alvarez, CS and Kaplan, RC and Camargo, MC and Avilés-Santa, ML and Daviglus, M and Garcia-Bedoya, O and Isasi, CR and Pattany, MS and Thyagarajan, B and Talavera, GA and Graubard, BI and McGlynn, KA}, title = {Associations of Helicobacter pylori with metabolic dysfunction-associated steatotic liver disease and related conditions: cross-sectional results from the Hispanic Community Health Study/Study of Latinos.}, journal = {Lancet regional health. Americas}, volume = {41}, number = {}, pages = {100953}, pmid = {40321654}, issn = {2667-193X}, abstract = {BACKGROUND: Hispanic/Latino populations have been reported to have high rates of both metabolic dysfunction-associated steatotic liver disease (MASLD) and Helicobacter pylori infection. Several observational studies, predominantly from Asian populations, have suggested a link between these conditions. Thus, the primary objective of the current study was to examine the association between H. pylori and MASLD and secondarily, to assess its association with related conditions in the Hispanic Community Health Study/Study of Latinos.
METHODS: In this cross-sectional study, a total of 16,144 participants with baseline data on H. pylori serology were included. Based on weighted statistics, the median age was 40 years [interquartile range (IQR): 28, 52]; 52.2% women (n = 9661) and 47.8% men (n = 6483). Participants' Hispanic/Latino heritage included 37.6% Mexicans (n = 6397), 20.1% Cubans (n = 2307), 15.8% Puerto Ricans (n = 2663), 10.0% Dominicans (n = 1447), 7.4% Central Americans (n = 1710), 4.9% South Americans (1052). MASLD was estimated using the Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI). Other conditions examined were obesity, central obesity, diabetes and metabolic syndrome. Multivariable logistic regression models were used to calculate the ratios of (adjusted) prevalences (RP) and 95% confidence intervals (CI) for the overall association of H. pylori seropositivity with MASLD and related conditions. Analyses were also stratified by Hispanic/Latino heritage.
FINDINGS: The overall prevalence of MASLD ranged from 47% (FLI) to 65% (HSI). After accounting for age, sex, education, and other key variables, the analysis found a modest association between H. pylori seropositivity and MASLD as determined by HSI (RP: 1.06, 95% CI: 1.02-1.10) overall, and among individuals of Puerto Rican and Mexican heritages. Furthermore, an overall association between H. pylori seropositivity and obesity was observed (RP: 1.09, 95% CI: 1.02-1.16).
INTERPRETATION: This study provides support for a positive association of H. pylori seropositivity with MASLD and obesity among Hispanic/Latino populations. However, given the exploratory nature of these findings, caution is warranted in their interpretation. Further research is necessary to establish causality and examine potential mechanisms of these associations.
FUNDING: The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), San Diego State University (N01-HC65237), and University of Illinois at Chicago (HHSN268201300003I). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, United States, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. This study was also funded in part by the Intramural Research Program of the National Cancer Institute.}, }
@article {pmid40321290, year = {2025}, author = {Samandari, T and Achola, M and Hutter, JN and Mboya, G and Otieno, W and Kee, JJ and Huang, Y and Aponte, JJ and Ockenhouse, CF and Lee, CK and Polakowski, L and Yacovone, M and Tapley, A and Dadabhai, S and Mkhize, NN and Kaldine, H and Bhebhe, S and Moore, PL and Hural, J and Garrett, N and Kublin, JG}, title = {Neutralizing Antibody Responses After mRNA COVID-19 Booster Vaccination are Unaffected by Parasitemia in a Malaria-Endemic Setting.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40321290}, support = {T32 AI007044/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; INV-007217/GATES/Gates Foundation/United States ; }, abstract = {Subclinical malaria may reduce the immunogenicity of mRNA vaccines. We evaluated neutralizing antibody responses in adults with (n=87) and without (n=221) PCR-confirmed Plasmodium falciparum who received a COVID-19 booster. Similar boosted ID50 geometric mean titers >22,000 in parasitemic and non-parasitemic participants suggests that COVID-19 mRNA vaccine responses are not impaired.}, }
@article {pmid40321251, year = {2025}, author = {Deslandes, B and Wu, X and Lee, MA and Goudswaard, LJ and Jones, GW and Gsur, A and Lindblom, A and Ogino, S and Vymetalkova, V and Wolk, A and Wu, AH and Huyghe, JR and Peters, U and Phipps, AI and Thomas, CE and Pai, RK and Grant, RC and Buchanan, DD and Yarmolinsky, J and Gunter, MJ and Zheng, J and Hazelwood, E and Vincent, EE}, title = {Transcriptome-wide Mendelian randomisation exploring dynamic CD4+ T cell gene expression in colorectal cancer development.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40321251}, support = {HHSN268201200008C/HL/NHLBI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Recent research has identified a potential protective effect of higher numbers of circulating lymphocytes on colorectal cancer (CRC) development. However, the importance of different lymphocyte subtypes and activation states in CRC development and the biological pathways driving this relationship remain poorly understood and warrant further investigation. Specifically, CD4+ T cells - a highly dynamic lymphocyte subtype - undergo remodelling upon activation to induce the expression of genes critical for their effector function. Previous studies investigating their role in CRC risk have used bulk tissue, limiting our current understanding of the role of these cells to static, non-dynamic relationships only.
METHODS: Here, we combined two genetic epidemiological methods - Mendelian randomisation (MR) and genetic colocalisation - to evaluate evidence for causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation stage. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across five CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). We repeated analyses stratified by CRC anatomical subsites and sex, and performed a sensitivity analysis to evaluate whether the observed effect estimates were likely to be CD4+ T cell-specific.
RESULTS: We identified six genes with evidence (FDR-P<0.05 in MR analyses and H4>0.8 in genetic colocalisation analyses) for a causal role of CD4+ T cell expression in CRC development - FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258. We observed differences in causal estimates of gene expression on CRC risk across different CD4+ T cell subtypes and activation timepoints, as well as CRC anatomical subsites and sex. However, our sensitivity analysis revealed that the genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes.
CONCLUSIONS: Our study demonstrates the importance of capturing the dynamic nature of CD4+ T cells in understanding disease risk, and prioritises genes for further investigation in cancer prevention research.}, }
@article {pmid40321081, year = {2025}, author = {Lottermoser, JA and Liu, H and Bai, J and Hu, Z and Dittman, JS}, title = {Complexin gains effective access to the assembling SNAREs via its membrane-binding C-terminal domain.}, journal = {The Journal of physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/JP286500}, pmid = {40321081}, issn = {1469-7793}, support = {NS116747/NS/NINDS NIH HHS/United States ; NS127534/NS/NINDS NIH HHS/United States ; R56NS128048//National Science Foundation/ ; }, abstract = {The conserved presynaptic SNARE-binding protein complexin (Cpx) promotes Ca[2+]-triggered synaptic vesicle (SV) fusion and inhibits spontaneous fusion at some synapses. A membrane-binding motif in the C-terminal domain (CTD) of Cpx plays a critical role in Cpx function, but it remains unclear whether the CTD participates in Cpx regulation of synaptic transmission beyond targeting Cpx to membranes. We examined the impact of the Caenorhabditis elegans CPX-1 CTD in vivo and found that this domain profoundly boosted the efficiency of CPX-1-mediated inhibition of spontaneous SV fusion as a function of protein abundance at the synapse. Removing the C-terminal half of CPX-1 and substituting it with the SV protein RAB-3 was able to fully restore both the fusogenic and inhibitory functions of CPX-1 whereas other SV proteins failed to restore CPX-1 function with the same efficiency regardless of abundance. These results indicate that regulation of spontaneous SV fusion requires a specific interaction of CPX-1 with the SV membrane. We propose that Cpx cannot efficiently access assembling SNAREs from the cytoplasm and that interactions of its CTD with the SV membrane guide Cpx to these sites of SNARE assembly. KEY POINTS: Complexin (Cpx) regulates presynaptic SNARE assembly to control synaptic transmission. A membrane curvature-sensing motif within the Cpx C-terminal domain (CTD) recruits Cpx to vesicles. Replacement of the CTD with the synaptic vesicle protein Rab3 can restore full Cpx function whereas other vesicle proteins fail to substitute regardless of abundance. The efficiency of Cpx-mediated inhibition of synaptic vesicle fusion is profoundly enhanced by the specific localization supplied by its CTD. These results suggest that Cpx reaches the assembling SNARE complexes via its specific CTD-membrane interactions and these SNAREs are inaccessible from the cytoplasmic compartment.}, }
@article {pmid40320146, year = {2025}, author = {Su, CT and Saber, W and Bansal, A and Li, L and Nakamura, R and Cutler, C and Roth, JA and Wright, W and Steuten, L and Ramsey, SD}, title = {Out-of-Pocket Expenditures and Financial Hardship Among Patients With Myelodysplastic Syndrome Undergoing Allogeneic Transplant or Hypomethylating Agent / Supportive Care (BMT CTN 1102).}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {459.e1-459.e6}, pmid = {40320146}, issn = {2666-6367}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; R01 HL126589/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Myelodysplastic Syndromes/therapy/economics ; Male ; Female ; *Hematopoietic Stem Cell Transplantation/economics ; *Health Expenditures ; Middle Aged ; Aged ; Transplantation, Homologous/economics ; Adult ; *Financial Stress/economics ; }, abstract = {INTRODUCTION: The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 trial demonstrated that allogeneic hematopoietic cell transplantation (HCT) was associated with superior overall survival compared to non-HCT approaches among elderly patients with higher-risk myelodysplastic syndrome (MDS). The trial included an ancillary cost diary component to assess the out-of-pocket (OOP) expenditures and financial hardship in the post-HCT period through 3 phased surveys for up to 19 months after enrollment.
OBJECTIVE: The purpose of the study is to assess the OOP costs and financial hardship experienced by participants of BMT CTN 1102.
STUDY DESIGN: BMT CTN 1102 assigned participants to Donor and No-Donor arms based on donor availability. Participants could additionally enroll in the ancillary cost diary component, with a total of 138 participants returning 267 surveys across 3 survey waves at 1-, 7-, and 19-months after enrollment. As participants who underwent HCT returned 78% (207/267) of the total surveys, we report on the collected data descriptively.
RESULTS: Participants who underwent HCT had high levels of monthly OOP expenditure ($1126, $812, $442) and financial hardship (47%, 53%, 57%) across the 3 survey waves. For reference, participants who did not undergo HCT generally reported lower levels of OOP expenditure ($478, $845, $256) and financial hardship (37%, 55%, 46%).
CONCLUSION: Among BMT CTN 1102 participants, those who underwent HCT reported high levels of OOP expenditures and financial hardship for up to 19 months after enrollment. Ongoing routine assessment of patient-level OOP expenditures and financial burden may be helpful in the post-HCT survivorship period.}, }
@article {pmid40319195, year = {2025}, author = {Merkel, EC and Meyer, CL and Yusuf, RA and Morrison, CF and Kelly, DL and Levine, DR and LeBlanc, TW and Ullrich, CK and El-Jawahri, A}, title = {What do pediatric transplant physicians think about palliative care? Results from a national survey study.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {40319195}, issn = {1476-5365}, abstract = {The benefits of palliative care (PC) for hematopoietic cell transplant (HCT) patients are well established, however, uptake in pediatric HCT remains limited. To understand pediatric transplant physicians' attitudes towards PC, we conducted a cross-sectional study with a 28-question survey. A composite score and regression model identified factors associated with positive attitudes towards subspecialty PC. Ninety-eight participants reported caring for pediatric patients. Most (81%) trust PC clinicians to care for their patients, yet 33% feel PC clinicians lack enough HCT knowledge to counsel patients. Nearly half (46%) see the name "PC" as a barrier to referral. Multivariable analysis showed that spiritual practice (β = 1.53, p = 0.029), <10 years of clinical practice (β = 2.23, p = 0.007), and perceived PC quality (β = 0.73, p < 0.001) were associated with a more positive attitude towards PC. More training in PC (β = -2.70, p = 0.003) and a higher sense of ownership over PC issues (β = -0.51, p = 0.001) were associated with a more negative attitude towards subspecialty PC. These findings highlight barriers to pediatric HCT and PC collaboration, including concerns about PC team knowledge of HCT and patient perceptions. While most pediatric transplant physicians trust PC to enhance patient care, interventions are needed to improve collaboration.}, }
@article {pmid40319052, year = {2025}, author = {Olivieri, DJ and Berridge-Green, A and Othus, M and Radich, JP and Advani, AS and Erba, HP and Walter, RB}, title = {Biobanking and consent to future biospecimen use among adults enrolled in SWOG trials from 2000 to 2024.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {85}, pmid = {40319052}, issn = {2044-5385}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; ASH HONORS Award (DJO)//American Society of Hematology (ASH)/ ; U10-CA180888, U10-CA180819//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid40318950, year = {2025}, author = {Grivas, P and Aragon-Ching, JB and Bellmunt, J and Loriot, Y and Climent Duran, MA and Sridhar, SS and Su, PJ and Park, SH and Kopyltsov, E and Yamamoto, Y and Jacob, N and Hoffman, J and Tyroller, K and Manitz, J and Kearney, M and Schlichting, M and Powles, T}, title = {Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Long-term Analyses of Patient-reported Outcomes and Quality-adjusted Time Without Symptoms or Toxicity from the JAVELIN Bladder 100 Trial.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.04.004}, pmid = {40318950}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival versus BSC alone, with no detrimental impact on quality of life (QOL), in patients with advanced urothelial carcinoma without progression following first-line platinum-based chemotherapy. We report long-term analyses of patient-reported outcomes (PROs) in patients treated with avelumab (any duration or ≥12 mo) and a post hoc analysis comparing quality-adjusted time without symptoms or toxicity (Q-TWiST) between arms.
METHODS: PROs were assessed using National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5-level EQ-5D (EQ-5D-5L). Q-TWiST was calculated as the utility-weighted sum of mean time in three health states: time with all-cause grade 3/4 toxicity prior to progression, time without grade 3/4 toxicity or symptoms of progression, and time after progression.
KEY FINDINGS AND LIMITATIONS: In the overall avelumab plus BSC arm (n = 350) and the subgroup treated for ≥12 mo (n = 118), completion rates for PRO assessments during treatment were >80%. FBlSI-18 total and EQ-5D-5L index scores remained stable throughout 24 mo of treatment, with no clinically important changes from baseline. The mean Q-TWiST was 18.46 mo with avelumab plus BSC versus 15.13 mo with BSC alone (22% relative improvement). Limitations include open-label trial design and small patient numbers at later cycles.
Patients receiving avelumab had preserved health-related QOL and control of cancer-related symptoms with manageable toxicity, further supporting avelumab first-line maintenance as the recommended treatment for advanced urothelial carcinoma not progressed after platinum-based chemotherapy.}, }
@article {pmid40318860, year = {2025}, author = {Tembhare, P and Chen, X and Chan, JKC and Wood, B and Naresh, KN}, title = {Fifth edition WHO classification: precursor lymphoid neoplasms, acute leukaemias of mixed or ambiguous lineage, myeloid/lymphoid neoplasms, and histiocytic and dendritic cell neoplasms, including strategies for application in resource-limited settings.}, journal = {Journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1136/jcp-2025-210135}, pmid = {40318860}, issn = {1472-4146}, abstract = {The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MPAL)), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), and histiocytic and dendritic cell neoplasms, reflecting the advances in the understanding of the genetic basis of these diseases. This review provides an overview of these changes, highlighting a shift to a more refined molecular-genetic approach. The incorporation of newly recognised genetic subtypes into the classification scheme underscores the evolving landscape of these entities. Challenges in diagnosing ALAL/MPAL and MLN-TK are discussed, along with recent insights into histiocytic and dendritic cell neoplasms, including newly defined entities such as ALK-positive histiocytosis.The review also explores the practical implications of WHO-HEM5, particularly in resource-limited settings, where comprehensive molecular testing may be unavailable. While morphology and immunohistochemistry remain essential diagnostic tools, strategic use of flow cytometry and targeted fluorescence in situ hybridisation can facilitate risk-adapted classification and improve survival in regions with limited resources and therapeutic options. Future large-scale studies are necessary to establish the diagnostic and prognostic value of these newly genetically defined entities for diverse healthcare environments, and to standardise guidelines in refining disease classification and optimising patient outcomes.}, }
@article {pmid40318736, year = {2025}, author = {Lee, SJ and Pavletic, S and Blazar, BR and Yao, Y and Ji, R and Marshall, K and Cutler, C and , }, title = {Belumosudil for Chronic Graft-Versus-Host Disease: Analysis of Long-Term Results from the KD025-208 and ROCKstar Studies.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {434.e1-434.e10}, doi = {10.1016/j.jtct.2025.04.020}, pmid = {40318736}, issn = {2666-6367}, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use ; Chronic Disease ; Follow-Up Studies ; *Graft vs Host Disease/drug therapy/etiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Protein Kinase Inhibitors/therapeutic use ; rho-Associated Kinases/antagonists & inhibitors ; Treatment Outcome ; Acetamides ; }, abstract = {Belumosudil is an oral selective rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) following an allogeneic hematopoietic cell transplant in patients aged ≥12 years after failure of ≥2 prior systemic lines of therapy. The KD025-208 (NCT02841995) and KD025-213 (ROCKstar; NCT03640481) studies demonstrated that belumosudil was well tolerated, with clinically meaningful responses in patients with cGVHD. KD025-217 (NCT05305989) is a follow-up study that evaluated extended treatment with belumosudil in patients enrolled in the parent studies, KD025-208 and ROCKstar. This pooled analysis reports the long-term follow-up (overall median follow-up duration of 31.4 months) results from these studies in patients with cGVHD. The study included a total of 208 patients across 3 cohorts. Cohort 1 (n = 95) received belumosudil 200 mg once daily, cohort 2 (n = 92) received belumosudil 200 mg twice daily, and cohort 3 (n = 21) received belumosudil 400 mg once daily. The primary endpoint was best overall response rate (ORR). Duration of response (DOR), failure-free survival (FFS), and time to next treatment (TTNT) were also evaluated in this analysis. The best ORR in the modified intent-to-treat (mITT) population was 72%. The median DOR for the responder population was 62.3 weeks (range, 36.1 to 82.6 weeks). The median FFS in the mITT population was 15.1 months (range, 11.3 to 20.6 months). The 1- and 2-year FFS rates were 56% and 40%, respectively. The median TTNT was 22.1 months (range, 15.2 to 40.3 months), where 47% of patients received a new systemic therapy for cGVHD by 36 months. When compared with the published data, the long-term results from this pooled analysis of these two phase 2 studies demonstrated belumosudil was associated with durable responses, and it remained well tolerated with no new safety concerns.}, }
@article {pmid40317503, year = {2025}, author = {Christie, JR and Romine, P and Eddy, K and Chen, DL and Daher, O and Abdelrazek, M and Malthaner, RA and Qiabi, M and Nayak, R and Kinahan, P and Nair, VS and Mattonen, SA}, title = {Thorax-encompassing multi-modality PET/CT deep learning model for resected lung cancer prognostication: A retrospective, multicenter study.}, journal = {Medical physics}, volume = {52}, number = {6}, pages = {4390-4402}, pmid = {40317503}, issn = {2473-4209}, support = {2020-06498//Discovery Grants program/ ; T32CA009515/CA/NCI NIH HHS/United States ; //Lawson Health Research Institute's Internal Research Fund (IRF)/ ; //London Health Sciences Foundation/ ; //Gerald C. Baines Foundation/ ; T32 CA009515/CA/NCI NIH HHS/United States ; //Natural Sciences and Engineering Research Council of Canada/ ; 152218//Cancer Research Society/ ; }, mesh = {Humans ; *Deep Learning ; *Lung Neoplasms/diagnostic imaging/surgery/pathology ; Retrospective Studies ; *Positron Emission Tomography Computed Tomography ; Male ; Female ; Prognosis ; Middle Aged ; Aged ; *Carcinoma, Non-Small-Cell Lung/diagnostic imaging/surgery/pathology ; *Thorax/diagnostic imaging ; Aged, 80 and over ; }, abstract = {BACKGROUND: Patients with early-stage non-small cell lung cancer (NSCLC) typically receive surgery as their primary form of treatment. However, studies have shown that a high proportion of these patients will experience a recurrence after their resection, leading to an increased risk of death. Cancer staging is currently the gold standard for establishing a patient's prognosis and can help clinicians determine patients who may benefit from additional therapy. However, medical images which are used to help determine the cancer stage, have been shown to hold unutilized prognostic information that can augment clinical data and better identify high-risk NSCLC patients. There remains an unmet need for models to incorporate clinical, pathological, surgical, and imaging information, and extend beyond the current staging system to assist clinicians in identifying patients who could benefit from additional therapy immediately after surgery.
PURPOSE: We aimed to determine whether a deep learning model (DLM) integrating FDG PET and CT imaging from the thoracic cavity along with clinical, surgical, and pathological information can predict NSCLC recurrence-free survival (RFS) and stratify patients into risk groups better than conventional staging.
MATERIALS AND METHODS: Surgically resected NSCLC patients enrolled between 2009 and 2018 were retrospectively analyzed from two academic institutions (local institution: 305 patients; external validation: 195 patients). The thoracic cavity (including the lungs, mediastinum, pleural interfaces, and thoracic vertebrae) was delineated on the preoperative FDG PET and CT images and combined with each patient's clinical, surgical, and pathological information. Using the local cohort of patients, a multi-modal DLM using these features was built in a training cohort (n = 225), tuned on a validation cohort (n = 45), and evaluated on testing (n = 35) and external validation (n = 195) cohorts to predict RFS and stratify patients into risk groups. The area under the curve (AUC), Kaplan-Meier curves, and log-rank test were used to assess the prognostic value of the model. The DLM's stratification performance was compared to the conventional staging stratification.
RESULTS: The multi-modal DLM incorporating imaging, pathological, surgical, and clinical data predicted RFS in the testing cohort (AUC = 0.78 [95% CI:0.63-0.94]) and external validation cohort (AUC = 0.66 [95% CI:0.58-0.73]). The DLM significantly stratified patients into high, medium, and low-risk groups of RFS in both the testing and external validation cohorts (multivariable log-rank p < 0.001) and outperformed conventional staging. Conventional staging was unable to stratify patients into three distinct risk groups of RFS (testing: p = 0.94; external validation: p = 0.38). Lastly, the DLM displayed the ability to further stratify patients significantly into sub-risk groups within each stage in the testing (stage I: p = 0.02, stage II: p = 0.03) and external validation (stage I: p = 0.05, stage II: p = 0.03) cohorts.
CONCLUSION: This is the first study to use multi-modality imaging along with clinical, surgical, and pathological data to predict RFS of NSCLC patients after surgery. The multi-modal DLM better stratified patients into risk groups of poor outcomes when compared to conventional staging and further stratified patients within each staging classification. This model has the potential to assist clinicians in better identifying patients that may benefit from additional therapy.}, }
@article {pmid40316478, year = {2025}, author = {Cavanaugh, D and Holt, SK and Dwyer, E and Petersen, E and Gore, JL and Schade, GR and Grivas, P and Hsieh, AC and Lee, JK and Montgomery, B and Schweizer, MT and Yezefski, T and Yu, EY and Chen, JJ and Liao, JJ and Weg, E and Zeng, J and Jannat, S and Berry, DL and Master, VA and Garcia, JM and Reed, MJ and Bentov, I and Wright, JL and Psutka, SP}, title = {Prospective evaluation of comprehensive geriatric assessments in multidisciplinary bladder cancer care and implications for personalized vulnerability phenotyping.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.03.025}, pmid = {40316478}, issn = {1873-2496}, abstract = {PURPOSE: Frailty predicts adverse outcomes in bladder cancer (BC). Current guidelines endorse completion of Comprehensive Geriatric Assessments (CGAs) in older adults prior to treatment election to objectively measure frailty, however, these are rarely performed in urologic practice due to inadequate resources. We hypothesized CGA implementation would be feasible and identify multifaceted vulnerabilities beyond standard risk assessments in a multidisciplinary BC clinic and developed a novel method to visualize "vulnerability phenotypes" to guide supportive interventions.
METHODS: Adults with BC were prospectively enrolled (June, 2020-July, 2021). Initially, patients underwent standard of care (SOC) risk assessment (N = 27). Subsequently, patients completed CGAs augmented with body composition assessments (N = 67). CGA completion time, rates, and patient-reported burden were assessed. Interdependence of CGA domains were quantified using Spearman correlation coefficients and compared decisional conflict and regret between arms. Vulnerability phenotypes were visualized using Spider Plots, generated in R. Clinical and survival associations with CGAs were evaluated using Cox proportional hazards models.
RESULTS: 94 patients were enrolled with a median age of 72 years. Instrument completion in the CGA cohort was 79% to 100%. 91% of patients reported CGA completion was at most minimally burdensome. CGAs identified vulnerabilities including 31% vulnerable-to-moderately frail, 21% with mild-to-severe depression, 3% with mild-moderate dementia, and 40% at risk for malnutrition-malnourished. Frailty measures across instruments were weakly correlated (rho <0.4). In this heterogeneous cohort, vulnerability domains were not significantly associated with decisional conflict/regret, survival, nor complication rates after treatment. A novel Spider Plot tool is proposed to facilitate communication of the dominant vulnerability-driving individual risks.
CONCLUSIONS: CGAs can be successfully incorporated into uro-oncology practice with low perceived burden, identifying key vulnerabilities with implications for clinical care. Weak correlations across instruments support the value of gathering information across discrete domains. We present a novel approach to visually characterize personalized vulnerability phenotypes.}, }
@article {pmid40315850, year = {2025}, author = {Wu, W and Ahmad, K and Henikoff, S}, title = {Chromatin-bound U2AF2 splicing factor ensures exon inclusion.}, journal = {Molecular cell}, volume = {85}, number = {10}, pages = {1982-1998.e4}, doi = {10.1016/j.molcel.2025.04.013}, pmid = {40315850}, issn = {1097-4164}, mesh = {Humans ; Splicing Factor U2AF/metabolism/genetics ; *Exons ; *Chromatin/metabolism/genetics ; K562 Cells ; RNA Splicing Factors/metabolism/genetics ; Histones/metabolism/genetics ; *Ribonucleoproteins/metabolism/genetics ; Promoter Regions, Genetic ; *Nuclear Proteins/metabolism/genetics ; Introns ; RNA Polymerase II/metabolism ; *RNA Splicing ; *Alternative Splicing ; Phosphoproteins/metabolism/genetics ; Protein Binding ; Methylation ; RNA, Messenger/genetics/metabolism ; }, abstract = {Most mRNA splicing occurs co-transcriptionally, but it is unclear how splicing factors accurately select exons for inclusion. Using CUT&RUN profiling in K562 cells, we demonstrate that three splicing factors-SF3B1, U2AF1, and U2AF2-bind near active promoters of intron-containing and intronless genes, implying their association with the general transcriptional machinery. RNase A treatment reduces factor binding at promoters, indicating that these proteins interact with nascent transcripts. Strikingly, the U2AF2 protein also accumulates throughout intron-containing gene bodies and requires histone H3-lysine36 trimethylation but not nascent transcripts or persistent RNA polymerase II. Chromatin-bound U2AF2 preferentially binds to exons of highly expressed, exon-dense genes, with greater occupancy at exons skipped after U2AF2 knockdown, suggesting that U2AF2 enhances exon selection accuracy. U2AF2-targeted genes include those encoding splicing factors, where it improves splicing accuracy and efficiency. Our findings provide a mechanistic basis for the homeostatic regulation of efficient co-transcriptional splicing by chromatin-bound U2AF2.}, }
@article {pmid40315406, year = {2025}, author = {Chen, W and Chang, TC and Rabin, KR and Raetz, EA and Devidas, M and Hunger, SP and Ramirez, NC and Mullighan, CG and Loh, ML and Wu, G}, title = {Performance of Two-Phase Designs for the Time-to-Event Outcome and a Case Study Assessing the Relapse Risk Associated With B-ALL Subtypes.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400223}, pmid = {40315406}, issn = {2473-4276}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA197695/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Case-Control Studies ; *Research Design ; Computer Simulation ; *Neoplasm Recurrence, Local ; }, abstract = {PURPOSE: To reduce costs in genomic studies of time-to-event phenotypes like survival, researchers often sequence a subset of samples from a larger cohort. This process usually involves two phases: first, collecting inexpensive variables from all samples, and second, selecting a subset for expensive measurements, for example, sequencing-based biomarkers. Common two-phase designs include nested case-control and case-cohort designs. Additional designs include sampling subjects based on follow-up time, like extreme case-control designs. Recently an optimal two-phase design using a maximum likelihood-based method was proposed, which could accommodate arbitrary sample selection in the second phase. However, direct comparisons of this optimal design with others in terms of power and computational cost is lacking.
METHODS: This study performs a direct evaluation of typical two-phase designs, including Tao's optimal design, on type I error, power, effect size estimation, and computational time, using both simulated and real data sets.
RESULTS: Results show that the optimal design had the highest power and accurate effect size estimation under the Cox regression model. Surprisingly, logistic regression achieved similar power with much lower computational cost than a more sophisticated method. The study further applied these methods to the MP2PRT study, reporting hazard ratios of cancer subtypes on relapse risk.
CONCLUSION: Recommendations for selecting two-phase designs and analysis methods are regarding power, bias of estimated effect size, and computational time.}, }
@article {pmid40315399, year = {2025}, author = {Carlsson, SV and Barata, PC and Bryce, AH and George, DJ and Gillessen, S and Loeb, S and Montgomery, B and Morris, D and Riaz, IB and Palapattu, G and Schoen, MW and Washington Iii, SL and Cornell, B and Levine, R and Aggarwal, P and McGowan, T and Cotter, M and Thompson, B and Devgan, G and Russell, D and Kuperman, G and Lenero, E and Iwata, K and Miyahira, AK and Soule, HR and Carithers, G and Oh, WK and Agarwal, N}, title = {Prostate Cancer Foundation White Paper on Combination Therapy for Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500050}, doi = {10.1200/OP-25-00050}, pmid = {40315399}, issn = {2688-1535}, abstract = {Despite several randomized controlled trials demonstrating the benefits of combination therapies for metastatic hormone-sensitive prostate cancer (mHSPC), a significant treatment gap persists. This initiative by the Prostate Cancer Foundation (PCF) convened stakeholders from academia, community practices, industry, and patient advocacy groups to address critical challenges in mHSPC care. Expert discussions and a review of real-world evidence and meta-analyses informed the development of strategies to improve care delivery. Evaluation of the data from global registries, such as IRONMAN, and large community databases was used to assess treatment utilization patterns and disparities. Combination therapies with two agents-androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI)-or three agents-ADT + ARPI + docetaxel-demonstrate significant survival improvements while preserving quality of life for patients with mHSPC, yet adoption remains inconsistent. Of the eligible patients, 20%-60% remain undertreated, with geographic, financial, and systemic barriers contributing to inconsistencies in care. Younger, White, urban-dwelling patients with fewer comorbidities are more likely to receive combination treatment, highlighting disparities across populations. Meta-analyses identified a lack of standardization due to varying inclusion criteria and comparators across trials. Real-world evidence underscored disparities influenced by geographic location, practice type, and access to specialty care. Initiatives such as the PANTHER study highlight improved outcomes in Black patients treated with combination therapies, emphasizing the importance of including diverse populations in clinical trials. To bridge gaps in care, this initiative prioritizes awareness, standardization, and equitable access to evidence-based therapies. Proposed solutions include targeted knowledge dissemination strategies, development of educational resources, and advocacy for policy changes to promote guideline-concordant care. By leveraging collaborative efforts, organizations, including PCF, can contribute to enhancing survival outcomes and quality of life for all patients with mHSPC.}, }
@article {pmid40315333, year = {2025}, author = {Geiger, RA and Khera, D and Tenthorey, JL and Kochs, G and Graf, L and Emerman, M and Malik, HS}, title = {Heterozygous and generalist MxA super-restrictors overcome breadth-specificity trade-offs in antiviral restriction.}, journal = {Science advances}, volume = {11}, number = {18}, pages = {eadu0062}, pmid = {40315333}, issn = {2375-2548}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, mesh = {*Myxovirus Resistance Proteins/genetics/metabolism/chemistry ; Humans ; Influenza A Virus, H5N1 Subtype ; *Antiviral Agents/pharmacology ; Thogotovirus ; }, abstract = {Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit many viruses. Viral escape drives restriction factors to evolve rapidly at virus-binding interfaces to regain defense. Here, we explore how antiviral proteins balance restricting many viruses with evolving specificity against individual viruses. Human MxA uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as thogotovirus (THOV) and influenza (IAV). Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 identified THOV "super-restrictors" and suggested an antiviral breadth-specificity trade-off. Using a modified combinatorial mutagenesis strategy, we find super-restrictor MxA variants specific to H5N1 IAV. A single L4 residue underlies the MxA breadth-specificity trade-off. However, rare "generalist" super-restrictors or a heterozygous combination of more common "specialist" super-restrictors can overcome the breadth-specificity trade-off. Our findings suggest that at least two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity trade-offs, which might be pervasive in host-virus conflicts.}, }
@article {pmid40314975, year = {2025}, author = {Zheng, Y and Ahmad, K and Henikoff, S}, title = {Total whole-arm chromosome losses predict malignancy in human cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {18}, pages = {e2505385122}, pmid = {40314975}, issn = {1091-6490}, support = {K99 HG012797/HG/NHGRI NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; Henikoff//Howard Hughes Medical Institute (HHMI)/ ; HG012797//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Neoplasms/genetics/pathology ; *Aneuploidy ; Centromere/genetics/metabolism ; Histones/genetics/metabolism ; }, abstract = {Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II level over the S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcomes across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for the generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential to reduce aneuploidy and slow cancer progression.}, }
@article {pmid40313749, year = {2025}, author = {Chanda, A and Song, Y and Nazir, J and Lin, C and Cheng, A and Sargent, J and Sikora, AE}, title = {Bridging Gaps in Antibody Responses and Animal Welfare: Assessing Blood Collection Methods and Vaginal Immunity in Mice Immunized with Intranasal Gonococcal Vaccines.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40313749}, issn = {2693-5015}, support = {R01 AI117235/AI/NIAID NIH HHS/United States ; }, abstract = {Assessing antibody titers and functional responses is essential for evaluating vaccine efficacy, yet the impact of blood collection methods on these immunological assessments remains unclear. Retro-orbital (RO) blood collection is commonly used but significant complications can occur. Increasingly, investigators have adopted alternative blood collection approaches, such as saphenous vein (SV) sampling to improve laboratory animal welfare. This study compared RO and SV sampling in the development of a Neisseria gonorrhoeae (Ng) vaccine, evaluating Adhesin Complex Protein (ACP) and multiple transferable resistance (Mtr) E protein (MtrE) as antigen candidates. Epitope mapping revealed that ACP and MtrE possess multiple, highly accessible B-cell and T-cell epitope clusters, reinforcing their immunological potential. Following intranasal immunization with rACP, rACP+CpG, and rMtrE+CpG, we assessed the specificity, magnitude, kinetics, and functional quality of immune responses elicited by the immunization regimens. Out of 45 comparisons, only eight significant differences were detected in antibody titers, while the human serum bactericidal assays revealed no differences between RO and SV in antigen-immunized groups. However, antibodies elicited by rACP alone or ACP+CpG in SV samples restored 30.05% and 75.2% of human lysozyme hydrolytic activity compared to 19.3 and 59.9 % in RO, respectively suggesting that SV sampling may be more reliable for assessing functional antibody responses. Beyond its immunological advantages, SV sampling reduces stress, minimizes ocular trauma, and improves animal welfare, making it a viable alternative to RO collection. Given its widespread use in vaccine research, standardizing SV sampling could improve data reliability, ethical compliance, and translational relevance in preclinical studies.}, }
@article {pmid40313741, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, A and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40313741}, issn = {2693-5015}, support = {DP5 OD029630/OD/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid40311704, year = {2025}, author = {Alfaifi, S and Louie, AV and Siva, S and Guckenberger, M and Videtic, GMM and Higgins, KA and Alshafa, F and AlGhamdi, H and Gillespie, EF and Stephans, K and Mula-Hussain, L and Harrow, S and Palma, DA}, title = {International Patterns of Practice for SABR for Early-Stage Non-Small Cell Lung Cancer: Are We All in Sync?.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.04.022}, pmid = {40311704}, issn = {1879-355X}, abstract = {PURPOSE: To generate an understanding of the similarities and variations in international practice patterns for SABR in early-stage non-small cell lung cancer.
METHODS AND MATERIALS: An online survey was conducted from October to December 2023, addressing general clinical and technical considerations for lung SABR, and for 5 specific anatomic non-small cell lung cancer locations (peripheral, abutting chest wall, near brachial plexus, central, and ultracentral). Invitations to participate were extended through email and were distributed on social media.
RESULTS: The survey was completed by 255 radiation oncologists, each representing a single institution across 51 countries. Respondents reported treating a median of 20 cases annually. A total of 38% of participants reported using single-fraction SABR, and 54% applied an upper limit on the maximum dose (Dmax). Among those who applied a Dmax limit, 58% reported a Dmax threshold at ≥130% of the prescription, though this limit varied by region and national economy status. Respondents from low- and middle-income countries were less likely to set a Dmax limit at ≥130% (30% vs 66%, P < .01) and less likely to use single-fraction SABR (14% vs 44%, P < .01). Higher annual SABR patient volumes were associated with higher Dmax adoption (г = 0.23, P < .01). Across the 5 clinical scenarios presented; 57 distinct dose regimens were recommended. The most common regimen in each scenario was: 54 Gy in 3 fractions for peripheral tumors, 50 Gy in 5 fractions for apical, central, and abutment of chest wall, and 60 Gy in 8 fractions for ultracentral tumors. Approximately two-thirds of practices recommend a biologically effective dose (BED10) <100 Gy for ≥1 anatomic sites.
CONCLUSIONS: The findings reveal considerable variation in global SABR practice. These differences highlight the need for further data to guide prescription practices, and an international experts' consensus may be beneficial to standardize practice.}, }
@article {pmid40311075, year = {2025}, author = {Sharma, R and Holtzman, NG and Pusic, I and Cutler, CS and Treister, N and Mehta, RS and Alousi, AS and Vigneswaran, N and Javaid, A and Boksa, FA and Mody, DP and Costa-da-Silva, AC and Schueller, O and Macé, S and Yao, Y and Ji, R and Hu, B and Marshall, K and Blazar, BR and Lee, SJ and Pavletic, SZ and Mays, JW}, title = {Belumosudil reduces oral chronic graft-versus-host disease tissue inflammation and fibrosis: a ROCKstar companion study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016170}, pmid = {40311075}, issn = {2473-9537}, abstract = {Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin (IL)-17 activity and promotes regulatory T-cell (Treg) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 subjects with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSG], and skin) and peripheral blood. Following belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased following treatment, while CD4 Tregs increased in both MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in OM. Additionally, salivary transforming growth factor β1 (TGF)-β1, a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.clinicaltrials.gov as NCT03640481.}, }
@article {pmid40309186, year = {2025}, author = {Andrews, SS and Brent, R}, title = {Individual yeast cells signal at different levels but each with good precision.}, journal = {Royal Society open science}, volume = {12}, number = {4}, pages = {241025}, pmid = {40309186}, issn = {2054-5703}, abstract = {Different isogenic cells exhibit different responses to the same extracellular signals. Several authors assumed that this variation arose from stochastic signalling noise with the implication that single eukaryotic cells could not detect their surroundings accurately, but work by us and others has shown that the variation is dominated instead by persistent cell-to-cell differences. Here, we analysed previously published data to quantify the sources of variation in pheromone-induced gene expression in Saccharomyces cerevisiae. We found that 91% of response variation was due to stable cell-to-cell differences, 8% from experimental measurement error, and 1% from signalling noise and expression noise. Low noise enabled precise signalling; individual cells could transmit over 3 bits of information through the pheromone response system and so respond differently to eight different pheromone concentrations. Additionally, if individual cells could reference their responses against constitutively expressed proteins, then cells could determine absolute pheromone concentrations with 2 bits of accuracy. These results help explain how individual yeast cells can accurately sense and respond to different extracellular pheromone concentrations.}, }
@article {pmid40308027, year = {2025}, author = {Gomez, RA and Hou, J and Gersuk, VH and Chow, IT and Farrington, ML and Robinson, D and Kwok, WW}, title = {Ara h 2105-124-Specific TH2A Cells Drive Peanut Allergy in DRB1*15:01 Individuals: A Detailed Epitope Analysis.}, journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology}, volume = {}, number = {}, pages = {}, doi = {10.1111/cea.70072}, pmid = {40308027}, issn = {1365-2222}, support = {U19 AI135817/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: The IgE-mediated CD4 T-cell response to peanut (Arachis hypogaea) is heterogeneous, yet TH2 cells remain central drivers of pathology. This study aimed to dissect this complexity at the epitope level by focusing on the HLA-DRB1*15:01-DRB5*01:01 haplotype. Specifically, we examined how distinct epitope-specific T-cell subsets shape the immunological landscape of peanut allergy in peanut-allergic (PA) versus non-peanut-allergic (NPA) individuals.
METHODS: Using in vitro and ex vivo MHC-II tetramer approaches, the phenotype, frequency, function, and transcriptome of CD4 T-cell responses to novel Ara h epitopes were assessed. Bulk RNA sequencing further characterised these T cells, allowing identification of subsets associated with TH2 polarisation in PA individuals.
RESULTS: Eleven HLA-DRB1*15:01 and DRB5*01:01-restricted epitopes were identified in Ara h 1, 2, 3, 6, 7, and 8 using tetramer-guided epitope mapping on cell lines, followed by ex vivo validation in peripheral blood. T-cell phenotype was epitope-dependent, with a distinct TH2A population specific to the epitope Ara h 2105-124 (Ara h 2 p14) detected only in PA donors. These TH2A cells were phenotypically and transcriptionally distinct, marked by high CRTH2/CD161, low CD27, IL-5 production, and gene enrichment in cytokine signalling and lipid metabolism. Other epitope-specific T-cell subsets displayed more heterogeneous gene profiles related to immune activation, differentiation, and antigen presentation, underscoring the complexity of peanut-specific responses even within a single HLA haplotype.
CONCLUSION: These findings reveal that the strong TH2 bias in DRB1*15:01-DRB5*01:01 PA individuals arises from a distinct subset of Ara h 2 p14-specific TH2A cells characterised by a specialised metabolic and cytokine signalling program. At the same time, the functional diversity observed in non-Ara h 2 p14 subsets highlights the potential for leveraging these populations in tolerance-promoting therapies. Understanding the epitope-level heterogeneity of peanut-specific T-cells provides insight into the epitope-specific mechanisms driving peanut allergy and has potential implications for therapeutic interventions.}, }
@article {pmid40307656, year = {2025}, author = {Keiser, E and Corbett, AM and Chido-Amajuoyi, O and Antoine, A and Stehman, C and Dorn, I and Goines, D and LoConte, NK}, title = {Acceptability of Stool-Based DNA Colorectal Cancer Screening among Black/African-American Patients Served by Federally Qualified Health Centers.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40307656}, issn = {1543-0154}, support = {UWCCC: University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520/CA/NCI NIH HHS/United States ; }, abstract = {Colorectal cancer (CRC) has an increased burden among Black/African-American populations. Following the COVID-19 pandemic, home-based CRC screening options are being used more frequently. We conducted focus groups to understand the acceptability of stool-based DNA testing for CRC screening in this population. Ten focus groups about the acceptability of various CRC screening modalities were held with Black/African-American participants at two federally qualified health centers (FQHCs) in Milwaukee, Wisconsin. Participants were separated into focus groups based on age and gender. Thematic analysis was carried out using NVivo. Across the groups, there were a total of 79 participants, of which 40.5% were aged 40-50 years ("younger participants"), 59.5% aged > 50 years ("older participants"), 53.2% male, and 46.8% female. Overall, knowledge was low regarding perceived risk of CRC. There was limited awareness of CRC screening options among younger patients and widespread lack of knowledge about stool-based DNA testing. Most respondents preferred colonoscopy as their first-choice screening test but were open to other screening tests. Stool-based DNA tests were more preferred among younger participants but was felt to be acceptable across all groups. Given the low awareness/knowledge of screening modalities identified in our study, educational interventions and shared decision making by primary care providers are needed.}, }
@article {pmid40307080, year = {2025}, author = {Melão, BVLA and Assel, M and Pere, M and Nalavenkata, S and Touijer, KA and Laudone, VP and Lin, DW and Rivas, JG and Bjartell, A and Carlsson, SV}, title = {Assessment of postoperative practices and discharge recommendations after radical prostatectomy.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.03.027}, pmid = {40307080}, issn = {1873-2496}, abstract = {PURPOSE: Consistent, accurate postoperative guidance is crucial for early recovery and patient satisfaction in urology, especially for radical prostatectomy (RP) patients. However, patients often receive inconsistent information, highlighting the need for standardized, evidence-based postoperative care guidelines.
MATERIALS AND METHODS: We conducted a comprehensive review and evaluation of current postoperative practices for RP. This involved (1) reviewing existing discharge information at Josie Robertson Surgery Center, Memorial Sloan Kettering Cancer Center to identify areas of improvement; (2) systematically evaluating inconsistencies in discharge instructions and their impact on patient care; (3) distributing an anonymous survey to urologists in the US and Europe via REDCap to gather insights into global postoperative care practices. The survey included questions on various aspects of postoperative care, such as catheter use, medication regimens, dietary restrictions, and physical activity guidelines.
RESULTS: We received 247 survey responses. Despite some consensus on certain postoperative practices and recommendations, significant variability existed, underscoring the lack of standardized guidelines. Notable differences were observed between US and European cohorts, particularly in postoperative length of stay and discharge practices. Only 1.4% of US responders discharged patients 3 or more days postsurgery compared to 46% in Europe. Variability was also noted in recommendations for erectile function medications and postoperative activity restrictions.
CONCLUSION: This study underscores the significant variability in postoperative care recommendations for RP and the urgent need for standardized, evidence-based guidelines. Implementing such guidelines will enhance patient recovery, satisfaction, and overall outcomes, improving postoperative care across various surgical procedures.}, }
@article {pmid40306967, year = {2025}, author = {Parihar, AS and Pant, N and Heidari, P and Fong, L and Iravani, A}, title = {Approaches to Imaging Immune Activation Using PET.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {6}, pages = {839-847}, pmid = {40306967}, issn = {1535-5667}, mesh = {Humans ; *Positron-Emission Tomography/methods ; Radiopharmaceuticals ; Neoplasms/immunology/diagnostic imaging/therapy ; Fluorodeoxyglucose F18 ; Animals ; }, abstract = {This review explores the role of PET in imaging immune activation, particularly in oncology. [18]F-FDG is widely used for assessing treatment response to immunotherapies and can demonstrate unique response patterns as well as immune-related adverse events. However, because of the limited specificity of [18]F-FDG, newer PET radiopharmaceuticals targeting specific cellular or subcellular components of the immune system have been developed that can provide more precise information. The development of immune-specific PET radiopharmaceuticals offers significant potential for improving immune monitoring in both clinical practice and research.}, }
@article {pmid40305682, year = {2025}, author = {Chappidi, MR and Newcomb, LF and Zheng, Y and Liu, M and Schenk, JM and Zhu, K and de la Calle, CM and Brooks, JD and Carroll, PR and Dash, A and Filson, CP and Gleave, ME and Liss, MA and Martin, F and McKenney, JK and Morgan, TM and Wagner, AA and Nelson, PS and Lin, DW}, title = {Magnetic Resonance Imaging at Second Surveillance Biopsy After Diagnosis in Patients With Grade Group 1 Prostate Cancer in the Canary Prostate Active Surveillance Study.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004592}, doi = {10.1097/JU.0000000000004592}, pmid = {40305682}, issn = {1527-3792}, abstract = {PURPOSE: No clear guidelines exist regarding MRI use after confirmatory biopsy during active surveillance. Our objective was to evaluate MRI performance after confirmatory biopsy in patients with vs without prior MRI-informed biopsy.
MATERIALS AND METHODS: Patients in Canary Prostate Active Surveillance Study with Gleason grade group (GG) 1 disease undergoing MRI-informed Biopsy 2, defined as second surveillance biopsy after diagnosis, were separated into prior vs no prior MRI-informed biopsy groups. Primary outcome was reclassification (≥GG2) at MRI-informed Biopsy 2. Reclassification rates and location (systematic cores, targeted cores, both) were compared between groups. Univariable and multivariable logistic regression identified predictors of reclassification.
RESULTS: Patients with (n = 101) vs without (n = 103) prior MRI-informed biopsy had lower reclassification rates at Biopsy 2 (21% vs 36%, P = .017) and lower GG at reclassification (95% vs 73% of reclassifications to GG2, P = .039). In multivariable modeling, PI-RADS 4 to 5 at MRI-informed Biopsy 2 was associated with increased odds of reclassification (OR = 2.04, 95% CI [1.04-4.05]). The negative predictive value of MRI at Biopsy 2 was 87% (95% CI [78-96]) and 73% (95% CI [61-85]) in with vs without prior MRI groups, respectively. Reclassification location was identified by targeted cores only in 36% vs 19% of patients with vs without prior MRI, respectively (P = .4). Reclassification location was identified by systematic cores only in 36% vs 58% of patients with vs without prior MRI, respectively (P = .4).
CONCLUSIONS: These results support MRI use at Biopsy 2 and suggest negative surveillance MRI should not replace Biopsy 2. Both targeted and systematic cores should be taken at Biopsy 2 in patients with and without prior MRI on active surveillance.}, }
@article {pmid40305509, year = {2025}, author = {Gabel, AM and Crosse, EI and Belleville, AE and Hogg, SJ and McKellar, SA and Abdel-Wahab, O and Thomas, JD and Bradley, RK}, title = {Muscleblind-like proteins are novel modulators of the tumor-immune microenvironment.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0321148}, pmid = {40305509}, issn = {1932-6203}, mesh = {*Tumor Microenvironment/immunology/genetics ; Animals ; Humans ; Mice ; *RNA-Binding Proteins/genetics/metabolism/immunology ; Cell Line, Tumor ; CD8-Positive T-Lymphocytes/immunology ; Female ; Interferon-gamma/pharmacology ; *Neoplasms/immunology/genetics/pathology ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; Antigen Presentation ; }, abstract = {Exploiting the immune system to eradicate cancer cells is an area of intense clinical study. However, the mechanisms that shape the tumor-immune microenvironment are incompletely understood. Here, we identify Muscleblind-like (MBNL) proteins as novel modulators of the tumor-immune microenvironment across diverse cancers. We demonstrate that loss of tumor MBNL expression results in an attenuated response to interferon gamma and reduced tumor antigen presentation in melanoma, breast cancer, and colorectal cancer cells. Parallel experiments in a syngeneic mouse melanoma model revealed that MBNL loss reduces tumor cell killing by CD8 + T cells in vitro and facilitates tumor escape from cytotoxic CD8 + T cell infiltration in vivo. Finally, we extended these studies to 29 human cancer types to find that MBNL expression levels are strongly associated with gene expression signatures of T cell tumor infiltration. These insights suggest that MBNL proteins play important roles in shaping the immune landscape across diverse malignancies.}, }
@article {pmid40305026, year = {2025}, author = {Montano-Campos, JF and Hahn, EE and Haupt, EC and Radich, J and Bansal, A}, title = {Oncologist-Patient Concordance and Treatment Adherence in Chronic Myeloid Leukemia.}, journal = {JAMA network open}, volume = {8}, number = {4}, pages = {e258039}, pmid = {40305026}, issn = {2574-3805}, }
@article {pmid40304602, year = {2025}, author = {Kopyeva, I and Bretherton, RC and Ayers, JL and Yu, M and Grady, WM and DeForest, CA}, title = {Matrix Stiffness and Biochemistry Govern Colorectal Cancer Cell Growth and Signaling in User-Programmable Synthetic Hydrogels.}, journal = {ACS biomaterials science & engineering}, volume = {11}, number = {5}, pages = {2810-2823}, pmid = {40304602}, issn = {2373-9878}, support = {R21 CA283686/CA/NCI NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; R01 CA289291/CA/NCI NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hydrogels/chemistry/pharmacology ; *Colorectal Neoplasms/pathology/metabolism ; Cell Proliferation/drug effects ; Signal Transduction/drug effects ; Cell Line, Tumor ; Fibronectins/chemistry ; *Extracellular Matrix/metabolism/chemistry ; Spheroids, Cellular ; Polyethylene Glycols/chemistry ; Oligopeptides/chemistry ; }, abstract = {Colorectal cancer (CRC) studies in vitro have been conducted almost exclusively on 2D cell monolayers or suspension spheroid cultures. Though these platforms have shed light on many important aspects of CRC biology, they fail to recapitulate essential cell-matrix interactions that often define in vivo function. Toward filling this knowledge gap, synthetic hydrogel biomaterials with user-programmable matrix mechanics and biochemistry have gained popularity for culturing cells in a more physiologically relevant 3D context. Here, using a poly(ethylene glycol)-based hydrogel model, we systematically assess the role of matrix stiffness and fibronectin-derived RGDS adhesive peptide presentation on CRC colony morphology and proliferation. Highlighting platform generalizability, we demonstrate that these hydrogels can support the viability and promote spontaneous spheroid or multicellular aggregate formation of six CRC cell lines that are commonly utilized in biomedical research. These gels are engineered to be fully degradable via a "biologically invisible" sortase-mediated reaction, enabling the triggered recovery of single cells and spheroids for downstream analysis. Using these platforms, we establish that substrate mechanics play a significant role in colony growth: soft conditions (∼300 Pa) encourage robust colony formation, whereas stiffer (∼2 kPa) gels severely restrict growth. Tuning the RGDS concentration did not affect the colony morphology. Additionally, we observe that epidermal growth factor receptor (EGFR) signaling in Caco-2 cells is influenced by adhesion ligand identity─whether the adhesion peptide was derived from collagen type I (DGEA) or fibronectin (RGDS)─with DGEA yielding a marked decrease in the level of downstream protein kinase phosphorylation. Taken together, this study introduces a versatile method to culture and probe CRC cell-matrix interactions within engineered 3D biomaterials.}, }
@article {pmid40304595, year = {2025}, author = {Abrams, HR and Saifee, NH and Miller, WS and Cortez, A and Hasan, RA and Panch, SR and Fertrin, KY}, title = {Alloimmunization as a barrier to gene therapy in sickle cell disease.}, journal = {Transfusion}, volume = {65}, number = {6}, pages = {1035-1039}, doi = {10.1111/trf.18266}, pmid = {40304595}, issn = {1537-2995}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Anemia, Sickle Cell/therapy/immunology/genetics ; *Genetic Therapy/methods ; Erythrocyte Transfusion ; Adult ; *Isoantibodies/immunology/blood ; }, abstract = {Alloimmunization is prevalent in patients with sickle cell disease (SCD) and can be a barrier to gene therapy (GT) due to the necessary transfusion support for successful stem cell collection and infusion. We estimate that standard-of-care GT for an adult with SCD will require an average of 35-45 units of red blood cells over a 6-month period. Institutions should actively plan for these transfusion needs and share information to inform national consensus policies on the management of alloimmunization during GT.}, }
@article {pmid40304490, year = {2025}, author = {Owen, MC and Zhou, Y and Dudley, H and Feehley, T and Hahn, A and Yokoyama, CC and Axelrod, ML and Lin, C-Y and Wang, D and Janowski, AB}, title = {Novel murine model of human astrovirus infection reveals cardiovascular tropism .}, journal = {Journal of virology}, volume = {99}, number = {5}, pages = {e0024025}, pmid = {40304490}, issn = {1098-5514}, support = {K08 AI132745/AI/NIAID NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; //Children's Discovery Institute/ ; }, mesh = {Animals ; *Disease Models, Animal ; *Astroviridae Infections/virology/pathology/immunology ; Mice ; *Viral Tropism ; Humans ; RNA, Viral/genetics ; Mice, Knockout ; *Mamastrovirus/physiology ; Mice, Inbred C57BL ; Endothelial Cells/virology ; Virus Replication ; Myocytes, Cardiac/virology ; Myocarditis/virology/pathology ; Myocardium/pathology ; }, abstract = {UNLABELLED: Astroviruses are a common cause of gastrointestinal disease in humans and have been linked to fatal cases of encephalitis. A major barrier to the study of human-infecting astroviruses is the lack of an in vivo model as previous attempts failed to identify a host that supports viral replication. We describe a novel murine model of infection using astrovirus VA1/HMO-C (VA1), an astrovirus with high seroprevalence in humans. VA1 is cardiotropic, and viral RNA levels peak in the heart tissue 7 days post-inoculation in multiple different murine genetic backgrounds. Infectious VA1 particles could be recovered from heart tissue 3 and 5 days post-inoculation. Viral capsid was detected intracellularly in the heart tissue by immunostaining, and viral RNA was detected in cardiac myocytes, endocardium, and endothelial cells based on fluorescent in situ hybridization and confocal microscopy. Histologically, we identified inflammatory infiltrates consistent with myocarditis in some mice, with viral RNA colocalizing with the infiltrates. These foci contained CD3 +T cells and CD68 +macrophages. Viral RNA levels increased by >10 fold in the heart tissue or serum samples from Rag1 or Stat1 knockout mice, demonstrating the role of both adaptive and innate immunity in the response to VA1 infection. Based on the in vivo tropisms, we tested cardiac-derived primary cells and determined that VA1 can replicate in primary human cardiac endothelial cells, suggesting a novel cardiovascular tropism in human cells. This novel in vivo model of a human-infecting astrovirus enables further characterization of the host immune response and reveals a new cardiovascular tropism of astroviruses.
IMPORTANCE: Astroviruses routinely cause infections in humans; however, few methods were available to study these viruses. Here, we describe the first animal system to study human-infecting astroviruses by using mice. We demonstrate that mice are susceptible to astrovirus VA1, a strain that commonly infects humans and has been linked to fatal brain infections. The virus infects the heart tissue and is associated with inflammation. When mice with impaired immune systems were infected with VA1, they were found to have higher amounts of the virus in their hearts and blood. We found that VA1 can infect cells from human blood vessels of the heart, which is associated with human health. This model will enable us to better understand how astroviruses cause disease and how the immune system responds to infection. Our findings also suggest that astroviruses could be linked to cardiovascular diseases, including in humans.}, }
@article {pmid40303999, year = {2025}, author = {Seber, A and Arcuri, LJ and Colturato, VR and Souza, MP and Zogbi, YAN and Funke, V and Lerner, D and Macedo, MC and Daudt, L and Kerbauy, MN and Zecchin, VG and Duarte, FB and Rabello Chiattone, R and Soares, RDA and Bettarello, G and Vaz de Macedo, A and Paton, E and Monteiro, TDM and Schmidt Filho, J and Astigarraga, CC and Scheinberg, P and Vigorito, AC and Vergueiro, CSV and Simione, A and Hashmi, S and Saber, W and Patel, J and Bonfim, CMS and Pasquini, M and Flowers, ME and Hamerschlak, N}, title = {Haploidentical, matched-related, and matched-unrelated hematopoietic cell transplant for acute leukemias in the early years of haploidentical transplant implementation in a developing country with a large unrelated donor registry.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1584631}, pmid = {40303999}, issn = {2234-943X}, abstract = {INTRODUCTION: Over the last decades, the donor network for hematopoietic cell transplantation (HCT) has grown exponentially, including unrelated and haploidentical (Haplo) donors. This study aimed to describe HCT outcomes with MSD, Haplo, and matched unrelated donors (MUD) in an early period of Haplo with posttransplant cyclophosphamide in a developing country with a large unrelated donor registry.
METHODS: This study was conducted in collaboration with the CIBMTR. We included patients with acute leukemias undergoing HCT between 2014-2018.
RESULTS: With 595 patients, 2-year overall survival (OS) was 69% for the MSD, 65% for the Haplo, and 71% for MUD (p=0.24) in CR1, confirmed in multivariable analysis. Relapse rate was lower for MUD (HR=0.35, p=0.0005) than MSD in patients with CR2+, leading to higher OS. Relapse was also higher with Haplo compared with MUD (HR=2.06, p=0.03).
DISCUSSION: Only survival bias can explain these findings in CR2+, suggesting some high-risk MUD patients, in which HCT timing is crucial, may not achieve HCT. Alternative donors were associated with higher non-relapse mortality, while PTCy-based Haplo offered the best protection against chronic graft-versus-host disease. Our study suggests Haplo and MUD are acceptable options for patients lacking MSD in developing countries like ours.}, }
@article {pmid40302927, year = {2025}, author = {Dharamshi, A and Neufeld, A and Motwani, K and Gao, LL and Witten, D and Bien, J}, title = {Generalized data thinning using sufficient statistics.}, journal = {Journal of the American Statistical Association}, volume = {120}, number = {549}, pages = {511-523}, pmid = {40302927}, issn = {0162-1459}, support = {P30 DA048736/DA/NIDA NIH HHS/United States ; R01 DA047869/DA/NIDA NIH HHS/United States ; R01 EB026908/EB/NIBIB NIH HHS/United States ; R01 GM123993/GM/NIGMS NIH HHS/United States ; }, abstract = {Our goal is to develop a general strategy to decompose a random variable X into multiple independent random variables, without sacrificing any information about unknown parameters. A recent paper showed that for some well-known natural exponential families, X can be thinned into independent random variables X (1) , … , X (K) , such that X = ∑ k = 1 K X (k) . These independent random variables can then be used for various model validation and inference tasks, including in contexts where traditional sample splitting fails. In this paper, we generalize their procedure by relaxing this summation requirement and simply asking that some known function of the independent random variables exactly reconstruct X . This generalization of the procedure serves two purposes. First, it greatly expands the families of distributions for which thinning can be performed. Second, it unifies sample splitting and data thinning, which on the surface seem to be very different, as applications of the same principle. This shared principle is sufficiency. We use this insight to perform generalized thinning operations for a diverse set of families.}, }
@article {pmid40302197, year = {2025}, author = {Nascimento de Lima, P and Maerzluft, C and Ozik, J and Collier, N and Rutter, CM}, title = {Stress-Testing US Colorectal Cancer Screening Guidelines: Decennial Colonoscopy from Age 45 is Robust to Natural History Uncertainty and Colonoscopy Sensitivity Assumptions.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {45}, number = {5}, pages = {557-568}, pmid = {40302197}, issn = {1552-681X}, support = {U01 CA253913/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colonoscopy/methods/standards ; *Colorectal Neoplasms/diagnosis ; Middle Aged ; Uncertainty ; *Early Detection of Cancer/methods/standards ; Male ; Female ; United States ; Aged ; *Practice Guidelines as Topic ; Sensitivity and Specificity ; Mass Screening/methods/standards ; Age Factors ; }, abstract = {PurposeThe 2023 American College of Physicians (ACP) guidelines for colorectal cancer (CRC) screening are at odds with the United States Preventive Task Force (USPSTF) guidelines, with the former recommending screening starting at age 50 y and the latter at age 45 y. This article "stress tests" CRC colonoscopy screening strategies to investigate their robustness to uncertainties stemming from the natural history of disease and sensitivity of colonoscopy.MethodsThis study uses the CRC-SPIN microsimulation model to project the life-years gained (LYG) under several colonoscopy CRC screening strategies. The model was extended to include birth cohort effects on adenoma risk. We estimated natural history parameters under 2 different assumptions about the youngest age of adenoma initiation. For each, we generated 500 parameter sets to reflect uncertainty in the natural history parameters. We simulated 26 colonoscopy screening strategies and examined 4 different colonoscopy sensitivity assumptions, encompassing the range of sensitivities consistent with prior tandem colonoscopy studies. Across this set of scenarios, we identify efficient screening strategies and report posterior credible intervals for benefits of screening (LYG), burden (number of colonoscopies), and incremental burden-effectiveness ratios.ResultsProjected absolute screening benefits varied widely based on assumptions, but strategies starting at age 45 y were consistently in the efficiency frontier. Strategies in which screening starts at age 50 y with 10-y intervals were never efficient, saving fewer life-years than starting screening at age 45 y and performing colonoscopies every 15 y while requiring more colonoscopies per person.ConclusionsDecennial colonoscopy screening initiation at age 45 y remained a robust recommendation. Colonoscopy screening with a 10-y interval starting at age 50 y did not result in an efficient use of colonoscopies in any of the scenarios evaluated.HighlightsColorectal cancer colonoscopy screening strategies initiated at age 45 y were projected to yield more life-years gained while requiring the least number of colonoscopies across different model assumptions about disease natural history and colonoscopy sensitivity.Colonoscopy screening starting at age 50 y with a 10-y interval consistently underperformed strategies that started at age 45 y.}, }
@article {pmid40301663, year = {2025}, author = {Goel, U and Dima, D and Davis, JA and Rashid, A and Wesson, W and Williams, L and Mazzoni, S and Bhurtel, E and Ullah, F and Rudoni, J and Rice, M and Tiger, YKR and Sauter, CS and Anwer, F and Raza, S and Shune, L and Khouri, J}, title = {Development of an Endothelial Activation and Stress Index (EASIX)-based predictive model for cytokine release syndrome and neurotoxicity after B-cell maturation antigen directed chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma.}, journal = {Bone marrow transplantation}, volume = {60}, number = {7}, pages = {1079-1081}, pmid = {40301663}, issn = {1476-5365}, }
@article {pmid40299982, year = {2025}, author = {Kubinski, HC and Despres, HW and Johnson, BA and Schmidt, MM and Jaffrani, SA and Turner, AH and Fanuele, CD and Mills, MG and Lokugamage, KG and Dumas, CM and Shirley, DJ and Estes, LK and Pekosz, A and Crothers, JW and Roychoudhury, P and Greninger, AL and Jerome, KR and Di Genova, BM and Walker, DH and Ballif, BA and Ladinsky, MS and Bjorkman, PJ and Menachery, VD and Bruce, EA}, title = {Variant mutation G215C in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.}, journal = {PLoS biology}, volume = {23}, number = {4}, pages = {e3003115}, pmid = {40299982}, issn = {1545-7885}, support = {P01 AI165075/AI/NIAID NIH HHS/United States ; P20 GM103449/GM/NIGMS NIH HHS/United States ; P20 GM125498/GM/NIGMS NIH HHS/United States ; R01 AI153602/AI/NIAID NIH HHS/United States ; }, mesh = {*SARS-CoV-2/genetics/physiology ; Humans ; Animals ; Mutation ; *COVID-19/virology ; *Coronavirus Nucleocapsid Proteins/genetics/metabolism ; Genome, Viral ; *Nucleocapsid/genetics/metabolism ; Chlorocebus aethiops ; Vero Cells ; *Viral Genome Packaging/genetics ; Virus Assembly/genetics ; Virion/genetics ; Phosphoproteins ; }, abstract = {The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of spike are not well studied, the entire viral genome is undergoing evolutionary selection, with several variants containing mutations in the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a more stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Mechanistically, we show that the N:G215C mutant has more encapsidation as measured by increased RNA binding to N, N incorporation into virions, and electron microscopy showing that individual virions are larger, with elongated morphologies.}, }
@article {pmid40299576, year = {2025}, author = {Kwek, SS and Yang, H and Li, T and Ilano, A and Chow, ED and Zhang, L and Chang, H and Luong, D and Lea, A and Clark, M and Starzinski, A and Shi, Y and McCarthy, E and Porten, S and Meng, MV and Ye, CJ and Fong, L and Oh, DY}, title = {Identification and regulation of circulating tumor-TCR-matched cytotoxic CD4+ lymphocytes by KLRG1 in bladder cancer.}, journal = {JCI insight}, volume = {10}, number = {11}, pages = {}, pmid = {40299576}, issn = {2379-3708}, support = {R01 LM013763/LM/NLM NIH HHS/United States ; U01 CA233100/CA/NCI NIH HHS/United States ; P30 DK063720/DK/NIDDK NIH HHS/United States ; R21 CA264381/CA/NCI NIH HHS/United States ; S10 OD021822/OD/NIH HHS/United States ; R01 CA194511/CA/NCI NIH HHS/United States ; S10 OD018174/OD/NIH HHS/United States ; R01 CA223484/CA/NCI NIH HHS/United States ; U01 CA244452/CA/NCI NIH HHS/United States ; K08 AI139375/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/immunology/pathology/blood ; *Receptors, Immunologic/metabolism/immunology ; *Lectins, C-Type/metabolism/immunology ; *Receptors, Antigen, T-Cell/metabolism/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; *T-Lymphocytes, Cytotoxic/immunology ; Granzymes/metabolism ; Female ; Male ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; }, abstract = {While cytotoxic CD4+ tumor-infiltrating lymphocytes have anticancer activity in patients, whether these can be noninvasively monitored and how these are regulated remains obscure. By matching single cells with T cell receptors (TCRs) in tumor and blood of patients with bladder cancer, we identified distinct pools of tumor-matching cytotoxic CD4+ T cells in the periphery directly reflecting the predominant antigenic specificities of intratumoral CD4+ tumor-infiltrating lymphocytes. On one hand, the granzyme B-expressing (GZMB-expressing) cytotoxic CD4+ subset proliferated in blood in response to PD-1 blockade but was separately regulated by the killer cell lectin-like receptor G1 (KLRG1), which inhibited their killing by interacting with E-cadherin. Conversely, a clonally related, GZMK-expressing circulating CD4+ population demonstrated basal proliferation and a memory phenotype that may result from activation of GZMB+ cells, but was not directly mobilized by PD-1 blockade. As KLRG1 marked the majority of circulating tumor-TCR-matched cytotoxic CD4+ T cells, this work nominates KLRG1 as a means to isolate them from blood and provide a window into intratumoral CD4+ recognition, as well as a putative regulatory receptor to mobilize the cytolytic GZMB+ subset for therapeutic benefit. Our findings also underscore ontogenic relationships of GZMB- and GZMK-expressing populations and the distinct cues that regulate their activity.}, }
@article {pmid40298902, year = {2025}, author = {Haack, AJ and Brown, LG and Goldstein, AJ and Mulimani, P and Berthier, J and Viswanathan, AR and Kopyeva, I and Whitten, JM and Lin, A and Nguyen, SH and Leahy, TP and Bouker, EE and Padgett, RM and Mazzawi, NA and Tokihiro, JC and Bretherton, RC and Wu, A and Tapscott, SJ and DeForest, CA and Popowics, TE and Berthier, E and Sniadecki, NJ and Theberge, AB}, title = {Suspended Tissue Open Microfluidic Patterning (STOMP).}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {25}, pages = {e2501148}, pmid = {40298902}, issn = {2198-3844}, support = {T32CA080416/NH/NIH HHS/United States ; F30HL158030/NH/NIH HHS/United States ; R35GM128648/NH/NIH HHS/United States ; F30 HL158030/HL/NHLBI NIH HHS/United States ; R35GM138036/NH/NIH HHS/United States ; P50AR065139//Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center - Seattle/ ; R90 DE023059/DE/NIDCR NIH HHS/United States ; 5TL1TR002318-08/NH/NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R01 HL149734/HL/NHLBI NIH HHS/United States ; R03DE029827/NH/NIH HHS/United States ; R35 GM128648/GM/NIGMS NIH HHS/United States ; R90DE023059/NH/NIH HHS/United States ; R03 DE029827/DE/NIDCR NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; R01HL149734/NH/NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, mesh = {*Microfluidics/methods ; *Tissue Engineering/methods ; Animals ; Humans ; Periodontal Ligament ; }, abstract = {Free-standing tissue structures tethered between pillars are powerful mechanobiology tools for studying cell contraction. To model interfaces ubiquitous in natural tissues and upgrade existing single-region suspended constructs, we developed Suspended Tissue Open Microfluidic Patterning (STOMP), a method to create multi-regional suspended tissues. STOMP uses open microfluidics and capillary pinning to pattern subregions within free-standing tissues, facilitating the study of complex tissue interfaces, such as diseased-healthy boundaries (e.g., fibrotic-healthy) and tissue-type interfaces (e.g., bone-ligament). We observed altered contractile dynamics in fibrotic-healthy engineered heart tissues compared to single-region tissues and differing contractility in bone-ligament enthesis constructs compared to single-tissue periodontal ligament models. STOMP is a versatile platform - surface tension-driven patterning removes material requirements common with other patterning methods (e.g., shear-thinning, photopolymerizable) allowing tissue generation in multiple geometries with native extracellular matrices and advanced four-dimensional (4D) materials. STOMP combines the contractile functionality of suspended tissues with precise patterning, enabling dynamic and spatially controlled studies.}, }
@article {pmid40298430, year = {2025}, author = {Cai, L and Wu, F and Zhou, Q and Gao, Y and Yao, B and DeBerardinis, RJ and Acquaah-Mensah, GK and Aidinis, V and Beane, JE and Biswal, S and Chen, T and Concepcion-Crisol, CP and Grüner, BM and Jia, D and Jones, RA and Kurie, JM and Lee, MG and Lindahl, P and Lissanu, Y and Lorz, C and MacPherson, D and Martinelli, R and Mazur, PK and Mazzilli, SA and Mii, S and Moll, HP and Moorehead, RA and Morrisey, EE and Ng, SR and Oser, MG and Pandiri, AR and Powell, CA and Ramadori, G and Santos, M and Snyder, EL and Sotillo, R and Su, KY and Taki, T and Taparra, K and Tran, PT and Xia, Y and van Veen, JE and Winslow, MM and Xiao, G and Rudin, CM and Oliver, TG and Xie, Y and Minna, JD}, title = {The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.}, journal = {Cancer research}, volume = {85}, number = {10}, pages = {1769-1783}, pmid = {40298430}, issn = {1538-7445}, support = {R01CA285336//National Cancer Institute (NCI)/ ; R01 CA244841/CA/NCI NIH HHS/United States ; R37 CA251629/CA/NCI NIH HHS/United States ; R01 CA272945/CA/NCI NIH HHS/United States ; SFB1430//Deutsche Forschungsgemeinschaft (DFG)/ ; PI21/00764//Instituto de Salud Carlos III (ISCIII)/ ; R01CA240317//National Cancer Institute (NCI)/ ; U01 AI156189/AI/NIAID NIH HHS/United States ; R35CA263816//National Cancer Institute (NCI)/ ; P50 CA070907/CA/NCI NIH HHS/United States ; U01CA213338//National Cancer Institute (NCI)/ ; R01 CA240317/CA/NCI NIH HHS/United States ; R01 CA285336/CA/NCI NIH HHS/United States ; R01CA212415//National Cancer Institute (NCI)/ ; R01DE030656//National Institute of Dental and Craniofacial Research (NIDR)/ ; R01GM141519//National Institute of General Medical Sciences (NIGMS)/ ; P50CA070907//National Cancer Institute (NCI)/ ; U24 CA213274/CA/NCI NIH HHS/United States ; R35 CA263816/CA/NCI NIH HHS/United States ; R01GM140012//National Institute of General Medical Sciences (NIGMS)/ ; //Howard Hughes Medical Institute (HHMI)/ ; U24CA213274//National Cancer Institute (NCI)/ ; R01 DE030656/DE/NIDCR NIH HHS/United States ; U01CA249245//National Cancer Institute (NCI)/ ; U01 CA213338/CA/NCI NIH HHS/United States ; R01 CA271540/CA/NCI NIH HHS/United States ; R01CA272945//National Cancer Institute (NCI)/ ; R01 GM140012/GM/NIGMS NIH HHS/United States ; R37CA251629//National Cancer Institute (NCI)/ ; R01 CA212415/CA/NCI NIH HHS/United States ; R35GM136375//National Institute of General Medical Sciences (NIGMS)/ ; R01CA244841//National Cancer Institute (NCI)/ ; R01 GM141519/GM/NIGMS NIH HHS/United States ; R35 CA220449/CA/NCI NIH HHS/United States ; GR4575/1-2//Deutsche Forschungsgemeinschaft (DFG)/ ; R01CA271540//National Cancer Institute (NCI)/ ; IRG-21-142-16//American Cancer Society (ACS)/ ; U01 CA249245/CA/NCI NIH HHS/United States ; R35 GM136375/GM/NIGMS NIH HHS/United States ; U01AI156189//National Institute of Allergy and Infectious Diseases (NIAID)/ ; P50 CA228944/CA/NCI NIH HHS/United States ; P50CA228944//National Cancer Institute (NCI)/ ; R35CA220449//National Cancer Institute (NCI)/ ; }, mesh = {Animals ; *Lung Neoplasms/genetics/pathology ; Mice ; *Transcriptome ; Disease Models, Animal ; Humans ; *Databases, Genetic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; }, abstract = {Lung cancer, the leading cause of cancer mortality, exhibits diverse histologic subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. In this study, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMM), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCAMGDB aligned 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in the GEMMs. To accompany this resource, a web application was developed that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCAMGDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance. Significance: The Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB) provides a comprehensive and accessible resource for the research community to investigate lung cancer biology in mouse models.}, }
@article {pmid40298376, year = {2025}, author = {Atmar, RL and Lyke, KE and Posavad, CM and Deming, ME and Brady, RC and Dobrzynski, D and Edupuganti, S and Mulligan, MJ and Rupp, RE and Rostad, CA and Jackson, LA and Martin, JM and Shriver, MC and Rajakumar, K and Coler, RN and El Sahly, HM and Kottkamp, AC and Branche, AR and Frenck, RW and Johnston, C and Babu, TM and Bäcker, M and Archer, JI and Crandon, S and Nakamura, A and Nayak, SU and Szydlo, D and Dominguez Islas, CP and Brown, ER and O'Connell, SE and Montefiori, DC and Eaton, A and Neuzil, KM and Stephens, DS and Beigel, JH and Pasetti, M and Roberts, PC}, title = {Mucosal and Systemic Antibody Responses After Boosting With a Bivalent Messenger RNA Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf176}, pmid = {40298376}, issn = {1537-6613}, support = {//Infectious Diseases Clinical Research Consortium/ ; //National Institute of Allergy and Infectious Diseases/ ; UM1AI48372/NH/NIH HHS/United States ; 75N93019C00050)//NIAID Collaborative Influenza Vaccine Innovation Centers/ ; //Vaccine Research Center/ ; }, abstract = {BACKGROUND: Mucosal immunity plays a critical role in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and replication. Understanding the capacity of coronavirus disease 2019 (COVID-19) vaccines to elicit both mucosal and systemic antibodies could help optimize vaccination strategies.
METHODS: We conducted an open-label, phase 1/2 adaptive-design clinical trial to evaluate the safety and immunogenicity of COVID-19 immunizations. Healthy adults received 2 priming doses of mRNA-1273, a booster dose of mRNA-1273, and a second booster of bivalent (WA-1 and BA.4/BA.5) mRNA-1273.222. Adverse event data were collected. Serum and mucosal immunity were evaluated.
RESULTS: One hundred six persons were enrolled. Thirty received all 4 study-related vaccine doses. All vaccines were well tolerated, with injection site pain, malaise, myalgias, and headache being the most frequently reported symptoms. Among those who received a second booster, 24 of 30 (80%) had serological evidence of SARS-CoV-2 infection. Following the second booster, increases in geometric mean binding and pseudovirus neutralization antibody titers to the ancestral strain and BA.1 and BA.5 variants were observed. Increases in mucosal immunoglobulin G and immunoglobulin A (IgA) antibodies in nasal and salivary samples were observed in both previously infected and infection-naive participants, although prior infection markedly boosted virus-specific mucosal IgA responses.
CONCLUSIONS: The mRNA-1273.222 booster vaccine was safe and immunogenic and induced mucosal antibody responses in previously infected and infection-naive persons.
CLINICAL TRIALS REGISTRATION: NCT04889209.}, }
@article {pmid40297938, year = {2025}, author = {Richardson, BD and Blette, BS and Gilbert, PB and Hudgens, MG}, title = {Addressing confounding and continuous exposure measurement error using corrected score functions.}, journal = {Biometrics}, volume = {81}, number = {2}, pages = {}, pmid = {40297938}, issn = {1541-0420}, support = {AI068635//U.S. Public Health Service/ ; R37 AI054165/AI/NIAID NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; R37AI029168/GF/NIH HHS/United States ; }, mesh = {Humans ; HIV Infections/prevention & control/epidemiology/immunology ; Bias ; Computer Simulation ; Confounding Factors, Epidemiologic ; *Models, Statistical ; Biomarkers ; Data Interpretation, Statistical ; *Biometry/methods ; }, abstract = {Confounding and exposure measurement error can introduce bias when drawing inference about the marginal effect of an exposure on an outcome of interest. While there are broad methodologies for addressing each source of bias individually, confounding and exposure measurement error frequently co-occur, and there is a need for methods that address them simultaneously. In this paper, corrected score methods are derived under classical additive measurement error to draw inference about marginal exposure effects using only measured variables. Three estimators are proposed based on g-formula, inverse probability weighting, and doubly-robust estimation techniques. The estimators are shown to be consistent and asymptotically normal, and the doubly-robust estimator is shown to exhibit its namesake property. The methods, which are implemented in the R package mismex, perform well in finite samples under both confounding and measurement error as demonstrated by simulation studies. The proposed doubly-robust estimator is applied to study the effects of two biomarkers on HIV-1 infection using data from the HVTN 505 preventative vaccine trial.}, }
@article {pmid40296864, year = {2025}, author = {Long, KJ and Silvestri, GA and Kammer, MN and Gibbs, S and Wu, W and Johal, M and Pipavath, S and Pitcher, T and Jett, J and Nair, VS}, title = {Validation of a High-Specificity Blood Autoantibody Test to Detect Lung Cancer in Pulmonary Nodules.}, journal = {CHEST pulmonary}, volume = {3}, number = {1}, pages = {}, pmid = {40296864}, issn = {2949-7892}, support = {T32 HL144470/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Pulmonary nodules (PNs) are frequently detected by chest CT scan, which is increasingly used in clinical practice. Accurately identifying malignant nodules can pose a diagnostic challenge; therefore, a high-specificity biomarker could help clinicians identify malignant nodules and ideally lead to the earlier diagnosis of lung cancer.
RESEARCH QUESTION: What are the performance characteristics of a blood-based biomarker for identifying malignancy in patients with a CT-detected PN?
STUDY DESIGN AND METHODS: Banked plasma samples from 2 independent prospective observational cohorts of patients presenting with benign or malignant PNs 8 to 30 mm in size were tested using a 7-autoantibody panel. Sensitivity, specificity, and positive predictive value of the autoantibody test (AAT) to identify cancer were calculated for the individual and combined cohorts.
RESULTS: Overall, 447 patients (263 and 184 from each cohort) were included in the analysis with a prevalence of malignancy of 55%. The performance of the AAT between the 2 cohorts was similar. The AAT demonstrated a specificity of 90% (95% CI, 85%-93%), a positive predictive value of 66% (95% CI, 52%-77%), sensitivity of 16% (95% CI, 12%-22%), and false-positive rate of 10% in the combined cohort. Using a pretest probability of cancer cutoff of 20% improved the positive predictive value to 76% (95% CI, 61%-88%) and resulted in a 52% decrease in the number of false-positive test results. In the subset of patients who had 18F-fluorodeoxyglucose PET imaging performed for clinical purposes (n = 222), specificity of the AAT was higher (93% vs 58%, P < .001), but the sensitivity was lower than 18F-fluorodeoxyglucose PET scan (17% vs 75%, P < .001).
INTERPRETATION: This study validates the specificity of a blood-based autoantibody biomarker for identifying malignancy in patients with indeterminate PNs. This rule-in biomarker may help to expedite workup of malignant nodules.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov CHEST Pulmonary 2025; 3(1):100130.}, }
@article {pmid40295790, year = {2024}, author = {Jelley, L and Aminisani, N and O'Neill, M and Jennings, T and Douglas, J and Utekar, S and Johnston, H and Welch, D and Hadfield, J and , and de Ligt, J and Winter, D and French, N and Thomas, PG and Webby, RJ and Huang, S and Geoghegan, JL}, title = {Tracing household transmission of SARS-CoV-2 in New Zealand using genomics.}, journal = {Npj viruses}, volume = {2}, number = {1}, pages = {21}, pmid = {40295790}, issn = {2948-1767}, support = {22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; 22/138//New Zealand Health Research Council Grant/ ; U01 AI 144616//US-NIAID/ ; 75N93021C00016/AI/NIAID NIH HHS/United States ; U01 AI 144616//US-NIAID/ ; }, abstract = {By early 2022, the highly transmissible Omicron variant of SARS-CoV-2 had spread across most of the world. For the first time since the pandemic began, New Zealand was experiencing high levels of community transmission of SARS-CoV-2. We enroled a cohort of households to better understand differences in transmission dynamics among subvariants of Omicron. We enroled 71 households, comprising 289 participants, and aimed to use viral genomes to gain a clearer understanding of variant-specific differences in epidemiological parameters affecting transmission dynamics. Approximately 80% of the households enroled experienced transmission of BA.2, while most of the remaining households had infections with BA.1 or BA.5. Using a logistic regression generalised linear mixed model, we found no difference in household secondary infection rate between Omicron subvariants BA.1, BA.2 and BA.5. Of the households recruited, the vast majority (92%) experienced a single chain of transmission with one inferred introduction. Further, we found that in 48% of the households studied, all household participants became infected following an index case. Most household participants tested positive within a week following an introduction, supporting the seven-day isolation requirement for household contacts that was in place in New Zealand at the time. By integrating genomic and epidemiological data, we show that viral transmission dynamics can be investigated with a higher level of granularity than with epidemiological data alone. Overall, households are a high risk setting for viral transmission in New Zealand.}, }
@article {pmid40294415, year = {2025}, author = {Riddler, SA and Moodie, Z and Clark, J and Yen, C and Allen, M and Furch, BD and Lu, H and Grant, S and Mondal, K and Anderson, M and Maenza, J and Lemos, MP and Woodward Davis, AS and Walsh, SR and Sobieszczyk, ME and Frank, I and Goepfert, P and Stephenson, KE and Baden, LR and Tieu, HV and Keefer, MC and McElrath, MJ and Kublin, JG and Corey, L}, title = {High Frequency of Chronic Urticaria Following an Investigational HIV-1 BG505 MD39.3 Trimer mRNA Vaccine in a Phase 1, Randomized, Open-Label Clinical Trial (HVTN 302).}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/ANNALS-24-02701}, pmid = {40294415}, issn = {1539-3704}, abstract = {BACKGROUND: The mRNA platform is under investigation for many vaccines, including HIV-1 vaccines.
OBJECTIVE: To evaluate the safety and tolerability of 3 investigational HIV-1 trimer mRNA vaccines.
DESIGN: Safety analysis of mRNA vaccination in a phase 1, randomized, open-label trial. (ClinicalTrials.gov: NCT05217641).
SETTING: Ten research sites in the United States.
PARTICIPANTS: 108 volunteers aged 18 to 55 years without HIV-1.
INTERVENTION: Investigational HIV-1 BG505 MD39.3 trimer mRNA vaccines (gp140 soluble trimer, gp151 membrane-bound trimer, and gp151 CD4KO membrane-bound trimer) at doses of 100 and 250 mcg at 0, 2, and 6 months.
MEASUREMENTS: Solicited and unsolicited adverse reactions and events reported during the 12 months after the first vaccination.
RESULTS: Participants (n = 108) were randomly assigned to 6 vaccine groups. Mild to moderate local and systemic solicited events were common. Eighty participants reported 190 unsolicited adverse events (AEs); 30 were considered to be related to a study product. Most (73%) related AEs were mild, and the rest were moderate. Among related AEs, urticaria was reported by 7 of 108 participants (7% [95% CI, 3% to 13%]), 4 of whom had unresolved, intermittent urticaria at 12 months. In post hoc analyses, demographic characteristics, history of allergy or medication use, and COVID-19 were not associated with urticaria. In a comparison of participants with versus without urticaria, 100% (7 of 7; CI, 65% to 100%) versus 37% (37 of 101; CI, 28% to 46%) reported previous Moderna COVID-19 vaccination, 29% (2 of 7; CI, 8% to 64%) versus 76% (77 of 101; CI, 67% to 84%) reported previous Pfizer-BioNTech COVID-19 vaccination, and 0% (0 of 7; CI, 0% to 35%) versus 5% (5 of 101; CI, 2% to 11%) reported no previous mRNA COVID-19 vaccination.
LIMITATIONS: Lack of a placebo group, open-label study, and post hoc evaluation of urticarial risk.
CONCLUSION: Urticarial reactions associated with experimental HIV-1 mRNA vaccines were observed in this trial. Studies to investigate the mechanism and approaches to mitigate these reactions are underway to further advance HIV-1 vaccine research.
PRIMARY FUNDING SOURCE: National Institutes of Health, National Institute of Allergy and Infectious Diseases.}, }
@article {pmid40294366, year = {2025}, author = {Huang, BJ and Meyer, LK and Alonzo, TA and Wang, YC and Lamble, AJ and Ries, RE and Wang, W and Hirsch, B and Raca, G and Ma, X and Gamis, AS and Aplenc, R and Kolb, EA and Cooper, TM and Tarlock, K and Loken, MR and Meshinchi, S and Chewning, JH and Woods, WG and Horan, JT}, title = {Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {17}, pages = {1961-1971}, pmid = {40294366}, issn = {1527-7755}, support = {K08 CA256489/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Child ; *Leukemia, Myeloid, Acute/therapy/mortality/genetics ; Male ; Female ; Child, Preschool ; Adolescent ; Neoplasm, Residual ; Infant ; Treatment Outcome ; Risk Factors ; Disease-Free Survival ; Remission Induction ; }, abstract = {PURPOSE: Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML.
METHODS: We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group.
RESULTS: Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P < .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss.
CONCLUSION: HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.}, }
@article {pmid40294356, year = {2025}, author = {Rosenberg, AR and Fladeboe, KM and Zhou, C and Bradford, MC and Kang, T and Maurer, S and Freyer, DR and Baker, KS and Comiskey, L and Junkins, CC and Taylor, MR and Yi-Frazier, JP}, title = {Promoting Resilience in Stress Management: A Randomized Controlled Trial of a Novel Psychosocial Intervention for Adolescents and Young Adults With Advanced Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500161}, doi = {10.1200/OP-25-00161}, pmid = {40294356}, issn = {2688-1535}, abstract = {PURPOSE: Adolescents and young adults (AYAs) with advanced cancer (AC) report poor quality of life (QOL), high psychological distress, and minimal engagement in health care discussions. We assessed the effect of a novel resilience coaching program (Promoting Resilience in Stress Management [PRISM]-AC) on AYA outcomes.
METHODS: We conducted a multisite randomized trial of PRISM-AC versus usual care (UC) among AYAs age 12-24 years, diagnosed with AC within 2 weeks before enrollment. PRISM-AC consists of four sessions targeting AYA-endorsed resilience resources (stress management, goal-setting, cognitive reframing, and meaning-making) plus a session integrating elements of advance care planning. Participants completed surveys at baseline, and 3, 6, 9, and 12 months. The primary outcome was Pediatric QOL at 3 months; secondary/exploratory outcomes included 3-month changes in resilience (10-item Connor-Davidson Resilience Scale) and hope (Snyder Hope Scale), and trajectories of QOL, anxiety, and depression (Hospital Anxiety and Depression Scale) over 12 months. We examined associations with linear mixed effects regression models. We also explored PRISM-AC's impact on AYA participation in critical health care discussions, as documented in the electronic health record.
RESULTS: Between April 2019 and January 2024, we enrolled 239 AYAs (56% of 426 approached) and randomly assigned 195 (82% of enrolled; 96 UC, 99 PRISM). They were of mean age 16.5 years (standard deviation, 3.9), mostly White (63%), non-Hispanic (59%), and publicly insured (53%). At 3 months, we detected no significant differences between groups with respect to QOL, anxiety, or depression; PRISM-AYAs demonstrated greater improvements in resilience (+1.3 [5.9] v -1.4 (7.5); P = .038) and hope (+2.4 [10.4] v -2.8 [11.2]; P = .001) than UC-AYAs. Over the 12-month study period, PRISM-AYAs reported more improvements in QOL and anxiety, with significant differences at later time points (PRISM-QOL improvements, 6 months: +3.4 [95% CI, 0.1 to 6.6]; P = .043; 12 months: +6.8 [95% CI, 3.3 to 10.3]; P < .001). Although participation in key health care discussions was similar between groups from baseline to 6 months, 67% (95% CI, 35 to 88) and 50% (95% CI, 22 to 78) of PRISM-AYAs participated at 9 and 12 months, respectively, compared with 39% (95% CI, 20 to 61) and 38% (95% CI, 21 to 59) of UC-AYAs.
CONCLUSION: Among AYAs with AC, PRISM-AC did not immediately improve QOL. Rather, it improved resilience and hope, potentially enabling longer-term improvements in QOL.}, }
@article {pmid40293383, year = {2025}, author = {Colbert, CM and Melancon, D and Kang, J and Ford, EC and Smith, WP}, title = {A Comparative Risk Analysis of Cone Beam Computed Tomography-based Daily Adaptive Radiation Therapy and Cone Beam Computed Tomography-based Radiation Therapy Alone.}, journal = {International journal of radiation oncology, biology, physics}, volume = {122}, number = {4}, pages = {873-880}, doi = {10.1016/j.ijrobp.2025.04.009}, pmid = {40293383}, issn = {1879-355X}, mesh = {*Cone-Beam Computed Tomography/methods/standards/adverse effects ; *Radiotherapy, Image-Guided/methods/adverse effects/standards/instrumentation ; Humans ; Particle Accelerators ; *Radiotherapy Planning, Computer-Assisted/methods/standards ; Risk Assessment ; *Healthcare Failure Mode and Effect Analysis ; Equipment Failure/statistics & numerical data ; Radiotherapy, Intensity-Modulated/methods ; Workflow ; }, abstract = {PURPOSE: When adopting a new therapeutic technology, a comparison to a standard of care is needed. We aim to directly compare the specific safety implications of adaptive radiation therapy (ART) to those of traditional image guided radiation therapy (IGRT), as implemented on a ring gantry linear accelerator with kilovoltage cone beam computed tomography-based online ART capability.
METHODS AND MATERIALS: An interdisciplinary committee performed a failure modes and effects analysis based on the American Association of Physicists in Medicine (AAPM) Task Group 100 method addressing initial treatment planning, quality assurance, and treatment delivery for both IGRT-alone and IGRT with ART on the Varian Ethos. Failure modes were categorized by process step and associated clinical roles, scored by severity, occurrence, and detectability, and ranked by risk priority number (RPN). Failure modes shared by IGRT and ART were scored and analyzed comparatively.
RESULTS: We identified 33 unique system failure modes as part of the IGRT-alone workflow, and 9 additional failure modes specific to ART. Most high-risk IGRT-alone system failure modes were associated with initial treatment planning errors. High-risk ART failure modes also included errors related to adaptive replanning. Reanalysis of 33 IGRT-alone failure modes in the ART setting found an overall decrease in median RPN from 96 (IQR, 56-144) to 72 (IQR, 32-120; P = .035). RPN decreased for 12 failure modes, with the greatest change observed among the highest-ranked failure modes for IGRT-alone.
CONCLUSIONS: Although online ART introduces new avenues for error in the adaptive replanning process, the enhanced staffing and iterative plan review reduce the risk associated with systematic errors originating in initial treatment planning. The finding that the RPN decreased in the adaptive setting provides a unique motivation for the adoption of ART from a patient safety perspective, beyond the well-documented dosimetric benefit of ART.}, }
@article {pmid40293363, year = {2025}, author = {Minalga, B and Siskind, R and Campbell, R and Adamson, T and Cermak, MA and Davis, A and Givens, ED and Dyer, M and McCarthy, K and Montañez, NA and White, R and , }, title = {The Representative Studies Rubric: A Tool for Diversity in Clinical Trials.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/23294515.2025.2497753}, pmid = {40293363}, issn = {2329-4523}, abstract = {When clinical trials fail to enroll diverse study populations, a multitude of consequences can occur, including compromised validity and generalizability, safety and efficacy uncertainties, regulatory limitations, widened disparities, distrust in science and medicine, and undermined efforts to address urgent health needs. We developed the Representative Studies Rubric (RSR), a questionnaire that evaluates the extent to which clinical trials are designed to enroll representative study populations with a focus on age, ethnicity, drug use, gender, pregnancy, race, and sex assigned at birth. We used the RSR to conduct an analysis of all active studies in the NIH-funded HIV/AIDS Clinical Trials Networks (Networks) and identified patterns of research practices that may limit the participation of underrepresented populations, with ethical implications. The Networks subsequently formalized the RSR as a required protocol development tool for all future studies to correct exclusionary research practices with the goal to achieve more representative study populations.}, }
@article {pmid40288610, year = {2025}, author = {Shouval, R and Strouse, C and Kim, S and Oloyede, T and Ahmed, S and Awan, FT and Luan, D and Bachanova, V and Badar, T and Bar, M and Barba, P and Beitinjaneh, AM and Cashen, A and Dholaria, B and Elsawy, M and Ganguly, S and Geethakumari, PR and Greenbaum, U and Hashmi, H and Hill, LC and Jain, MD and Jain, T and Kebriaei, P and Kittai, AS and Locke, FL and Lulla, PD and Mead, E and McGuirk, JP and Mussetti, A and Nishihori, T and Olson, AL and Pennisi, M and Perales, MA and Riedell, PA and Saber, W and Mirza, AS and Magalhaes-Silverman, M and Shpall, EJ and Sorror, M and Wudhikarn, K and Turtle, CJ and Moskop, A and Pasquini, MC}, title = {Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {419-433}, doi = {10.1016/j.jtct.2025.03.011}, pmid = {40288610}, issn = {2666-6367}, mesh = {Humans ; *Cytokine Release Syndrome/etiology ; Female ; Male ; Middle Aged ; *Neurotoxicity Syndromes/etiology ; *Immunotherapy, Adoptive/adverse effects/methods ; *Lymphoma, B-Cell/therapy/immunology ; Aged ; *Antigens, CD19/immunology ; Adult ; *Receptors, Chimeric Antigen ; Biological Products ; }, abstract = {Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk factors were assessed using Cox proportional hazards model. Among patients developing CRS (75.2%), 11.3% had grade ≥3 CRS. Among patients developing ICANS (43.5%), 47.7% had grade ≥3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P< .01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P= .10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95% CI, 3.65 to 5.81) and ICANS (OR, 5.85; 95% CI, 4.48 to 7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days postinfusion, patients with severe CRS or severe ICANS had shorter OS compared to those without these toxicities. High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety.}, }
@article {pmid40288368, year = {2025}, author = {Lespine, LF and Rueda-Delgado, LM and Vahey, N and Ruddy, KL and Kiiski, H and Enz, N and Boyle, R and Rai, L and Pragulbickaite, G and Bricker, JB and McHugh, L and Whelan, R}, title = {Changes in Inhibition-Related Brain Function and Psychological Flexibility during Smoking Abstinence: A Machine-Learning Prediction of Time to Relapse.}, journal = {European addiction research}, volume = {}, number = {}, pages = {1-14}, pmid = {40288368}, issn = {1421-9891}, abstract = {INTRODUCTION: Despite substantial health benefits, smoking cessation attempts have high relapse rates. Neuroimaging measures can sometimes predict individual differences in substance use phenotypes - including relapse - better than behavioral metrics alone. No study to date has compared the relative prediction ability of changes in psychological processes across prolonged abstinence with corresponding changes in brain activity.
METHODS: Here, in a longitudinal design, measurements were made 1 day prior to smoking cessation, and at 1 and 4 weeks post-cessation (total n = 120). Next, we tested the relative role of changes in psychosocial variables versus task-based functional brain measures predicting time to nicotine relapse up to 12 months. Abstinence was bio-verified 4-5 times during the first month. Data were analyzed with a novel machine-learning approach to predict relapse.
RESULTS: Results showed that increased electrophysiological brain activity during inhibitory control predicted longer time to relapse (c-index = 0.56). However, reward-related brain activity was not predictive (c-index = 0.45). Psychological variables, notably an increase during abstinence in psychological flexibility when experiencing negative smoking-related sensations, predicted longer time to relapse (c-index = 0.63). A model combining psychosocial and brain data was predictive (c-index = 0.68). Using a best-practice approach, we demonstrated generalizability of the combined model on a previously unseen holdout validation dataset (c-index = 0.59 vs. 0.42 for a null model).
CONCLUSION: These results show that changes during abstinence - increased smoking-specific psychological flexibility and increased inhibitory control brain function - are important in predicting time to relapse from smoking cessation. In the future, monitoring and augmenting changes in these variables could help improve the chances of successful nicotine smoking abstinence.}, }
@article {pmid40287589, year = {2025}, author = {Vo, P and Ng, K and Schoch, G and Cooper, J and Vupalanchi, A and Flowers, M and Sandmaier, BM and Gooley, T and Storb, R}, title = {Subsequent cancers following non-myeloablative conditioning for allogeneic hematopoietic cell transplantation.}, journal = {Bone marrow transplantation}, volume = {60}, number = {7}, pages = {1052-1056}, pmid = {40287589}, issn = {1476-5365}, support = {CA 078902//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA 015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Male ; Female ; *Transplantation Conditioning/adverse effects/methods ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Middle Aged ; Adult ; Aged ; Graft vs Host Disease/etiology ; *Neoplasms, Second Primary/epidemiology/etiology ; Adolescent ; *Hematologic Neoplasms/therapy ; Follow-Up Studies ; Transplantation, Homologous ; Allografts ; SEER Program ; Young Adult ; Child ; }, abstract = {We examined the risk of subsequent malignant neoplasms (SMNs) in 1720 patients with hematologic cancers given allogeneic hematopoietic grafts from 03/1998 to 08/2023 after nonmyeloablative conditioning regimens. With a median follow-up of 12 years, the cumulative incidence of SMNs was 17% (95% CI, [15%, 19%]). Most SMNs (n = 543) were non-melanoma skin cancers seen in 208 patients; unfortunately, information on these cancers was not available in the Surveillance, Epidemiology, and End Results (SEER) database for comparison with such tumors in the general population. However, developing non-melanoma skin cancers was statistically significantly associated with chronic GVHD and, thus, unlikely to be conditioning regimen related. Eighty-six patients (5%) developed 93 other SMNs. This number (93 SNMs) significantly exceeded the expected 73.4 cases in the comparison group (p = 0.03). This increase was driven exclusively by increases in uterine adenocarcinoma (n = 2), squamous lip cancer (n = 5), and squamous penile cancer (n = 2); the latter two cancers were, again, associated with chronic GVHD. Apart from these three tumor types, there were no observed increases in the risk of other tumors compared to those in the general population.}, }
@article {pmid40281324, year = {2025}, author = {Posluszny, DM and Nezu, AM and Bovbjerg, DH and Syrjala, KL and Dew, MA}, title = {Intervention Development to Promote Medical Adherence After Stem Cell Transplant.}, journal = {Journal of clinical psychology in medical settings}, volume = {}, number = {}, pages = {}, pmid = {40281324}, issn = {1573-3572}, support = {K23CA149082 and P30CA047904/CA/NCI NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) can be a lifesaving treatment for patients with hematologic disease. However, adherence to the post-HCT clinical regimen has many challenges that patients and their family caregivers must manage after hospital discharge. To address their needs, we developed a Dyadic Problem-Solving Therapy (DPST) intervention, then examined its feasibility and acceptability to patients and their family caregivers. Twelve patient-family caregiver dyads participated. Four dyads received DPST in person, four received it via online video conferencing. Another four received an enhanced usual care (EUC) intervention of the same length. Feasibility was assessed using completion rates, while acceptability was assessed using satisfaction ratings on the Client Satisfaction Questionnaire. DPST and EUC were both feasible (100% of dyads who started the intervention completed it) and acceptable with satisfaction ratings ranging from 3.6 to 4 for patients and 3.6-3.9 for family caregivers on a 1-4 scale for both DPST groups and ranging from 3.3 to 3.8 for EUC patients and 3.5-4 for EUC family caregivers. There were no evident differences by mode of intervention delivery. DPST, both in person and via video, appears feasible and acceptable for training patient-family caregiver dyads to manage challenges to adherence to the post-HCT regimen.}, }
@article {pmid40280707, year = {2025}, author = {Wang, M and Guo, Y and Hippe, DS and Zhao, X and Yuan, C and Saba, L and Zhang, B and Mossa-Basha, M}, title = {Plaque RADS Related to Cerebrovascular Event Risk with Mild/moderate Stenosis: a CARE II study.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A8819}, pmid = {40280707}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Carotid Plaque-Reporting And Data System (Plaque-RADS) provides a standardized approach for evaluating carotid plaque morphology and composition. The aim of this study was to evaluate carotid Plaque-RADS, and its relationship with clinical risk factors and ipsilateral cerebrovascular symptoms, in a prospectively-acquired multi-center, vessel-wall MRI dataset.
MATERIALS AND METHODS: Symptomatic patients were recruited from the CARE-II (Chinese Atherosclerosis Risk Evaluation, NCT02017756) study. This cross-sectional study included patients with recent stroke or transient ischemia attack and atherosclerotic plaques in at least one carotid artery. Lipid-rich necrotic core, ulceration, intraplaque hemorrhage, thick or thin fibrous cap, fibrous cap rupture and intraluminal thrombi were identified from multiple contrast vessel wall imaging and used to determine carotid Plaque-RADS. In addition, ancillary features including calcification and plaque burden via maximum normalized wall index (max_NWI) were collected. Degree of stenosis was classified as mild (<30%), moderate (30-69%), and severe (70-99%). Generalized Estimating Equation-based logistic regression was performed to assess the relationship between the Plaque-RADS score and cerebrovascular events.
RESULTS: A total of 433 patients (62 years ± 9.97, 302 males (69.7%)) with 866 carotid arteries were included in this study. Symptomatic carotid arteries had higher stenosis degree (11.8%±24.7 vs 8.6%±18.8, p=0.01), plaque-RADS score (≥3: 33.9% vs 28.4%, p=0.02) and max_NWI (0.53±0.14 vs 0.51±0.13, p=0.002) compared to the asymptomatic side. Plaque RADS was significantly associated with cerebrovascular events (OR=1.11 per 1-level increase, 95%CI=1.01-1.24; p=0.04). In patients with mild/moderate bilateral carotid artery stenosis, plaque RADS≥3 was significantly associated with symptomatic events (OR=1.30, 95%CI=1.01-1.68; p=0.04). Higher plaque-RADS on the symptomatic side was related to advanced age (OR=1.27 per 10-year increase, 95%CI=1.03-1.56; p=0.03), male sex (OR=1.90, 95%CI=1.05-3.43; p=0.03), and smoking history (OR=1.99, 95%CI=1.20-3.31; p=0.007).
CONCLUSIONS: Male patients of advanced age and with a smoking history were associated with an increased risk of higher plaque-RADS scores. Plaque-RADS demonstrated the ability to stratify patients experiencing cerebrovascular events, even in cases with mildto-moderate stenosis. However, this association did not retain statistical significance after adjusting for stenosis or max_NWI.
ABBREVIATIONS: IPH = intraplaque hemorrhage; Max-NWI = maximum normalized wall index; MWT = maximum wall thickness; RADS = Reporting And Data System; VWI = vessel wall imaging.}, }
@article {pmid40280142, year = {2025}, author = {Luetkemeyer, AF and Donnell, D and Celum, C}, title = {Doxy-PEP could select for ceftriaxone resistance in Neisseria gonorrhoeae - Authors' reply.}, journal = {The Lancet. Infectious diseases}, volume = {25}, number = {6}, pages = {e317}, doi = {10.1016/S1473-3099(25)00235-X}, pmid = {40280142}, issn = {1474-4457}, }
@article {pmid40279415, year = {2025}, author = {Freie, B and Ibrahim, AH and Carroll, PA and Bronson, RT and Augert, A and MacPherson, D and Eisenman, RN}, title = {MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadt3177}, pmid = {40279415}, issn = {2375-2548}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248762/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Animals ; *Proto-Oncogene Proteins c-myc/genetics/metabolism ; Mice ; *Neuroendocrine Tumors/genetics/pathology/metabolism ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Humans ; *Gene Regulatory Networks ; Carcinoma, Neuroendocrine/genetics/pathology ; Tumor Suppressor Protein p53/genetics ; Cell Proliferation ; }, abstract = {The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma, and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find that Max inactivation alone produces pituitary adenomas, while Max inactivation cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a marked shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival, and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.}, }
@article {pmid40277348, year = {2025}, author = {Chung, Y and Cai, T and Newcomb, L and Lin, DW and Zheng, Y}, title = {Improving Efficiency and Robustness of the Prognostic Accuracy of Biomarkers With Partial Incomplete Failure-Time Data and Auxiliary Outcome: Application to Prostate Cancer Active Surveillance Study.}, journal = {Statistics in medicine}, volume = {44}, number = {8-9}, pages = {e70072}, doi = {10.1002/sim.70072}, pmid = {40277348}, issn = {1097-0258}, support = {R01 CA236558/NH/NIH HHS/United States ; U01 CA86368/NH/NIH HHS/United States ; UH3CA234196/NH/NIH HHS/United States ; R01 HL089778/NH/NIH HHS/United States ; }, mesh = {Humans ; *Prostatic Neoplasms/diagnosis/therapy ; Male ; Prognosis ; Computer Simulation ; *Biomarkers, Tumor ; Disease Progression ; Models, Statistical ; *Watchful Waiting ; Prostate-Specific Antigen/blood ; }, abstract = {When novel biomarkers are developed for the clinical management of patients diagnosed with cancer, it is critical to quantify the accuracy of a biomarker-based decision tool. The evaluation can be challenging when the definite outcome T $$ T $$ , such as time to disease progression, is only partially ascertained on a limited set of study patients. Under settings where T $$ T $$ is only observed on a subset but an auxiliary outcome correlated with T $$ T $$ is available on all subjects, we propose an augmented estimation procedure for commonly used time-dependent accuracy measures. The augmented estimators are easy to implement without imposing modeling assumptions between the two types of time-to-event outcomes and are more efficient than the complete-case estimator. When the ascertainment of the outcome is non-random and subject to informative censoring, we further augment our proposed method with inverse probability weighting to improve robustness. Results from simulation studies confirm the robustness and efficiency properties of the proposed estimators. The method is illustrated with data from the Canary Prostate Active Surveillance Study.}, }
@article {pmid40276374, year = {2025}, author = {Raskin, S and de Blank, P and Billups, CA and Li, Y and Olson, JM and Leary, SES}, title = {Isotretinoin has no effect on event-free survival across high-risk medulloblastoma molecular groups when added to maintenance: A secondary analysis of the Children's Oncology Group ACNS0332 data.}, journal = {Neuro-oncology advances}, volume = {7}, number = {1}, pages = {vdaf054}, pmid = {40276374}, issn = {2632-2498}, abstract = {BACKGROUND: The Children's Oncology Group (COG) study ACNS0332 examined the effect of adding carboplatin and isotretinoin to high-risk medulloblastoma therapy. Isotretinoin arms were closed early due to futility, but the effect of carboplatin was shown to vary by individual medulloblastoma subgroups. Because isotretinoin arms were closed before subgroup classification was available, a differential effect of isotretinoin among various subgroups was not examined. Here, we conduct a secondary analysis of ACNS0332 data examining the effect of isotretinoin on event-free survival (EFS) among individual medulloblastoma subgroups.
METHODS: Among 261 patients enrolled in ACNS0332, a subgroup was evaluable in 231 patients. Fisher's exact tests and chi-square tests were used to compare distributions of categorical variables among patients with and without exposure to isotretinoin. EFS for subgroups was estimated, and the log-rank test was used to examine differences in outcome distributions among patient groups.
RESULTS: Among 231 evaluable patients, 85 were randomized to isotretinoin, 85 were randomized to no isotretinoin, and 61 received no isotretinoin without randomization. All 4 medulloblastoma groups were identified: Randomization to isotretinoin was not associated with any difference in EFS in patients with group 3 (n = 79, P = .87), group 4 (n = 101, P = .53), SHH (n = 37, P = .69) or WNT (n = 14, P = 1) medulloblastoma.
CONCLUSIONS: This study confirms that isotretinoin in addition to radiation and chemotherapy did not improve EFS in pediatric high-risk medulloblastoma regardless of molecular subgroup.}, }
@article {pmid40275643, year = {2025}, author = {Rodriguez, CP and Wu, QV and Ng, K and Voutsinas, J and Fromm, JR and Dumenigo-Jimenez, A and Martins, RG and Eaton, KD and Santana-Davila, R and Baik, C and Lee, SM and Tseng, D and Futran, N and Barber, B and Marchiano, E and Laramore, G and Lo, SS and Liao, JJ and Parvathaneni, U}, title = {Dual PD-1 and CTLA4 Immune Checkpoint Blockade and Hypofractionated Radiation in Patients With Advanced Salivary Gland Cancers.}, journal = {Head & neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.28169}, pmid = {40275643}, issn = {1097-0347}, support = {//Bristol-Myers Squibb/ ; }, abstract = {BACKGROUND: No standard systemic therapy exists for recurrent/metastatic salivary gland cancer (R/M SGC). We explored the safety and activity of nivolumab and ipilimumab with palliative hypofractionated radiation (XRT) in this population.
METHODS: This Phase I/II Trial enrolled R/M SGCs with evidence of progression, ECOG 0-1, no prior anti-PD-1 or CTLA4 therapy, measurable disease excluding the XRT site. Nivolumab 3 mg/kg iv Q2 weeks × 12 doses followed by 480 mg iv Q4 weeks × 8 doses and ipilimumab 1 mg/kg iv Q6 weeks × 4 doses was given. Twenty four gray XRT was given over three fractions, 2 weeks after the first dose of nivolumab. The primary endpoint was safety; secondary endpoints included RECIST 1.1 response (non-radiated lesions), progression free, and overall survival.
RESULTS: Between April 2019 and May 2022, 20 pts. were enrolled, the median age was 58 (range 27-77 years), 10 (50%) were male, and 12 (60%) had ECOG 0. Five (20%) Grade 3 AEs were observed in three pts.; no Grade 4 or 5 toxicities were observed. Among 19 response-evaluable patients, RECIST 1.1 PRs were observed in 4 (21%), in 2 pts. with salivary duct, 1 acinic cell, and 1 adenoid cystic, SD in 6 (31.5%) and PD in 9 (47.5%). With a median follow-up of 16 months, median OS was 25 months (95% CI: [18.7, 31]) and median PFS was 7.3 months (95% CI [2.5, 18.7]).
CONCLUSION: Nivolumab/ipilimumab and palliative XRT result in low rates of severe toxicities and modest response rates for SGC; further work is necessary to explore predictors for response.}, }
@article {pmid40274741, year = {2025}, author = {Juels, M and Larson, JC and Ensrud, KE and Stefanick, ML and Shadyab, AH and Garcia, L and Nassir, R and Schnatz, PF and Nelson, R and Crandall, CJ}, title = {Race, Ethnicity, and Mortality Following Major Osteoporotic Fracture: Results from the Women's Health Initiative Study.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {40274741}, issn = {1525-1497}, abstract = {BACKGROUND: Major osteoporotic fracture (MOF) is associated with increased mortality; however, few studies in postmenopausal women have examined racial and ethnic differences in 1-year and 5-year mortality following MOF.
OBJECTIVE: To assess 1-year and 5-year mortality following MOF by race and ethnicity.
DESIGN: This prospective cohort study included postmenopausal women enrolled in the Women's Health Initiative (WHI), a population-based, multisite US study. Participants were followed from September 1994 to February 2023. Data were analyzed between August 2023 and November 2023.
PARTICIPANTS: Postmenopausal women aged 50 to 79 years old who experienced a MOF (N = 32,675 in 1 year and 29,506 in 5 years following MOF).
MAIN MEASURES: Self-reported race and ethnicity. All-cause mortality was determined by death certificates, reports of surrogates, and the National Death Index Search.
KEY RESULTS: The baseline mean age of participants was 77.0 [SD = 8.5] years with 31,223 [95.6%] White participants in the 1-year mortality analysis, and 76.3 [SD = 8.5] years with 28,212 [95.6%] White participants in the 5-year mortality analysis. In fully adjusted models, compared to White women, Black women had a higher risk of mortality (adjusted odds ratio (aOR) = 1.42, 95% CI [1.06, 1.90], while Asian women had a lower risk of mortality (aOR = 0.48 95% CI [0.27, 0.88]), within 1 year following MOF. Compared to White women, the mortality risk within 5 years after MOF was significantly higher among American Indian/Alaska Native (aOR = 3.30, 95% CI [1.65, 6.60]) and lower among Asian (aOR = 0.58, 95% CI [0.42,0.80]) women. While there were no mortality differences by ethnicity 1 year following MOF, Hispanic/Latina women were less likely to die 5 years following MOF (aOR = 0.74, [95% CI 0.57-0.96]) compared to Non-Hispanic/Latina women.
CONCLUSIONS: In this large prospective study, mortality following MOF differed by race. Future research is needed to delineate the mechanism behind these associations.}, }
@article {pmid40274389, year = {2025}, author = {Chan, M and Zhu, S and Nukaya, M and Ferreira, LT and Ronnekleiv-Kelly, SM and Riehle, KJ and Scott, JD and Yeung, RS and Gujral, TS}, title = {DNAJ-PKAc fusion heightens PLK1 inhibitor sensitivity in fibrolamellar carcinoma.}, journal = {Gut}, volume = {}, number = {}, pages = {}, doi = {10.1136/gutjnl-2024-334274}, pmid = {40274389}, issn = {1468-3288}, abstract = {BACKGROUND: Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumour growth remains enigmatic.
OBJECTIVE: We sought to determine the protein kinase-mediated signalling networks that drive growth and proliferation in FLC.
DESIGN: We integrated a combination of newly established preclinical models of FLC and an unbiased polypharmacology-based approach to identify downstream kinases involved in DNAJ-PKAc-mediated FLC cell growth. We validated our findings in multiple patient-derived mouse models and patient tumours.
RESULTS: Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumour growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues.
CONCLUSION: Our findings underscore the role of DNAJ-PKAc in rewiring signalling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.}, }
@article {pmid40274340, year = {2025}, author = {Patel, D and Reese Koç, J and Otegbeye, F}, title = {Creating a GMP cell processing program: A focus on quality and regulation.}, journal = {Best practice & research. Clinical haematology}, volume = {38}, number = {1}, pages = {101614}, doi = {10.1016/j.beha.2025.101614}, pmid = {40274340}, issn = {1532-1924}, mesh = {Humans ; United States ; *Cell- and Tissue-Based Therapy/standards ; Quality Control ; United States Food and Drug Administration ; }, abstract = {Implementing current Good Manufacturing Practice (GMP) regulations and principles even in early phases of cell-based therapy studies is crucial for ensuring safety and reproducible quality of these products. This paper outlines the comprehensive steps necessary to establish a robust GMP-compliant cell processing program in academic programs with emphases on adherence to regulatory and quality standards. While there are different regulatory agencies governing practice across the globe, the prevailing quality principles described here incorporate common requirements and guidelines from agencies such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The goal of this review is to provide guidance for developing a quality management program (QMP) that addresses all critical factors impacting each step in the cell therapy product lifecycle: from procurement and receipt of starter material, through manufacturing, testing, storage, distribution, and administration. The QMP should be designed to assure quality outcomes by maintaining qualified and trained staff at all levels as applicable to their job functions; establishing clear policies and procedures; ensuring the qualification of facilities and equipment; using qualified materials for human use; and providing a framework for detection of trends and implementing process improvement.}, }
@article {pmid40273911, year = {2025}, author = {Kim, WJ and Crosse, EI and De Neef, E and Etxeberria, I and Sabio, EY and Wang, E and Bewersdorf, JP and Lin, KT and Lu, SX and Belleville, A and Fox, N and Castro, C and Zhang, P and Fujino, T and Lewis, J and Rahman, J and Zhang, B and Winick, JH and Lewis, AM and Stanley, RF and DeWolf, S and Urben, BM and Takizawa, M and Krause, T and Molina, H and Chaligne, R and Koppikar, P and Molldrem, J and Gigoux, M and Merghoub, T and Daniyan, A and Chandran, SS and Greenbaum, BD and Klebanoff, CA and Bradley, RK and Abdel-Wahab, O}, title = {Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.}, journal = {Cell}, volume = {188}, number = {13}, pages = {3422-3440.e24}, pmid = {40273911}, issn = {1097-4172}, support = {R01 CA269733/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; R01 CA242020/CA/NCI NIH HHS/United States ; R01 CA286507/CA/NCI NIH HHS/United States ; T32 GM152349/GM/NIGMS NIH HHS/United States ; F30 HL172602/HL/NHLBI NIH HHS/United States ; P50 CA254838/CA/NCI NIH HHS/United States ; R37 CA259177/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA283364/CA/NCI NIH HHS/United States ; P50 CA217694/CA/NCI NIH HHS/United States ; R01 CA251138/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Serine-Arginine Splicing Factors/genetics ; *Receptors, Antigen, T-Cell/metabolism/immunology/genetics ; Mutation ; *RNA Splicing/genetics ; CD8-Positive T-Lymphocytes/immunology ; *Antigens, Neoplasm/immunology/genetics ; *RNA Splicing Factors/genetics ; *Leukemia/genetics/immunology ; }, abstract = {Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8[+] T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.}, }
@article {pmid40272942, year = {2025}, author = {Karvonen, KA and Vu, A and Lin, K and Gibbons, J and Mendoza, JA and Chow, EJ and Winestone, LE and Gomez, SL}, title = {Historical redlining and mortality in children, adolescents, and young adults with cancer in California, 2000-2019.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf105}, pmid = {40272942}, issn = {1460-2105}, abstract = {BACKGROUND: Historical redlining, or the Home Owners Loan Corporation (HOLC) program's racially biased mortgage risk monitoring maps in the 1930s, is implicated in shaping modern neighborhoods and health outcomes. This retrospective cohort study evaluates the association between redlining and mortality in young cancer patients.
METHODS: Using the California Cancer Registry, we identified patients <25 years old diagnosed with malignant cancer between 2000-2019. HOLC maps were spatially joined with patient address at diagnosis to determine redlining status (A "Best", B "Still Desirable", C "Declining", D "Hazardous"). Census tract-level U.S. Census and American Community Survey data were appended to determine modern neighborhood characteristics. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox proportional hazards models to estimate the associations between HOLC grade and mortality, adjusting for clinical and multilevel social drivers of health.
RESULTS: In total 8,108 patients resided in HOLC-graded neighborhoods among 51,084 patients statewide. Overall survival at 5 years was inferior for patients who resided in D graded neighborhoods at diagnosis vs A graded neighborhoods (80.3%, 95% CI: 78.6-81.8 vs 88.5%, 95% CI: 84.3-91.6). Adjusting for clinical characteristics, patients in D graded neighborhoods experienced greater mortality (HR 1.32, 95% CI: 1.12-1.56) compared with those in A and B graded neighborhoods. Additional adjustment for insurance attenuated the effect (HR 1.17, 95%CI: 1.00-1.36) and for neighborhood socioeconomic status marginally attenuated the effect (HR 0.96, 95% CI: 0.81-1.13).
CONCLUSION: Findings suggest enduring legacy effects of historical redlining on young individuals with cancer, potentially mediated social factors including health insurance.}, }
@article {pmid40272674, year = {2025}, author = {Fest, SN and Farland, LV and Doody, DR and Eliassen, AH and Rosner, BA and Fung, TT and Hankinson, SE and Kensler, TW and Willett, WC and Harris, HR}, title = {Correction: Hormone-associated dietary patterns and premenopausal breast cancer risk.}, journal = {Breast cancer research and treatment}, volume = {212}, number = {1}, pages = {187}, doi = {10.1007/s10549-025-07706-6}, pmid = {40272674}, issn = {1573-7217}, }
@article {pmid40272393, year = {2025}, author = {Prada, D and Kalia, V and Gao, F and Rexrode, K and Kooperberg, C and Reiner, A and Balasubramanian, R and Wu, HC and Crandall, CJ and Horowitz, C and Cantu-de-Leon, D and Garcia-Cuellar, C and Ramirez, A and González-Ruiz, J and Liao, D and Yanosky, J and Stewart, JD and Whitsel, EA and Baccarelli, AA}, title = {Metabolomic evaluation of air pollution-related bone damage and potential mediation in Women's Health Initiative participants.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {40}, number = {7}, pages = {834-846}, pmid = {40272393}, issn = {1523-4681}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; R35ES031688/NH/NIH HHS/United States ; R01AG058704/NH/NIH HHS/United States ; R01 ES032242/ES/NIEHS NIH HHS/United States ; R35 ES031688/ES/NIEHS NIH HHS/United States ; R01 AG069120/AG/NIA NIH HHS/United States ; R01 AG058704/AG/NIA NIH HHS/United States ; P30ES009089/NH/NIH HHS/United States ; U54CA267776/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 AG088684/AG/NIA NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 ES025225/ES/NIEHS NIH HHS/United States ; R01ES025225/NH/NIH HHS/United States ; R01AG069120/NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; //US National Institutes of Health/ ; U01AG088684//National Institute of Aging/ ; R01ES032242/NH/NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; U54 CA267776/CA/NCI NIH HHS/United States ; R01 ES027747/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; R01ES027747/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Air Pollution/adverse effects ; Middle Aged ; *Women's Health ; *Metabolomics ; Aged ; *Bone and Bones/metabolism/pathology ; Bone Density ; Particulate Matter/adverse effects ; Postmenopause/blood ; Air Pollutants/adverse effects ; }, abstract = {Ambient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic response to air pollutants and its potential influence on bone health in postmenopausal women. We analyzed data from Women's Health Initiative (WHI) participants with plasma samples. Whole-body, TH, FN, and spine BMD were determined using DXA at enrollment and follow-up visits (years 1, 3, 6, and 9 visits; Y1, Y3, Y6, Y9, respectively). Geocoded, participant address-specific, daily particulate matter nitrogen oxide (NO), nitrogen dioxide (NO2), particulate matter ≤10 μm (PM10), and sulfur dioxide (SO2) concentrations were averaged over 1-, 3-, and 5-yr periods before plasma sampling for metabolomic assessments (at baseline and Y1 visit). The averages were then integrated using masked WHI participant identifiers. Statistical analyses included multivariable-adjusted linear mixed models, pathway analyses, and mediation modeling. At all averaging periods, NO, NO2, and SO2, but not PM10, were associated with taurine, inosine, and C38:4 phosphatidylethanolamine (PE). We found a partial potential mediation of C38:4 PE in the association between 1-yr average NO and LS BMD (p-value: .032). This is the first study suggesting phospholipids may partially mediate air pollution-related bone damage in postmenopausal women.}, }
@article {pmid40269324, year = {2025}, author = {Bajunaid, R and Niu, C and Hambly, C and Liu, Z and Yamada, Y and Aleman-Mateo, H and Anderson, LJ and Arab, L and Baddou, I and Bandini, L and Bedu-Addo, K and Blaak, EE and Bouten, CVC and Brage, S and Buchowski, MS and Butte, NF and Camps, SGJA and Casper, R and Close, GL and Cooper, JA and Cooper, R and Das, SK and Davies, PSW and Dabare, P and Dugas, LR and Eaton, S and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and El Hamdouchi, A and Haisma, HH and Hoffman, D and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kimura, M and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Lanerolle, P and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Matsiko, E and Medin, AC and Morehen, JC and Morton, JP and Must, A and Neuhouser, ML and Nicklas, TA and Nyström, CD and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, LM and Reilly, JJ and Reynolds, R and Roberts, SB and Samaranayakem, D and Sardinha, LB and Silva, AM and Sjödin, AM and Stamatiou, M and Stice, E and Urlacher, SS and Van Etten, LM and van Mil, EGAH and Wilson, G and Yanovski, JA and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Sinha, S and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Speakman, JR}, title = {Author Correction: Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.}, journal = {Nature food}, volume = {6}, number = {5}, pages = {523-524}, doi = {10.1038/s43016-025-01175-2}, pmid = {40269324}, issn = {2662-1355}, }
@article {pmid40269243, year = {2025}, author = {Mielke, D and Li, SS and Schuster, DJ and Li, X and Hu, J and Karuna, S and Seaton, KE and Brackett, C and Dunn, B and Keyes, T and Zalaquett, A and Stanfield-Oakley, S and Zhang, L and Wesley, MS and Eisel, N and Yates, NL and Shen, X and Premkumar, L and Germain, RS and Sholukh, AM and Cohen, K and de Rosa, S and Randhawa, AK and Hural, JA and Corey, L and McElrath, MJ and Tomaras, GD and Hyrien, O and Ferrari, G}, title = {Distinct immune responses in people living with HIV following SARS-CoV-2 recovery.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {132}, pmid = {40269243}, issn = {2730-664X}, support = {T32 AI141342/AI/NIAID NIH HHS/United States ; INV008612//Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; U01 AI068618/AI/NIAID NIH HHS/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; UM1 AI148452/AI/NIAID NIH HHS/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; INV-008612/GATES/Gates Foundation/United States ; }, abstract = {BACKGROUND: SARS-CoV-2 infection results in greater disease severity among immunocompromised individuals compared to healthy individuals. However, there is conflicting information about the impact of chronic HIV infection on immune responses to SARS-CoV-2 infection and vaccination.
METHOD: We used a combination of machine learning approaches and network analysis to explore 56 immune markers and comprehensively profile humoral and cellular immunity in a cross-sectional observational cohort of people without HIV (PWOH; n = 216) and people living with HIV (PLWH; n = 43) who recovered from SARS-CoV-2 infection (13-131 days since SARS-COV-2 diagnosis) early in the pandemic.
RESULTS: PLWH recovered from symptomatic outpatient COVID-19 exhibit lower humoral and B cell responses to SARS-CoV-2 vs. PWOH but, surprisingly, both symptomatic outpatient and hospitalized PLWH have higher anti-endemic coronavirus antibody responses compared to PWOH counterparts and asymptomatic PLWH. The latter observation suggests that this was not strictly due to broadly elevated levels of anti-endemic coronavirus antibodies in PLWH. Moreover, correlation-based analysis reveals that while different compartments of the immune response to SARS-CoV-2 infection are positively correlated in PWOH recovered from symptomatic outpatient COVID-19, these correlations are weaker in PLWH.
CONCLUSION: Our analyses reveal significant differences in the coordinated immune responses elicited by infection in PLWH compared to PWOH.}, }
@article {pmid40269155, year = {2025}, author = {Kang, Y and Lehmann, KS and Long, H and Jefferson, A and Purice, M and Freeman, M and Clark, S}, title = {Structural basis of lipid transfer by a bridge-like lipid-transfer protein.}, journal = {Nature}, volume = {642}, number = {8066}, pages = {242-249}, pmid = {40269155}, issn = {1476-4687}, mesh = {*Caenorhabditis elegans/chemistry/metabolism/genetics/ultrastructure ; *Cryoelectron Microscopy ; Animals ; *Caenorhabditis elegans Proteins/chemistry/metabolism/ultrastructure/genetics ; Models, Molecular ; *Carrier Proteins/chemistry/metabolism/ultrastructure/genetics ; Protein Subunits/chemistry/metabolism ; Animals, Genetically Modified ; }, abstract = {Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle[1]. Although BLTPs are fundamentally important for a wide array of cellular functions, their architecture, composition and lipid-transfer mechanisms remain poorly characterized. Here we present the subunit composition and the cryogenic electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic Caenorhabditis elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein-lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.}, }
@article {pmid40269088, year = {2025}, author = {Touré, H and Durand, N and Orgeur, M and Galindo, LA and Girard-Misguich, F and Guénal, I and Herrmann, JL and Szuplewski, S}, title = {ENaC is a host susceptibility factor to bacterial infections in cystic fibrosis context.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {653}, pmid = {40269088}, issn = {2399-3642}, mesh = {Animals ; *Epithelial Sodium Channels/genetics/metabolism ; *Cystic Fibrosis/microbiology/genetics/metabolism/complications ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism ; *Mycobacterium abscessus ; Drosophila melanogaster/microbiology/genetics ; *Drosophila Proteins/genetics/metabolism ; *Mycobacterium Infections, Nontuberculous/microbiology/genetics ; Disease Susceptibility ; Humans ; Host-Pathogen Interactions ; }, abstract = {Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, we took advantage of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+). We observed that the ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, we observed that ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, our results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens.}, }
@article {pmid40268927, year = {2025}, author = {Werner, J and Lee, AG and Zhang, C and Abelson, S and Xirenayi, S and Rivera, J and Yousuf, K and Shin, H and Patiño-Escobar, B and Bachl, S and Mandal, K and Barpanda, A and Ramos, E and Izgutdina, A and Chaudhuri, S and Temple, WC and Bhatnagar, S and Dardis, JK and Meyer, J and Morales, C and Meshinchi, S and Loh, ML and Braun, B and Tasian, SK and Wiita, AP and Stieglitz, E}, title = {Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3804}, pmid = {40268927}, issn = {2041-1723}, support = {P30 CA082103/CA/NCI NIH HHS/United States ; R37 CA266550/CA/NCI NIH HHS/United States ; R50 CA274213/CA/NCI NIH HHS/United States ; U54 CA196519/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelomonocytic, Juvenile/therapy/immunology/genetics/pathology ; Animals ; Mice ; *Immunotherapy, Adoptive/methods ; *Lectins, C-Type/genetics/immunology/metabolism ; *Receptors, Mitogen/genetics/immunology/metabolism ; Female ; Receptors, Chimeric Antigen/immunology/genetics ; Male ; Xenograft Model Antitumor Assays ; Child ; Mice, SCID ; Neoplastic Stem Cells/immunology ; Infant ; T-Lymphocytes/immunology/transplantation ; }, abstract = {Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML.}, }
@article {pmid40268594, year = {2025}, author = {Gupta, S and Hensley, PJ and Li, R and Choudhury, A and Daneshmand, S and Faltas, BM and Flaig, TW and Grass, GD and Grivas, P and Hansel, DE and Hassanzadeh, C and Kassouf, W and Kukreja, J and Mendoza-Valdés, A and Moschini, M and Mouw, KW and Navai, N and Necchi, A and Rosenberg, JE and Ross, JS and Siefker-Radtke, AO and Taylor, J and Willliams, SB and Zlotta, AR and Buckley, R and Kamat, AM}, title = {Bladder Preservation Strategies in Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.03.017}, pmid = {40268594}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Patient-centric management necessitates providing care aligned with patients' values, preferences, and expressed needs. Therefore, critical assessment of bladder preservation therapies (BPTs) as alternatives to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and practical recommendations on the optimal selection of patients for BPTs are needed urgently.
METHODS: A global committee of bladder cancer experts was assembled to develop BPT recommendations for MIBC. Working groups reviewed the literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined based on discussions. Final recommendations achieved ≥75% agreement during the meeting, with further refinements through web conferences and e-mail discussions.
KEY FINDINGS AND LIMITATIONS: Patients with newly diagnosed MIBC should be offered evaluation in a multidisciplinary setting for consideration of BPTs. The main alternative to RC is trimodal therapy (TMT), and favorable prognostic factors for TMT include unifocal cT2 stage, lack of hydronephrosis, and no multifocal carcinoma in situ (CIS). Other options should be reserved for very select patients who are ineligible for or who decline TMT or RC after thorough consideration of benefits versus risks. These include partial cystectomy (PC) for urachal adenocarcinoma and PC or radical transurethral resection alone for solitary tumors amenable to resection with adequate margins and without concomitant CIS or histologic subtypes.
The IBCG consensus recommendations provide practical guidance on BPTs for MIBC.}, }
@article {pmid40268054, year = {2025}, author = {Bhatt, NS and Lehmann, L and Dandoy, CE and Auletta, JJ and Badia, P and Ballard, SA and Blacken, R and Daraiseh, NM and Desmond, C and Dunseath, C and Epling, P and Fitch, TJ and Flesch, L and Hartley, D and Huber, J and Jenssen, K and Kent, G and Klunk, A and Kapadia, M and Kusnier, K and Liberio, N and Maier, S and Myers, KC and O'Connor, G and Tarquini, S and Phelan, R and Pai, A and Rotz, S}, title = {Multicenter Study on Caregiver Experiences in Pediatric Hematopoietic Stem Cell Transplantation Part I: Integrative Analysis of Mental Health, Psychosocial Stressors, and Support Mechanisms.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {456.e1-456.e16}, doi = {10.1016/j.jtct.2025.04.013}, pmid = {40268054}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; *Caregivers/psychology ; Female ; Male ; Child ; *Stress, Psychological/psychology ; *Mental Health ; Adolescent ; Adult ; Adaptation, Psychological ; Longitudinal Studies ; Child, Preschool ; Middle Aged ; }, abstract = {Caregivers of children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) face substantial psychological, social, and logistical challenges throughout the transplant journey. This multicenter, longitudinal qualitative study explored the evolving mental health experiences, stressors, and coping strategies of 49 caregivers interviewed across four key time points: transplant (d 0), d +30, d +100, and d +180. Participants reported acute distress early in the process, exacerbated by restrictive hospital environments, the demands of hypervigilant caregiving, financial strain, and the emotional toll of family separation. As care transitioned to the outpatient setting, challenges shifted toward navigating complex home care, managing lingering uncertainty, and balancing the needs of other family members. Throughout the process, caregivers expressed heightened anxiety related to fear of relapse, infection, and long-term complications. Despite these burdens, many caregivers described powerful sources of resilience. Children's emotional strength, honest communication, and a desire to return to normal life helped sustain caregiver optimism. Support from the healthcare team, financial assistance, and access to professional mental health services further alleviated stress. Caregivers emphasized the need for enhanced inpatient environments, clearer outpatient guidance, structured mental health resources, and practical tools like caregiver handbooks. These findings underscore the need for holistic, family-centered care that addresses caregiving's psychological and practical dimensions during pediatric HSCT. Tailored, time-sensitive support strategies are essential to improving caregiver well-being and, in turn, optimizing patient outcomes across the transplant continuum.}, }
@article {pmid40267200, year = {2025}, author = {Brumage, L and Best, S and Hippe, DS and Grunblatt, E and Chanana, P and Wu, F and Lee, MC and Ying, Z and Ibrahim, A and Chung, JH and Vigil, A and Fatherree, J and Beronja, S and Paddison, P and Sullivan, L and Nabet, B and MacPherson, D}, title = {In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq7084}, pmid = {40267200}, issn = {2375-2548}, mesh = {*Small Cell Lung Carcinoma/drug therapy/genetics ; Humans ; *Drug Resistance, Neoplasm ; *Kelch-Like ECH-Associated Protein 1/genetics ; DNA, Complementary/analysis ; Proto-Oncogene Proteins c-myc/metabolism ; Animals ; Mice ; CRISPR-Cas Systems ; Signal Transduction ; *Lung Neoplasms/drug therapy/genetics ; Male ; Female ; Immunologic Deficiency Syndromes ; HEK293 Cells ; }, abstract = {Exquisitely chemosensitive initially, small cell lung cancer (SCLC) exhibits dismal outcomes owing to rapid transition to chemoresistance. Elucidating the genetic underpinnings has been challenging owing to limitations with cellular models. As SCLC patient-derived xenograft (PDX) models mimic therapeutic responses, we perform genetic screens in chemosensitive PDX models to identify drivers of chemoresistance. cDNA overexpression screens identify MYC, MYCN, and MYCL, while CRISPR deletion screens identify KEAP1 loss as driving chemoresistance. Deletion of KEAP1 switched a chemosensitive SCLC PDX model to become chemoresistant and resulted in sensitivity to inhibition of glutamine metabolism. Data from the IMpower133 clinical trial revealed ~6% of patients with extensive-stage SCLC exhibit KEAP1 genetic alterations, with activation of a KEAP1/NRF2 transcriptional signature associated with reduced survival upon chemotherapy treatment. While roles for KEAP1/NRF2 have been unappreciated in SCLC, our genetic screens revealed KEAP1 loss as a driver of chemoresistance, while patient genomic analyses demonstrate clinical importance.}, }
@article {pmid40266065, year = {2025}, author = {Mielke, D and Tuyishime, M and Kelkar, NS and Wang, Y and Parks, R and Santra, S and Rountree, W and Williams, LD and Peters, T and Eisel, N and Sawant, S and Zhang, L and Goodman, D and Jha, S and Zalaquett, A and Ramasubramanian, P and Stanfield-Oakley, S and Matyas, G and Beck, Z and Rao, M and Ake, J and Denny, TN and Montefiori, DC and Ackerman, ME and Corey, L and Tomaras, GD and Korber, BT and Haynes, BF and Shen, X and Ferrari, G}, title = {Computationally Selected Multivalent HIV-1 Subtype C Vaccine Protects Against Heterologous SHIV Challenge.}, journal = {Vaccines}, volume = {13}, number = {3}, pages = {}, pmid = {40266065}, issn = {2076-393X}, abstract = {Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy trial to date to demonstrate any efficacy. Genetic signatures suggested that antibodies targeting the variable loop 2 (V2) of the HIV-1 envelope played an important protective role. The ALVAC prime and protein boost follow-up trial in southern Africa (HVTN702) failed to show any efficacy. One hypothesis for this is the greater diversity of subtype C viruses in southern Africa relative to CRF01_AE in Thailand. Methods: Here, we determined whether an ALVAC prime with computationally selected gp120 boost immunogens maximizing coverage of diversity of subtype C viruses in the variable V1 and V2 regions (V1V2) improved the protection of non-human primates (NHPs) from a heterologous subtype C SHIV challenge compared to more traditional regimens. Results: An ALVAC prime with Trivalent subtype C gp120 boosts resulted in statistically significant protection from repeated intrarectal SHIV challenges compared to the control. Evaluation of the immunogenicity of each vaccine regimen at the time of challenge demonstrated that different gp120 combination boosts elicited similar high magnitudes of gp120 and breadth of V1V2-binding antibodies, as well as strong Fc-mediated immune responses. Low-to-no neutralization of the challenge virus was detected. A Cox proportional hazard analysis of five pre-selected immune parameters at the time of challenge identified ADCC against the challenge envelope as a correlate of protection. Systems serology analysis revealed that immune responses elicited by the different vaccine regimens were distinct and identified further correlates of resistance to infection. Conclusions: Computationally designed vaccines with maximized subtype C V1V2 coverage mediated protection of NHPs from a heterologous Tier-2 subtype C SHIV challenge.}, }
@article {pmid40265297, year = {2025}, author = {Mahla, RS}, title = {Epitope spreading and systemic sclerosis: comment on the article by Kotani et al.}, journal = {Arthritis & rheumatology (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/art.43196}, pmid = {40265297}, issn = {2326-5205}, }
@article {pmid40264918, year = {2025}, author = {Ghosh, N and Bellasea, S and Li, H and Olszewski, AJ and Bryan, L and Danilov, A and Smith, S and LeBlanc, M and Friedberg, JW}, title = {SWOG 2308: Randomized Phase III Study of Mosunetuzumab Versus Rituximab for Low-Tumor Burden Follicular Lymphoma.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2500037}, pmid = {40264918}, issn = {2994-9750}, }
@article {pmid40264148, year = {2025}, author = {Montaño, MA and Chen, Y and Saldarriaga, EM and Thuo, N and Kiptinness, C and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Willingness to pay for HIV pre- and post-exposure prophylaxis services delivered via an online pharmacy in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {576}, pmid = {40264148}, issn = {1472-6963}, support = {INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; INV-037646/GATES/Gates Foundation/United States ; K99/R00 MH121166/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *HIV Infections/prevention & control ; Male ; *Pre-Exposure Prophylaxis/economics ; Female ; Adult ; Surveys and Questionnaires ; *Post-Exposure Prophylaxis/economics ; *Pharmaceutical Services, Online/economics ; Young Adult ; Middle Aged ; Adolescent ; *Financing, Personal ; }, abstract = {BACKGROUND: HIV pre- and post-exposure prophylaxis (PrEP/PEP) provision via online pharmacies could expand reach of HIV prevention in Eastern and Southern Africa, but designing sustainable delivery models will require assessing the amount potential users are willing to pay for online PrEP/PEP provision.
METHODS: We administered willingness to pay (WTP) questionnaires to both potential online PrEP users and current online PrEP/PEP users in Nairobi, Kenya using a stated preference approach to measure the amount participants were willing to pay for PrEP/PEP service delivery components. Participants ≥ 18 years were recruited via banner ads on an online pharmacy website on pages displaying sexual health products. We used multivariable gamma regression models to assess characteristics associated with differences in mean WTP for a 30-day PrEP or 28-day PEP course (including HIV self-testing, remote clinical consultation, drugs, and delivery fees).
RESULTS: From May 2022 and December 2023, 1,512 participants completed WTP questionnaires: 772 potential online PrEP users and 740 current online PrEP/PEP users. Most participants (98.3%, 1486/1,512) were willing to pay some amount for online PrEP services. For a one-month PrEP supply, potential online PrEP users were willing to pay 1388 KSH ($11.77 USD) and current online PrEP/PEP users were willing to pay 1271.2 KSH ($10.77 USD) on average. Most current online PrEP/PEP users (81.4%, 602/740) were also willing to pay for online PEP services; for a 28-day PEP supply, they were willing to pay 812.9 KSH ($6.89 USD) on average. Among potential online PrEP users, male sex, current enrollment in school, high income, and a history of online pharmacy purchases were associated with higher WTP for PrEP. Among current online PrEP/PEP users, higher income and prior online pharmacy purchases were associated with higher WTP for PrEP, and older age (> 24) and prior online pharmacy purchases were associated with higher WTP for PEP.
CONCLUSION: Most potential and current online PrEP/PEP users in Nairobi were willing to pay for online pharmacy-based PrEP/PEP and demonstrated similar WTP. Providing PrEP/PEP through online pharmacies may sustainably expand coverage of these HIV prevention services.}, }
@article {pmid40262193, year = {2025}, author = {Shigesi, N and Harris, HR and Fang, H and Ndungu, A and Lincoln, MR and , and , and Cotsapas, C and Knight, J and Missmer, SA and Morris, AP and Becker, CM and Rahmioglu, N and Zondervan, KT}, title = {The phenotypic and genetic association between endometriosis and immunological diseases.}, journal = {Human reproduction (Oxford, England)}, volume = {40}, number = {6}, pages = {1195-1209}, pmid = {40262193}, issn = {1460-2350}, support = {RG2031//Wellbeing of Women UK/ ; 101017562//EU Horizon 2020 funded project FEMaLe/ ; 32170663//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Female ; *Endometriosis/genetics/epidemiology/complications/immunology ; Phenotype ; Genome-Wide Association Study ; *Immune System Diseases/genetics/epidemiology/complications ; Genetic Predisposition to Disease ; Adult ; Retrospective Studies ; *Autoimmune Diseases/genetics/epidemiology ; Cross-Sectional Studies ; Middle Aged ; Polymorphism, Single Nucleotide ; United Kingdom/epidemiology ; }, abstract = {STUDY QUESTION: Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk?
SUMMARY ANSWER: Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis.
WHAT IS KNOWN ALREADY: The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank.
STUDY DESIGN, SIZE, DURATION: Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64 620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493-77 052 cases) were conducted.
Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways.
In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30-80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P = 3.25 × 10-15), rheumatoid arthritis (rg = 0.27, P = 1.5 × 10-5) and multiple sclerosis (rg = 0.09, P = 4.00 × 10-3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR = 1.16, 95% CI = 1.02-1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1).
We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results.
Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions.
We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid40261872, year = {2025}, author = {Unsworth, M and Fabens, I and Setswe, G and Moyo, K and Pienaar, J and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Sardini, M and Dong, T and Sharma, M and Tweya, H and Ndebele, F and Holec, M and Feldacker, C}, title = {Expanding two-way texting for post-operative follow-up: A cost analysis of the implementation and scale-up in routine voluntary medical male circumcision settings in South Africa.}, journal = {PLOS global public health}, volume = {5}, number = {4}, pages = {e0004049}, pmid = {40261872}, issn = {2767-3375}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, abstract = {Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa region. Yet, all clients in South Africa are required to attend in-person reviews, creating added effort for providers and clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with nurse-led telehealth support. 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this study were:1) assess the additive cost of 2wT vs. standard of care (SoC) during a stepped wedge design (SWD) expansion trial; 2) determine the cost of augmenting 2wT implementation with dedicated personnel during peak VMMC periods; and 3) estimate the cost savings of 2wT from the payer perspective if scaled in routine settings. Data were collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods. Sensitivity analysis to estimates 2wT costs at scale. Data included 6,842 males; 2,586 (38%) opted for 2wT. 2wT participants attended an average of zero in-person visits; SoC males had an average of 2 in-person visits. Under 2wT, quality care improved: AE ascertainment increased while loss to follow-up decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When scaled, 2wT appears to significantly reduce healthcare system costs while improving the quality of post-operative care without additional client costs. Further scale-up of 2wT for eligible males across VMMC and other post-operative contexts in South Africa would likely increase cost savings while dramatically reducing the burden of in-person visits on patients and clinics.}, }
@article {pmid40261064, year = {2025}, author = {Žuštra, A and Leonard, VR and Holland, LA and Hu, JC and Mu, T and Holland, SC and Wu, LI and Begnel, ER and Ojee, E and Chohan, BH and Richardson, BA and Kinuthia, J and Wamalwa, D and Slyker, J and Lehman, DA and Gantt, S and Lim, ES}, title = {Longitudinal dynamics of the nasopharyngeal microbiome in response to SARS-CoV-2 Omicron variant and HIV infection in Kenyan women and their children.}, journal = {mSystems}, volume = {10}, number = {5}, pages = {e0156824}, pmid = {40261064}, issn = {2379-5077}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; 390237/CAPMC/CIHR/Canada ; BAA 75D30121C11084/CC/CDC HHS/United States ; 447944/CAPMC/CIHR/Canada ; R01HD092311/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *COVID-19/virology/epidemiology/microbiology/complications ; *HIV Infections/microbiology/virology/epidemiology/complications ; *Nasopharynx/microbiology/virology ; Kenya/epidemiology ; *SARS-CoV-2/genetics ; *Microbiota ; Longitudinal Studies ; Adult ; Child ; Male ; Child, Preschool ; Infant ; }, abstract = {UNLABELLED: The nasopharynx and its microbiota are implicated in respiratory health and disease. The interplay between viral infection and the nasopharyngeal microbiome is an area of increased interest. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 pandemic, on the nasopharyngeal microbiome among individuals living with HIV is not fully characterized. Here, we describe the nasopharyngeal microbiome before, during, and after SARS-CoV-2 infection in a longitudinal cohort of Kenyan women (21 living with HIV and 14 HIV-uninfected) and their children (18 HIV-exposed, uninfected and 7 HIV-unexposed, uninfected) between September 2021 and March 2022. We show using genomic epidemiology that mother and child dyads were infected with the same strain of the SARS-CoV-2 Omicron variant that spread rapidly across Kenya. We used metagenomic sequencing to characterize the nasopharyngeal microbiome of 20 women and children infected with SARS-CoV-2, six children negative for SARS-CoV-2 but experiencing respiratory symptoms, and 34 timepoint-matched SARS-CoV-2-negative mothers and children. Since individuals were sampled longitudinally before and after SARS-CoV-2 infection, we could characterize the short- (within a week of infection) and longer- (average of 38 days post-infection) term impact of SARS-CoV-2 infection on the nasopharyngeal microbiome. We found that mothers and children had significantly different microbiome composition and bacterial load (P-values < 0.0001). In both mothers and children, the nasopharyngeal microbiome did not differ before and after SARS-CoV-2 infection, regardless of HIV exposure status. Our results indicate that the nasopharyngeal microbiome is resilient to SARS-CoV-2 infection and was not significantly modified by HIV.
IMPORTANCE: The nasopharyngeal microbiome plays an important role in human health. The degree of impact that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has on the nasopharyngeal microbiome varies among studies and may be influenced by diverse SARS-CoV-2 variants and variations in the microbiome between individuals. Our results show that the nasopharyngeal microbiome was not altered substantially by SARS-CoV-2 infection nor by HIV infection in mothers or HIV exposure in children. Our findings highlight the resilience of the nasopharyngeal microbiome after SARS-CoV-2 infection. These findings advance our understanding of the nasopharyngeal microbiome and its interactions with viral infections.}, }
@article {pmid40261015, year = {2025}, author = {Radford, CE and Bloom, JD}, title = {Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains.}, journal = {Journal of virology}, volume = {99}, number = {5}, pages = {e0019525}, pmid = {40261015}, issn = {1098-5514}, support = {U01AI169385//National Institute of Allergy and Infectious Diseases/ ; R01 AI140891/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01AI140891//National Institute of Allergy and Infectious Diseases/ ; /HHMI/Howard Hughes Medical Institute/United States ; S10 OD020069/OD/NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV Antibodies/immunology/genetics ; *Antibodies, Neutralizing/immunology ; Humans ; *HIV-1/immunology/genetics ; *Mutation ; HIV Infections/virology/immunology ; *Immune Evasion/genetics ; *HIV Envelope Protein gp120/immunology/genetics ; Neutralization Tests ; *env Gene Products, Human Immunodeficiency Virus/genetics/immunology ; }, abstract = {Antibodies capable of neutralizing many strains of HIV are being explored as prophylactic and therapeutic agents, but viral escape mutations pose a major challenge. Efforts have been made to experimentally define the escape mutations from specific antibodies in specific viral strains, but it remains unclear how much the effects of mutations on neutralization differ among HIV strains. Here, we use pseudovirus deep mutational scanning to comprehensively map escape mutations from the V3 loop targeting antibody 10-1074 and the CD4-binding site targeting antibody 3BNC117 for both a clade A (BF520) and a clade B (TRO.11) HIV Envelope (Env). Mutations that escape neutralization by antibody 10-1074 are largely similar for the two Envs, but mutations that escape 3BNC117 differ greatly between Envs. Some differences in the effects of mutations on escape between Envs can be explained by strain-to-strain variation in mutational tolerance or potential N-linked glycosylation motifs, but other mutations have different effects on escape for unclear reasons. Overall, the extent to which measurements of mutational effects on antibody neutralization can be generalized across HIV strains differs among antibodies 10-1074 and 3BNC117.IMPORTANCEBroadly neutralizing antibodies are promising candidates as prophylactics and therapeutics for HIV. This study uses pseudoviruses to map all escape mutations for antibodies 10-1074 and 3BNC117 for the Envelope proteins from two different HIV strains. These maps can inform analyses of viral mutations observed in clinical trials and help understand how the escape mutations from these antibodies differ across HIV strains.}, }
@article {pmid40260855, year = {2025}, author = {Jatt, LP and Mgodi, NM and Buchbinder, SP and Gray, GE and Kublin, JG}, title = {An HIV Vaccine in the Era of Twice-Yearly Lenacapavir for PrEP - Essential or Irrelevant?.}, journal = {The New England journal of medicine}, volume = {392}, number = {16}, pages = {1561-1563}, doi = {10.1056/NEJMp2415893}, pmid = {40260855}, issn = {1533-4406}, }
@article {pmid40259184, year = {2025}, author = {Zelaya, DG and Janssen, T and Windes, B and Wheeler, DP and Fields, SD and Beauchamp, G and Kahler, CW and Wilton, L and Mayer, KH}, title = {The Association of Positive Intersectionality Latent Classes with Psychosocial Factors and PrEP Outcomes in Black Men Who Have Sex with Men (HPTN 073).}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {40259184}, issn = {2196-8837}, support = {K23AA030339/AA/NIAAA NIH HHS/United States ; K01AA026335/AA/NIAAA NIH HHS/United States ; AA019072/AA/NIAAA NIH HHS/United States ; P30AI042853//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI069412//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Experiences of discrimination and HIV risk in Black men who have sex with men (MSM) need to be examined from the perspective of strength and resilience and not just risk. Scholars have theorized that a strong connection with one's sociocultural identities may increase individuals' ability to cope with discrimination which has been related to positive health outcomes. Scholars have coined the term positive intersectionality to refer to how one's stigmatized identity(ies) can be used to draw strength and create a positive sense of self. The current study is a secondary data analysis of a study of 225 Black MSM. We utilized Latent Class Analysis to determine profiles of positive intersectionality measured by indicators of racial/ethnic identity, having an integrated sexual orientation and racial/ethnic identity, and levels of internalized homophobia. Fit indices suggested a five-latent class solution: low positive intersectionality (n = 3), ambivalent positive intersectionality (n = 19), moderate positive intersectionality (n = 66), salient/high positive intersectionality (n = 124), and conflict(ed) positive intersectionality (n = 13). Differences were found across classes on key outcomes, broadly individuals in classes with more positive intersectionality tended to report more positive psychosocial outcomes (i.e., more social support and less depression) than those in classes with lower positive intersectionality. Regarding PrEP outcomes, adherence (examined via a biomarker) was highest among those reporting ambivalent or conflict positive intersectionality compared to those with low positive intersectionality. Our findings underscore the need for the development of strengths-based and culturally tailored interventions may help to improve well-being for Black MSM.}, }
@article {pmid40255392, year = {2025}, author = {Manghisi, B and Cotilli, G and Fedele, M and Perfetti, P and Terruzzi, E and Verga, L and Borin, LM and Carrer, A and Fumagalli, M and Ferrari, MB and Moretti, A and Rona, R and Benini, A and Vergnano, B and Palumbo, G and Zincone, A and Maglia, O and Scollo, C and Steidl, C and Iovino, L and Balduzzi, A and Piazza, R and Gambacorti-Passerini, C and Parma, M and Aroldi, A}, title = {Case Report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1563736}, pmid = {40255392}, issn = {1664-3224}, mesh = {Adult ; Humans ; *Antibodies, Monoclonal/therapeutic use ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Cytokine Release Syndrome ; *Immunotherapy, Adoptive/adverse effects ; *Lymphohistiocytosis, Hemophagocytic/etiology/drug therapy/diagnosis ; *Neurotoxicity Syndromes/etiology/drug therapy/diagnosis ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/immunology ; Receptors, Chimeric Antigen ; Treatment Outcome ; }, abstract = {Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases. We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, high-dose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.}, }
@article {pmid40253488, year = {2025}, author = {Li, X and Mamouni, K and Zhao, R and Bai, L and Chen, Y and Wu, Y and Xie, ZR and Sautto, GA and Liu, D and Bowen, NJ and Danaher, A and Li, D and Cook, N and Grayson, S and Zhu, J and Coleman, IM and Nelson, PS and Bao, Q and Zhou, J and Osunkoya, AO and Kucuk, O and Gera, L and Wu, D}, title = {Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer.}, journal = {British journal of cancer}, volume = {132}, number = {12}, pages = {1188-1199}, pmid = {40253488}, issn = {1532-1827}, support = {R21 CA277368/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R50CA274336//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P50CA097186//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R21CA277368//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA256058//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U54 MD007590/MD/NIMHD NIH HHS/United States ; R42CA217491//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA256058/CA/NCI NIH HHS/United States ; R42 CA217491/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology/metabolism ; *S-Phase Kinase-Associated Proteins/antagonists & inhibitors/metabolism ; Animals ; Mice ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; *Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND: Metastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC.
METHODS: The anticancer activities and mechanism of action of the small-molecule lead compound were investigated in preclinical models of human prostate cancer. Immunohistochemistry was employed to determine the expression of S-phase kinase-associated protein 1 (Skp1) in human prostate tissues.
RESULTS: GH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind Skp1 and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, β-catenin, cyclin D1, enhancer of zeste homolog 2 (EZH2), c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. Skp1 expression is significantly increased in human prostate cancer specimens.
CONCLUSION: These results indicate that interrupting Skp1-Skp2 interaction is an effective approach to target mCRPC and warrant further preclinical development of GH501 as a promising therapeutic candidate.}, }
@article {pmid40251235, year = {2025}, author = {Dimopoulou, O and Fuller, H and Richmond, RC and Bouras, E and Hayes, B and Dimou, N and Murphy, N and Brenner, H and Gsur, A and Le Marchand, L and Moreno, V and Pai, RK and Phipps, AI and Um, CY and van Duijnhoven, FJB and Vodicka, P and Martin, RM and Platz, EA and Gunter, MJ and Peters, U and Lewis, SJ and Cao, Y and Tsilidis, KK}, title = {Mendelian randomization study of sleep traits and risk of colorectal cancer.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13478}, pmid = {40251235}, issn = {2045-2322}, support = {001/WHO_/World Health Organization/International ; C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Colorectal Neoplasms/genetics/epidemiology ; Male ; Female ; *Sleep/genetics ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Circadian Rhythm/genetics ; Sleep Initiation and Maintenance Disorders/genetics ; }, abstract = {A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.}, }
@article {pmid40250799, year = {2025}, author = {Karvonen, KL and Anunwah, E and Gilmore, S and Griffiths-Randolph, U and Karvonen, KA and Moore, D and Miller, K and Overall, J and Wooten, L and Afulani, PA}, title = {Gaps, Successes, and Opportunities Related to Social Drivers of Health from the Perspectives of Black Preterm Infant Caregivers: A Qualitative Study.}, journal = {The Journal of pediatrics}, volume = {282}, number = {}, pages = {114598}, pmid = {40250799}, issn = {1097-6833}, support = {T32 HD098057/HD/NICHD NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Infant, Newborn ; Male ; *Black or African American/psychology ; *Caregivers/psychology ; *Infant, Premature ; Interviews as Topic ; Qualitative Research ; San Francisco ; *Social Determinants of Health ; Social Support ; }, abstract = {OBJECTIVE: To identify Black preterm infant caregiver experiences and institutional priorities regarding screening and addressing social drivers of health (SDH).
STUDY DESIGN: In the Centering Black Preterm Infant Caregiver Priorities study, Black female researchers conducted semistructured interviews in 2024 with Black caregivers of preterm infants born in the San Francisco Bay Area of California. Transcripts were coded using a book generated from an interview guide, and the resulting data were analyzed using thematic analysis. Themes were generated and refined through discussion.
RESULTS: Twenty sociodemographically diverse caregivers participated. Five themes were identified: (1) financial insecurity and inadequate access to resources for everyday social needs contribute negatively to caregiver and child health and well-being; (2) a trusted provider who takes a personal approach to screening and addressing SDH is needed in medical settings; (3) inequitably distributed, fragmented, and disorganized medical and social support systems in the transition to home period are burdensome and a source of stress; (4) community-based organizations centering Black families holistically address SDH and promote social well-being and connectedness; and (5) state and federal legislation, policies, and programs are critical opportunities to address SDH.
CONCLUSIONS: SDH are a significant source of stress for caregivers after preterm birth, and there are opportunities across state and federal legislative policies, community-based organizations, medical systems, and connections across the systems to address them.}, }
@article {pmid40249911, year = {2025}, author = {Perales, MA and Riches, M and He, N and Martens, MJ and Chemaly, RF and Dandoy, CE and Hill, JA and Díaz, MA and Hashmi, S and Prockop, SE and Lazarus, HM and Beitinjaneh, AM and Hildebrandt, GC and Auletta, JJ and Szabolcs, P}, title = {Delayed T cell recovery after hematopoietic cell transplantation is associated with decreased overall survival in adults.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024015288}, pmid = {40249911}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic cell transplantation (alloHCT) can provide curative treatment for hematologic malignancies but is associated with prolonged lymphopenia that may contribute to an increased risk of infection and relapse, resulting in decreased survival. We hypothesized that patients with rapid and robust CD4 T and B cell recovery have improved survival and decreased treatment-related mortality (TRM). 2089 patients were included who underwent first alloHCT for AML/ALL/MDS from 2008 to 2019 reported to CIBMTR with available CD4 counts at days 100 (D100) and 180 (D180). Patients (median age 51, range 2-75) were categorized into four groups based on GVHD prophylaxis: ex-vivo T cell depletion (TCD/CD34), post-transplant cyclophosphamide (PTCy), calcineurin-inhibitor alone (CNI) or with anti-thymocyte globulin (CNI+ATG). Based upon survival we could identify optimal cut-points for CD4+ T cells in pediatric (age <20y) patients: 248 x 106/L and 420 x 106/L at D100 and D180, respectively; and in adult (age >20y) patients: 104 x 106/L and 115 x 106/L at D100 and D180, respectively. In adults, D100 CD4 count was associated with overall survival, progression-free survival (PFS) and TRM, but not relapse, incidence of infections, or chronic GVHD. Similarly, CD4 counts above the cut-point at D180 in adults were associated with improved OS, PFS, and TRM but no other outcomes. No clinical associations for CD4 counts were identifiable in pediatric patients. These findings underscore the importance of tailoring transplant strategies for adults to optimize immune recovery and improve patient outcomes.}, }
@article {pmid40249804, year = {2025}, author = {Bhattacharya, T and Alleman, EM and Freeman, TS and Noyola, AC and Emerman, M and Malik, HS}, title = {A conserved opal termination codon optimizes a temperature-dependent trade-off between protein production and processing in alphaviruses.}, journal = {Science advances}, volume = {11}, number = {16}, pages = {eads7933}, doi = {10.1126/sciadv.ads7933}, pmid = {40249804}, issn = {2375-2548}, mesh = {*Codon, Terminator/genetics ; Animals ; *Temperature ; *Alphavirus/genetics ; *Protein Biosynthesis ; Virus Replication/genetics ; *Sindbis Virus/genetics ; *Viral Proteins/genetics/metabolism ; Humans ; RNA, Viral/genetics ; Mutation ; Cell Line ; }, abstract = {Most mosquito-transmitted alphaviruses encode a premature opal termination codon upstream of their viral polymerase. We show that the Sindbis virus (SINV) opal codon outperforms other stop codons in primate cells at 37°C due to optimal translational readthrough. However, increased readthrough of all stop codons reduces opal preference at 28°C in primate and mosquito cells. Opal also outperforms all sense codons because opal-to-sense substitutions lead to excess polyprotein production at 37°C, disrupting orderly polyprotein processing and production of viral genomic RNAs (gRNAs) required for virus production. Increased readthrough at 28°C dampens the fitness advantages of opal codons. Unexpectedly, we find that a naturally occurring SINV mutation restores sense-codon fitness by further delaying polyprotein processing, allowing adequate time to produce gRNAs. Similar temperature-dependent mechanisms occur in the distantly related dual-host alphavirus, Ross River virus. Our work highlights sophisticated strategies dual-host alphaviruses use to optimize replication in divergent temperatures through a single codon.}, }
@article {pmid40249111, year = {2025}, author = {Sievers, P and Arora, S and Hielscher, T and Savran, D and Schrimpf, D and Banan, R and Vonhören, D and Pusch, S and Sill, M and Appay, R and Wirsching, HG and Hortobagyi, T and Dohmen, H and Acker, T and Kohlhof-Meinecke, P and Schweizer, L and Wefers, AK and Harter, PN and Hartmann, C and Beschorner, R and Schittenhelm, J and Behling, F and Tabatabai, G and Mawrin, C and Snuderl, M and Maas, SLN and Wesseling, P and Brandner, S and Korshunov, A and Ratliff, M and Krieg, SM and Wick, W and Jones, DTW and Pfister, SM and Holland, EC and von Deimling, A and Szulzewsky, F and Sahm, F}, title = {Molecular signatures define BAP1-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf105}, pmid = {40249111}, issn = {1523-5866}, abstract = {BACKGROUND: Meningiomas are the most common primary intracranial neoplasms, with highly variable patient outcomes. While most meningiomas are benign, a significant subset recurs postoperatively, presenting substantial treatment challenges. BAP1 gene inactivation has been suggested as a marker for aggressive meningiomas, although its precise molecular and clinical roles remain poorly understood.
METHODS: To comprehensively investigate BAP1-altered meningiomas, we used six meningiomas with known BAP1 alterations as a discovery set. Genome-wide DNA methylation profiling of these samples, along 11,151 reference meningiomas, identified a distinct molecular cluster (n = 42) using unsupervised visualization approaches. These tumors were further characterized by DNA/RNA sequencing, histopathological examination, and a retrospective review of clinical data, compared to reference meningioma cohorts, providing a thorough characterization of this rare tumor subtype.
RESULTS: Our integrative analysis revealed BAP1-altered meningiomas as a distinct CNS tumor subtype, characterized by recurrent loss of chromosome 3p21 and driven by various BAP1-inactivating alterations. Although rhabdoid morphology is present in some cases, it is not exclusive and should not be used as a grading criterion. Progression-free survival analysis showed a median of 21 months (95% CI: 12-NA), with a 2-year overall survival rate of 79% (95% CI: 60%-100%), highlighting the aggressive nature of these tumors. Gene expression profiling revealed upregulation of PRC target genes, dysregulated Polycomb signaling, and elevated expression in several cellular and growth factor pathways.
CONCLUSIONS: BAP1-altered meningiomas represent a distinct and aggressive CNS tumor subtype associated with PRC dysregulation and recurrent 3p chromosome loss. These findings support the designation "meningioma, BAP1-altered."}, }
@article {pmid40248714, year = {2025}, author = {Girard, B and Figueroa, AL and De Rosa, SC and McElrath, MJ and Azzi, JR and Stolman, D and Siangphoe, U and de Windt, E and Miller, JM and Das, R and Priddy, F}, title = {mRNA-1273 COVID-19 vaccine induces CD4+ T-cell responses among solid organ transplant recipients.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1505871}, pmid = {40248714}, issn = {1664-3224}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; 2019-nCoV Vaccine mRNA-1273/immunology ; *CD4-Positive T-Lymphocytes/immunology ; *COVID-19/prevention & control/immunology ; *COVID-19 Vaccines/immunology/administration & dosage ; Cytokines ; Immunity, Cellular ; Kidney Transplantation ; *Organ Transplantation ; *SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Transplant Recipients ; }, abstract = {BACKGROUND: Cell-mediated immunity may provide durable protection against severe COVID-19, including among solid organ transplant recipients (SOTRs). This exploratory analysis in the open-label phase 3b trial evaluated cell-mediated immunity of mRNA-1273 in a subset of participants (59 kidney and 33 liver SOTRs; 12 immunocompetent participants).
METHODS: In Part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received two doses. In Part B, an additional 100-µg dose was offered ≥4 months after the primary series. SARS-CoV-2 spike (S) protein-specific T-cell responses were measured by intracellular cytokine staining and polyfunctionality analyses.
RESULTS: The primary series and additional dose of mRNA-1273 induced S protein-specific CD4[+] T-cell responses exhibiting a Th-1-biased profile in both SOTRs and immunocompetent participants; however, response rates and magnitudes were lower among SOTRs. S protein-specific Th-2 CD4[+] T-cell responses were below those observed for Th-1; CD8[+] T-cell responses were not as robust among SOTRs compared with immunocompetent participants. Kidney SOTRs received multiple immunosuppressants and had lower cell-mediated immunity responses than liver SOTRs. Polyfunctional responses exhibited Th-1 cytokine signatures with ≤5 functional markers reported in SOTRs and immunocompetent participants.
CONCLUSION: Overall, a three-dose mRNA-1273 primary series elicited Th-1-biased CD4[+] T-cell responses among SOTRs that were improved with an additional dose.
CLINICAL TRIAL REGISTRATION: https://beta.clinicaltrials.gov/study/NCT04860297?term=NCT04860297%20&rank=1, identifier NCT04860297.}, }
@article {pmid40246795, year = {2025}, author = {Szabados, BE and Guerrero-Ramos, F and Grande, E and Grivas, P and Grünwald, V and Miguel, MC and Hussain, SA and Kulkarni, GS and Wilson, AL and Shore, ND and Sridhar, SS and Hoyt, M and Strumeier, S and Sutton, J and Brinkmann, J and Teresi, RE and Todenhöfer, T}, title = {On the Horizon: A Global Multidisciplinary Perspective on Delivering Emerging Therapies for Patients with BCG-Naïve High-Risk NMIBC.}, journal = {Oncology and therapy}, volume = {13}, number = {2}, pages = {275-291}, pmid = {40246795}, issn = {2366-1089}, abstract = {Patients with high-risk non-muscle invasive bladder cancer (NMIBC) are generally treated with transurethral resection of the bladder tumor followed by intravesical bacillus Calmette-Guérin (BCG), the current standard of care. However, recurrence or progression is common and may result in patients requiring radical cystectomy. Additionally, BCG continues to be in short supply worldwide. Therefore, there is an unmet need for new therapies that provide durable disease control and maintain quality of life. In the BCG-naïve high-risk NMIBC setting, potential new treatment options are emerging, with several regimens combining intravesical therapy with systemic PD-1 or PD-L1-directed immune checkpoint inhibitors (ICIs) currently under investigation in several Phase 3 trials. In routine clinical practice, NMIBC has traditionally been managed almost entirely by urologists. However, the introduction of systemic ICIs would likely require medical oncology expertise to help assess patients' fitness for these therapies and potentially for treatment administration and immune-related adverse event management. While multidisciplinary workflows are common practice for advanced bladder cancer, they would represent a paradigm shift in NMIBC. Based on current experience of managing patients with NMIBC across different countries and healthcare systems from our perspective as urologists, medical oncologists, and nurses, we discuss best practices for the potential integration of emerging therapies such as ICIs into the treatment of BCG-naïve high-risk NMIBC. We emphasize the need for multidisciplinary care, either through formalized multidisciplinary teams or cross-discipline collaborative workflows adapted to local needs, to ensure efficient coordination and sharing of responsibilities. Specialized nurses have the potential to play key roles across multiple aspects of patient care. We also highlight the crucial importance of effective communication across teams, increases in resourcing, and education for healthcare professionals, patients, and caregivers to enable eligible patients with high-risk NMIBC to benefit optimally from the introduction of these potential new treatment options. Supplementary file2 (MP4 407382 kb).}, }
@article {pmid40245370, year = {2025}, author = {Triplette, M}, title = {Do Differences in Comorbidity Explain Sex-based Differences in Lung Cancer Screening Outcomes?.}, journal = {Annals of the American Thoracic Society}, volume = {22}, number = {6}, pages = {824-825}, pmid = {40245370}, issn = {2325-6621}, }
@article {pmid40245079, year = {2025}, author = {Trouth, A and Ravichandran, K and Gafken, PR and Martire, S and Boyle, GE and Veronezi, GMB and La, V and Namciu, SJ and Banaszynski, LA and Sarthy, JF and Ramachandran, S}, title = {The length of the G1 phase is an essential determinant of H3K27me3 landscapes across diverse cell types.}, journal = {PLoS biology}, volume = {23}, number = {4}, pages = {e3003119}, pmid = {40245079}, issn = {1545-7885}, support = {R35 GM133434/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM124958/GM/NIGMS NIH HHS/United States ; R35 GM156411/GM/NIGMS NIH HHS/United States ; R01 HD109239/HD/NICHD NIH HHS/United States ; }, mesh = {*Histones/metabolism/genetics ; *G1 Phase/physiology/genetics ; Animals ; Humans ; Mice ; Mouse Embryonic Stem Cells/metabolism/cytology ; HEK293 Cells ; Methylation ; Cell Differentiation ; Heterochromatin/metabolism ; Lysine/metabolism ; Embryonic Stem Cells/metabolism ; }, abstract = {Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted 2-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a short G1 phase restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mouse embryonic stem cells (mESCs) globally and at specific loci upon G1 phase lengthening - accomplished by thymidine block or growth in the absence of serum (with the "2i medium"). H3K27me3 levels in mESCs increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of G1 length as a critical regulator of the stem cell epigenome. Furthermore, we demonstrate the inverse effect - that G1 shortening in differentiated human HEK293 cells results in a loss of H3K27me3 levels. Finally, in human tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.}, }
@article {pmid40243688, year = {2025}, author = {Yap, TA and Goldman, JW and Vinayak, S and Tomova, A and Hamilton, E and Naito, Y and Giordano, A and Bondarenko, I and Yamashita, T and Zhou, L and Moreau, A and Neumann, H and Tougias, J and Liu, F and Park, J and Delioukina, M and Jhaveri, K}, title = {First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2740}, pmid = {40243688}, issn = {1557-3265}, abstract = {PURPOSE: The discovery that cyclin E overexpression is a key CDK4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2, and simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6.
PATIENTS AND METHODS: Dose escalation included 78 patients with advanced breast cancer, triple negative breast cancer, or ovarian cancer who received oral PF-06873600 1-50 mg twice daily (BID) (Part 1A, n=51), or PF-06873600 with endocrine therapy (Part 1B, n=16; Part 1C n=11) to determine the recommended dose for expansion (RDE). Dose expansion (Part 2A, n=45; Part 2C, n=28) assessed preliminary antitumor activity, safety and tolerability at the RDE in combination with fulvestrant in patients with HR+/HER2- mBC. Pharmacodynamics and translational readouts were assessed by phosphorylated Rb and Ki67 in tumor biopsies and circulating tumor DNA (ctDNA).
RESULTS: The RDE of PF-06873600 was 25mg BID. During dose escalation, six of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. Most common all-causality adverse events (N=151) were nausea (62.9%), anemia (44.4%) and fatigue (43.7%). Reductions in Ki67-positive cells, pRb H-score, and ctDNA levels were observed. Three RECIST partial responses (PRs) were observed in Part 1. In Part 2A there were three PRs (objective response rate [ORR] 6.7%, 95% CI: 1.4-18.3%) and, in Part 2C, five PRs (ORR 22.7%, 95% CI: 7.8-45.4%).
CONCLUSIONS: PF-06873600 demonstrated a benefit-risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in HR+/HER2- mBC.
CLINICALTRIALS: gov identifier: NCT03519178.}, }
@article {pmid40243533, year = {2025}, author = {Thomas, CE and Takashima, Y and Buchanan, DD and Wesselink, E and Qu, C and Hsu, L and Dias Costa, A and Gallinger, S and Grant, RC and Huyghe, JR and Thomas, S and Ugai, S and Zhong, Y and Matsuda, K and Ugai, T and Peters, U and Ogino, S and Nowak, JA and Phipps, AI}, title = {Density of T-cell Subsets in Colorectal Cancer in Relation to Disease-Specific Survival.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {7}, pages = {1122-1133}, pmid = {40243533}, issn = {1538-7755}, support = {CA137088//National Institutes of Health (NIH)/ ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA244588/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 112746//Canadian Institutes of Health Research (CIHR)/ ; L70 CA284301/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; S10OD028685//Office of Research Infrastructure Programs (ORIP)/ ; P01 CA087969/CA/NCI NIH HHS/United States ; C10674/A27140//Cancer Research UK (CRUK)/ ; R50 CA274122/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA206279/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; GNT1194896//National Health and Medical Research Council (NHMRC)/ ; R21 CA191312/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; HHSN268201700006I//National Institutes of Health (NIH)/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; R50 CA247122//National Institutes of Health (NIH)/ ; UM1 CA167552/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/mortality/immunology/pathology ; Prognosis ; *T-Lymphocyte Subsets/immunology/pathology ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Prior studies have demonstrated that the overall density of T cells in colorectal tumors is favorably associated with colorectal cancer survival; however, few studies have considered the potentially distinct roles of heterogeneous T-cell subsets in different tissue regions in relation to colorectal cancer outcomes.
METHODS: Including 1,113 colorectal cancer tumors from three observational studies, we conducted in situ T-cell profiling using a customized nine-plex [CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT (keratin), MKI67 (Ki-67), and DAPI] multispectral immunofluorescence assay. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the associations of T-cell subset densities in both epithelial and stromal tissue areas in colorectal cancer with disease-specific survival.
RESULTS: Higher CD3+CD4+ and CD3+CD8+ naïve, memory, and regulatory T-cell densities were significantly associated with better colorectal cancer-specific survival in both epithelial and stromal tissue areas (HR highest quantile vs. lowest quantile ranging 0.41-0.68). These associations persisted in models further adjusted for stage at diagnosis and were largely consistent when stratified by microsatellite instability status. However, the further stratification into CD4+ or CD8+ T-cell subsets beyond CD3+ subsets did not significantly improve the performance of our model in explaining colorectal cancer prognosis.
CONCLUSIONS: The density of T cells in colorectal cancer tissue, both overall and for several T-cell subset populations, is significantly associated with colorectal cancer-specific survival independent of microsatellite instability status and stage at diagnosis.
IMPACT: Higher levels of T-cell densities in different locations with different functions are associated with better colorectal cancer-specific survival.}, }
@article {pmid40241769, year = {2025}, author = {Pang, Y and Li, Q and Sergi, Z and Yu, G and Kim, O and Lu, P and Chan, M and Sang, X and Wang, H and Ranjan, A and Robey, RW and Soheilian, F and Tran, B and Núñez, FJ and Zhang, M and Song, H and Zhang, W and Davis, D and Gilbert, MR and Gottesman, MM and Liu, Z and Thomas, CJ and Castro, MG and Gujral, TS and Wu, J}, title = {Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.}, journal = {iScience}, volume = {28}, number = {4}, pages = {112283}, pmid = {40241769}, issn = {2589-0042}, abstract = {Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that potentially render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).}, }
@article {pmid40240612, year = {2025}, author = {Nesselbush, MC and Luca, BA and Jeon, YJ and Jabara, I and Meador, CB and Garofalo, A and Binkley, MS and Hui, AB and van 't Erve, I and Xu, N and Shi, WY and Liu, KJ and Sugio, T and Kastelowitz, N and Hamilton, EG and Liu, CL and Olsen, M and Bonilla, RF and Wang, YP and Jiang, A and Lau, B and Eichholz, J and Banwait, M and Schroers-Martin, J and Boegeholz, J and King, DA and Luikart, H and Esfahani, MS and Mehrmohamadi, M and Stehr, H and Raclin, T and Tibshirani, R and Khush, K and Srinivas, S and Yu, H and Rogers, AJ and Nair, VS and Isbell, JM and Li, BT and Piotrowska, Z and Sequist, LV and Hata, AN and Neal, JW and Wakelee, HA and Gentles, AJ and Alizadeh, AA and Diehn, M}, title = {An ultrasensitive method for detection of cell-free RNA.}, journal = {Nature}, volume = {641}, number = {8063}, pages = {759-768}, pmid = {40240612}, issn = {1476-4687}, mesh = {Humans ; *Cell-Free Nucleic Acids/blood/genetics/analysis ; Carcinoma, Non-Small-Cell Lung/genetics/blood/pathology/drug therapy ; Lung Neoplasms/genetics/blood/pathology/drug therapy ; Limit of Detection ; Sensitivity and Specificity ; Gene Expression Profiling ; Female ; Male ; ErbB Receptors/genetics/antagonists & inhibitors ; Sequence Analysis, RNA/methods ; Blood Platelets/metabolism ; RNA-Seq ; Transcriptome/genetics ; }, abstract = {Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases[1-6]. Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it. In analytical validations, we find RARE-seq to be approximately 50-fold more sensitive for detecting tumour-derived cfRNA than whole-transcriptome RNA sequencing (RNA-seq), with a limit of detection of 0.05%. To explore clinical utility, we profiled 437 plasma samples from 369 individuals with cancer or non-malignant conditions and controls. Detection of non-small-cell lung cancer expression signatures in cfRNA increased with stage (6 out of 20 (30%) in stage I; 5 out of 8 (63%) in stage II; 10 out of 15 (67%) in stage III; 80 out of 96 (83% sensitivity) in stage IV at 95% specificity) and RARE-seq was more sensitive than tumour-naive circulating tumour DNA (ctDNA) analysis. In patients with EGFR-mutant non-small-cell lung cancer who developed resistance to tyrosine kinase inhibitors, we detected both histological transformation and mutation-based resistance mechanisms. Finally, we demonstrate the potential utility of RARE-seq for determination of tissue of origin, assessing benign pulmonary conditions and tracking response to mRNA vaccines. These results highlight the potential value of ultrasensitive cfRNA analysis and provide proof of concept for diverse clinical applications.}, }
@article {pmid40240607, year = {2025}, author = {Mahendrawada, L and Warfield, L and Donczew, R and Hahn, S}, title = {Low overlap of transcription factor DNA binding and regulatory targets.}, journal = {Nature}, volume = {642}, number = {8068}, pages = {796-804}, pmid = {40240607}, issn = {1476-4687}, mesh = {*Transcription Factors/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; Binding Sites/genetics ; *Gene Expression Regulation, Fungal/genetics ; Protein Binding ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Promoter Regions, Genetic/genetics ; *DNA/metabolism ; *DNA, Fungal/metabolism/genetics ; }, abstract = {DNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes[1,2]. How multiple TFs cooperate to regulate individual genes is still unclear. In yeast, most TFs are thought to regulate transcription via binding to upstream activating sequences, which are situated within a few hundred base pairs upstream of the regulated gene[3]. Although this model has been validated for individual TFs and specific genes, it has not been tested in a systematic way. Here we integrated information on the binding and expression targets for the near-complete set of yeast TFs and show that, contrary to expectations, there are few TFs with dedicated activator or repressor roles, and that most TFs have a dual function. Although nearly all protein-coding genes are regulated by one or more TFs, our analysis revealed limited overlap between TF binding and gene regulation. Rapid depletion of many TFs also revealed many regulatory targets that were distant from detectable TF binding sites, suggesting unexpected regulatory mechanisms. Our study provides a comprehensive survey of TF functions and offers insights into interactions between the set of TFs expressed in a single cell type and how they contribute to the complex programme of gene regulation.}, }
@article {pmid40240114, year = {2025}, author = {Ebadi, M and Tseng, YD}, title = {Old but Gold Radiation.}, journal = {International journal of radiation oncology, biology, physics}, volume = {122}, number = {1}, pages = {7-8}, doi = {10.1016/j.ijrobp.2024.12.042}, pmid = {40240114}, issn = {1879-355X}, }
@article {pmid40239994, year = {2025}, author = {Shen, BW and Heiter, D and Yang, W and Xu, SY and Stoddard, BL}, title = {Cryo-EM structures of DNA-free and DNA-bound BsaXI: architecture of a Type IIB restriction-modification enzyme.}, journal = {Nucleic acids research}, volume = {53}, number = {7}, pages = {}, pmid = {40239994}, issn = {1362-4962}, support = {R01 GM049857/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; grid.436923.9//EMSL/ ; U24 GM129547/GM/NIGMS NIH HHS/United States ; U24GM129547/GF/NIH HHS/United States ; }, mesh = {Cryoelectron Microscopy ; *DNA/chemistry/metabolism ; *Deoxyribonucleases, Type II Site-Specific/chemistry/ultrastructure/genetics/metabolism ; Models, Molecular ; DNA Cleavage ; Protein Binding ; Binding Sites ; Protein Conformation ; }, abstract = {We have determined multiple cryogenic electron microscopy (cryo-EM) structures of the Type IIB restriction-modification enzyme BsaXI. Such enzymes cleave DNA on both sides of their recognition sequence and share features of Types I, II, and III restriction systems. BsaXI forms a heterotrimeric (RM)2S assemblage in the presence and absence of bound DNA. Two unique structural motifs-a multi-helical "knob" and a long antiparallel double-helical "paddle"-are involved in DNA binding and cleavage. Binding of the DNA target triggers a large conformational change from an 'open' to 'closed' configuration, resulting in a mixture of two different conformations with respect to the positioning of the S subunit and its target recognition domains on the enzyme's bipartite DNA target site. Structure-guided mutagenesis studies implicated two clusters of residues in the RM subunit as being critical for DNA cleavage, both are located proximal to a DNA cleavage site. One corresponds to a canonical PD-(D/E)xK endonuclease site in the N-terminal endonuclease domain, while the other corresponds to residues clustered within the paddle motif (near to the C-terminal end of the RM subunit). This analysis facilitates a comparison of three potential mechanisms by which such enzymes cleave DNA on each side of the bound target.}, }
@article {pmid40239646, year = {2025}, author = {Zhu, Y and Balaji, A and Han, M and Andronov, L and Roy, AR and Wei, Z and Chen, C and Miles, L and Cai, S and Gu, Z and Tse, A and Yu, BC and Uenaka, T and Lin, X and Spakowitz, AJ and Moerner, WE and Qi, LS}, title = {High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH.}, journal = {Cell}, volume = {188}, number = {12}, pages = {3310-3328.e27}, pmid = {40239646}, issn = {1097-4172}, support = {R01 CA266470/CA/NCI NIH HHS/United States ; R35 GM118067/GM/NIGMS NIH HHS/United States ; DP1 NS137219/NS/NINDS NIH HHS/United States ; R21 HG013133/HG/NHGRI NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; }, mesh = {*Chromatin/metabolism ; *DNA/metabolism ; Animals ; *In Situ Hybridization, Fluorescence/methods ; Humans ; Promoter Regions, Genetic ; Mice ; Enhancer Elements, Genetic ; Imaging, Three-Dimensional/methods ; }, abstract = {Three-dimensional (3D) genome dynamics are crucial for cellular functions and disease. However, real-time, live-cell DNA visualization remains challenging, as existing methods are often confined to repetitive regions, suffer from low resolution, or require complex genome engineering. Here, we present Oligo-LiveFISH, a high-resolution, reagent-based platform for dynamically tracking non-repetitive genomic loci in diverse cell types, including primary cells. Oligo-LiveFISH utilizes fluorescent guide RNA (gRNA) oligo pools generated by computational design, in vitro transcription, and chemical labeling, delivered as ribonucleoproteins. Utilizing machine learning, we characterized the impact of gRNA design and chromatin features on imaging efficiency. Multi-color Oligo-LiveFISH achieved 20-nm spatial resolution and 50-ms temporal resolution in 3D, capturing real-time enhancer and promoter dynamics. Our measurements and dynamic modeling revealed two distinct modes of chromatin communication, and active transcription slows enhancer-promoter dynamics at endogenous genes like FOS. Oligo-LiveFISH offers a versatile platform for studying 3D genome dynamics and their links to cellular processes and disease.}, }
@article {pmid40239400, year = {2025}, author = {Shatila, M and Cruz, CC and Lu, L and Abdul-Baki, K and Baerman, E and Takigawa, K and Rivera, AU and Lee, IJ and Ngo, S and Sperling, G and Aleem, AS and Menon, R and Sullivan, A and Vemulapalli, V and Natha, C and Gupta, T and Khan, A and Mittal, N and Coleman, G and Salim, H and Wali, S and Varatharajalu, K and Kim, KC and Reddy, SA and Grivas, P and Thomas, AS and Wang, Y}, title = {The association between metformin use, immune mediated colitis and overall survival in patients treated with checkpoint inhibitor.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {221}, number = {}, pages = {115405}, doi = {10.1016/j.ejca.2025.115405}, pmid = {40239400}, issn = {1879-0852}, mesh = {Humans ; *Metformin/adverse effects/therapeutic use ; Male ; Female ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; *Colitis/chemically induced/immunology/mortality/epidemiology ; Retrospective Studies ; Middle Aged ; Aged ; *Hypoglycemic Agents/adverse effects/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy ; *Neoplasms/drug therapy/mortality/immunology ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Metformin is frequently prescribed to treat type 2 diabetes. Its primarily regulates hepatic and colonic glucose metabolism, but recent studies have suggested an anti-inflammatory effect, especially in colitis. It has been suggested that metformin may enhance immune checkpoint inhibition (ICI) efficacy for cancer treatment. Our study aims to explore the impact of metformin on ICI efficacy and the risk for colitis.
METHODS: This was a single center, retrospective analysis of consecutive patients at a tertiary cancer center who received ICI between 01/2010-12/2022 and developed immune-mediated colitis (IMC). Patients were screened for colitis based on stool tests, then divided into two groups depending on metformin use prior to colitis onset. We collected data on demographic and colitis clinical information including treatments, and outcomes.
RESULTS: A total of 953 patients were included. The incidence of IMC was higher among metformin users (7.6 %) than non-metformin users (4.9 %; p < 0.01). There were no significant differences in colitis features and outcomes, except for longer hospital stay among metformin users (8 days vs 6 for non-metformin users; p = 0.03). Metformin use was associated with shorter overall survival vs non-metformin users among patients with IMC (p = 0.03).
DISCUSSION: Our study is among the first to explore the impact of metformin on IMC and overall survival. We found that metformin use may be associated with higher risk of IMC. We also found an association between metformin use and shorter overall survival among patients who developed IMC. Larger studies with risk-stratified analysis are needed to validate our findings.}, }
@article {pmid40239123, year = {2025}, author = {Giri, VN and Rumble, RB and Yu, EY and Lu, K}, title = {Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline Clinical Insights.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500186}, doi = {10.1200/OP-25-00186}, pmid = {40239123}, issn = {2688-1535}, }
@article {pmid40233328, year = {2025}, author = {Annesley, C and Seidel, KD and Wu, Q and Summers, C and Wayne, AS and Pulsipher, MA and Agrawal, AK and Brown, CT and Mgebroff, S and Lindgren, CG and Rawlings-Rhea, SD and Huang, W and Wilson, A and Jensen, MC and Park, JR and Gardner, RA}, title = {Outcomes of PLAT-02 and PLAT-03: Evaluating CD19 CAR T-Cell Therapy and CD19-expressing T-APC Support in Pediatric B-ALL.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025028359}, pmid = {40233328}, issn = {1528-0020}, abstract = {This study reports outcomes of PLAT-02, a phase 2 trial of SCRI-CAR19, a second-generation CAR T-cell product with FMC63 scFv and 41BB costimulation, in pediatric and young adult patients with B-cell acute lymphoblastic leukemia; and PLAT-03, a companion study evaluating exogenous CD19 antigen stimulation with serial infusions of T cells expressing truncated CD19, T-cell antigen presenting cells (T-APCs). The efficacy cohort of PLAT-02 (n=72 patients, median age 12.5 years) received fludarabine/cyclophosphamide lymphodepletion followed by a dose of 1X106 CAR+ T cells/kg. MRD-negative complete remission rate was 89%. Leukemia free survival (LFS) with 95% CI at 1 and 2 years was 0.71 (0.58, 0.81) and 0.64 (0.51, 0.75). Patients with low disease burden had significantly higher 1-year LFS (0.91 vs. 0.42). Rapid in vivo contraction of CAR T cells after infusion was associated with CAR loss within six months compared to those without rapid contraction (57% vs. 19%, respectively). Most common grade 3/4 adverse events included cytokine release syndrome in 13% and neurotoxicity in 16%. The companion pilot, PLAT-03, enrolled 26 patients, and 19 received T-APCs. Neither cytokine-release syndrome nor neurotoxicity were observed after T-APC infusion. T-APC infusion in patients improved persistence (P=0.03) with rapid CAR T-cell contraction was associated with decreased early CAR loss (20% with T-APC vs. 57% without). Further exploration of serial artificial CD19 antigen exposure is warranted based on these pilot results. PLAT-02 (NCT02028455) and PLAT-03 (NCT03186118).}, }
@article {pmid40228175, year = {2025}, author = {Subbiah, V and Othus, M and Palma, J and Cuglievan, B and Kurzrock, R}, title = {Designing Clinical Trials for Patients With Rare Cancers: Connecting the Zebras.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e100051}, doi = {10.1200/EDBK-25-100051}, pmid = {40228175}, issn = {1548-8756}, mesh = {Humans ; *Neoplasms/therapy/diagnosis/genetics ; *Clinical Trials as Topic/methods ; *Rare Diseases/therapy/diagnosis ; Precision Medicine ; *Research Design ; }, abstract = {The field of rare cancer research is rapidly transforming, marked by significant progress in clinical trials and treatment strategies. Rare cancers, as defined by the National Cancer Institute, occur in fewer than 150 cases per million people each year, yet they collectively represent a significant portion of all cancer diagnoses. Because of their infrequency, these cancers pose distinct challenges for clinical trials, including limited patient populations, geographical dispersion, and a general lack of awareness of treatment options. Economic limitations further complicate drug development, making initiatives such as the Orphan Drug Act essential for incentivizing research. The advent of next-generation sequencing (NGS) and precision medicine has been instrumental in identifying actionable genetic alterations in parallel with an explosion in the development of genomically targeted therapies, immunotherapies, and antibody drug conjugates. Advances in clinical NGS, precision medicine, and tumor-agnostic therapies have become central to the progress in rare cancer research. The development and approval of tumor-agnostic drugs, such as BRAF, NTRK, and RET inhibitors, and immunotherapy for mismatch repair deficient/microsatellite instability-high status cancers highlight the potential of personalized treatments across diverse cancer types and across the age spectrum. Collaborative trials from cooperative groups including SWOG DART, ASCO TAPUR, NCI-MATCH, pediatric COG-match, DRUP, IMPRESS, and innovative registrational basket and platform trials (eg, VE-Basket, ROAR, LIBRETTO-001, ARROW), along with patient advocacy group-run trials like TRACK, are enhancing access to clinical trials. In addition, artificial intelligence has the potential to improve the trial matching process. An integrated approach, combining these innovations in collaboration with multiple stakeholders, is crucial for advancing rare cancer research, offering hope for better patient outcomes and quality of life.}, }
@article {pmid40227208, year = {2025}, author = {Kaaks, R and Cooley, V and Mukama, T and Teras, LR and Patel, AV and Masala, G and Crous-Bou, M and Harris, HR and Langseth, H and Surcel, HM and Wentzensen, N and Terry, K and Sasamoto, N and Tworoger, S and Fortner, RT}, title = {A Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer - Baseline Findings for CA125.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {12}, pages = {2441-2453}, doi = {10.1158/1078-0432.CCR-24-1845}, pmid = {40227208}, issn = {1557-3265}, support = {W81XWH-19-1-030//Congressionally Directed Medical Research Programs (CDMRP)/ ; 70114737//Deutsche Krebshilfe (German Cancer Aid)/ ; UM1CA186107//National Cancer Institute (NCI)/ ; P01 CA87969//National Cancer Institute (NCI)/ ; R01 CA9449//National Cancer Institute (NCI)/ ; U01 CA176726/CA/NCI NIH HHS/United States ; R01 CA67262//National Cancer Institute (NCI)/ ; 75N92021D0001//National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92021D0002//National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92021D0003//National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92021D0003//National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; Female ; *CA-125 Antigen/blood ; *Biomarkers, Tumor/blood ; *Early Detection of Cancer/methods ; *Ovarian Neoplasms/blood/diagnosis ; Prospective Studies ; Middle Aged ; Aged ; Carcinoma, Ovarian Epithelial/blood/diagnosis ; *Membrane Proteins/blood ; Adult ; }, abstract = {PURPOSE: Epithelial ovarian cancer (EOC) is a lethal malignancy. Cancer antigen 125 (CA125), the "best" available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by "omics" technologies. Discovery studies for EOC biomarkers should be conducted in prediagnosis blood samples from prospective cohorts to maximize the likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage while reducing methodologic biases.
EXPERIMENTAL DESIGN: Individual cohorts with prediagnosis blood samples have insufficient sample size for such studies. Thus, we established "Prospective Early Detection Consortium for Ovarian Cancer" ("PREDICT")-a collaboration of nine prospective studies-to assemble a sufficient number of EOC cases with blood samples collected ≤18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay.
RESULTS: The discrimination capacity for single CA125 measurements in samples collected <6 months prior to diagnosis was high (AUC; PREDICT overall = 0.92; range across cohorts of nonpregnant individuals = 0.89-0.98) and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed.
CONCLUSIONS: Ongoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and miRNAs using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multimodal screening as a complement to CA125 and combined with imaging.}, }
@article {pmid40226958, year = {2025}, author = {Heng, AK and Gooley, T and Lo, SS and Yang, JT and Gillespie, EF and Halasz, LM and Tseng, YD}, title = {The Impact of Race and Ethnicity on Location and Delivery of Palliative Radiotherapy.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000001202}, pmid = {40226958}, issn = {1537-453X}, abstract = {OBJECTIVES: Among patients that underwent palliative RT (pRT) at a single institution, we evaluated whether differences exist across race and ethnicity in location of pRT consultation and delivery of pRT.
METHODS: This retrospective study included cancer patients aged 18 years or older who received pRT between 10/2021 and 10/2022. Logistic regression models were used to examine univariable (UVA) and multivariable (MVA) associations between race and pRT consult in the inpatient (vs. outpatient) setting. A subset analysis of quality metrics for pRT delivery was limited to patients who had outpatient consults for pain.
RESULTS: Four hundred forty patients underwent 548 pRT consults (104 inpatient and 444 outpatient) followed by a course of pRT. Most patients were male (58.2%), White non-Hispanic (WNH) (72.6%), and English-speaking (92.9%). On MVA adjusting for histology, language, and insurance type, consults for Black/African American (BAA) patients had 2.92 higher odds of being performed in the inpatient setting compared with consults for WNH patients (95% CI: 1.28-6.70, P=0.011), although the global P-value was P=0.217. Among 290 outpatient consults for painful lesions, no differences in time to pRT start (global P=0.84), number of prescribed fractions of RT (global P=0.94), or new prescriptions for opioids (global P=0.69) were noted by race and ethnicity.
CONCLUSIONS: In this study, BAA race was associated with the location of pRT consultation, but no discernible differences were noted regarding the outpatient delivery of pRT for pain. These findings support the importance of inpatient pRT programs to ensure equitable access. More research is needed to understand barriers to outpatient consult.}, }
@article {pmid40224258, year = {2025}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Hyde, J and Martínez, J and Ahmed, CA and Briceno, G and Patel, H and Pena, J and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Sex differences in global electrical heterogeneity: The Hispanic Community Health Study/Study of Latinos.}, journal = {Heart rhythm O2}, volume = {6}, number = {1}, pages = {97-102}, pmid = {40224258}, issn = {2666-5018}, }
@article {pmid40222449, year = {2025}, author = {Alver, SK and Peters, BA and Mossavar-Rahmani, Y and Qi, Q and McClain, AC and Van Horn, L and Burk, RD and Kaplan, RC}, title = {Association of meal timing with adiposity measures and gut microbiome characteristics in a cohort study: the Hispanic Community Health Study/Study of Latinos.}, journal = {The American journal of clinical nutrition}, volume = {121}, number = {6}, pages = {1365-1379}, pmid = {40222449}, issn = {1938-3207}, mesh = {Humans ; *Adiposity ; Male ; *Hispanic or Latino ; Female ; *Gastrointestinal Microbiome/physiology ; Adult ; Middle Aged ; *Meals ; Prospective Studies ; Energy Intake ; Cohort Studies ; Exercise ; *Feeding Behavior ; }, abstract = {BACKGROUND: Time-restricted eating may help control weight through caloric restriction, circadian rhythm, or influence on the gut microbiome (GMB). Physical activity (PA) also plays a role, as people with a longer eating window (EW, time between first and last daily intake) may be more active. The associations between meal timing, adiposity, PA, sedentary behavior (SB), and GMB characteristics are of interest in Hispanic/Latino persons, who experience a high burden of cardiometabolic diseases.
OBJECTIVES: We explored the relationship of EW with energy intake and accelerometer-measured activity and assessed whether a longer EW and later midpoint of intake (MOI, midpoint time of intake) are associated with adiposity and GMB differences in Hispanic/Latino adults.
METHODS: Using data from the prospective Hispanic Community Health Study/Study of Latinos (n = 11,778 participants with valid 24-h dietary recall and accelerometer data, no unplanned weight loss, and BMI ≥ 18.5 kg/m[2]; n = 1925 with GMB data), we explored the relationship between EW, SB, and energy intake. We used multivariable linear regression models to study the relationship between EW or MOI and adiposity measures and GMB characteristics, adjusted for clinical, behavioral, and demographic characteristics.
RESULTS: Those with longer EW tended to have less SB and greater energy intake, suggesting that some individuals may balance greater intake with greater expenditure. After adjustments including energy balance, each hour of EW was associated with 0.29% higher BMI (95% confidence interval [CI]: 0.07, 0.51; P = 0.011). Longer EW and caloric EW (EWC, EW, caloric meals only) were associated with several obesity-associated GMB taxa, such as Streptococcus (enriched, β: 0.04; 95% CI: 0.01, 0.07, for EW). MOI was not significantly associated with adiposity or GMB characteristics.
CONCLUSIONS: Shorter EW may promote healthy weight, but some individuals with longer compared with shorter EWs tend to have greater activity that could balance their greater energy intake. EW and EWC may influence GMB characteristics.}, }
@article {pmid40221882, year = {2025}, author = {Dima, D and Goel, U and Ullah, F and Faiman, B and Basali, D and Mazzoni, S and Williams, LS and Samaras, C and Valent, J and Anwer, F and Khouri, J and Raza, S}, title = {Presentation and Outcomes of Localized Immunoglobulin Light Chain Amyloidosis: 14-Year Experience of an Academic Center.}, journal = {Hematological oncology}, volume = {43}, number = {3}, pages = {e70082}, pmid = {40221882}, issn = {1099-1069}, mesh = {Humans ; Male ; Female ; *Immunoglobulin Light-chain Amyloidosis/therapy/mortality/diagnosis/pathology ; Middle Aged ; Aged ; Retrospective Studies ; Adult ; Aged, 80 and over ; Prognosis ; Survival Rate ; Academic Medical Centers ; Follow-Up Studies ; Treatment Outcome ; }, abstract = {Localized light chain amyloidosis (loc-AL) is a rare disorder characterized by localized deposition of misfolded AL fibrils. There are limited data on patterns of disease presentation and long-term outcomes. In this study, we retrospectively reviewed 146 patients with loc-AL at our institution between January 1, 2010, and March 1, 2024. We excluded patients with evidence of systemic AL amyloidosis. We calculated local (PFSL) and systemic (PFSs) progression free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We found that loc-AL most commonly involved the respiratory (26%), gastrointestinal (17%), head and neck (17%) and genitourinary (10%) systems. Overall, 51% patients were asymptomatic at presentation, and 16% had a co-existent autoimmune disease. First line management included observation (52%), surgical resection (39%), chemotherapy (3%), and radiation (2%). Most patients (59%) had a response with first-line therapy. The median PFSL was ∼15 years (10-year PFSL 68%), and median OS was not reached (10-year OS 83%). None of the patients had progression to systemic amyloidosis. Seventeen patients had local recurrence and required second line therapy. In conclusion, loc-AL has an excellent prognosis and does not progress to systemic AL amyloidosis. Observation and/or surgical removal are usually adequate first-line approaches; however, a small proportion of patients can relapse locally requiring repeated interventions for symptom control.}, }
@article {pmid40221372, year = {2025}, author = {Lawrence, MG and Keerthikumar, S and Townley, SL and Clark, AK and Cuffe, GB and Laven-Law, G and Hanson, AR and Shrestha, RK and Knutson, TP and Richards, MG and Teng, L and Choo, N and Crumbaker, M and Joshua, AM and Corey, E and Nelson, PS and Dehm, SM and Risbridger, GP and Tilley, WD and Hickey, TE and Taylor, RA and Selth, LA}, title = {Reprogramming of Androgen Receptor Activity in Castration-resistant Prostate Cancer is Shaped by Truncated Variants.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2025.03.017}, pmid = {40221372}, issn = {2405-4569}, abstract = {BACKGROUND AND OBJECTIVE: Under the selective pressure of treatment, prostate cancer cells express constitutively active androgen receptor (AR) variants. Whether AR variants mediate therapy resistance remains contested, because they are often coexpressed with abundant full-length AR. Therefore, we sought to determine how truncated variants shape AR chromatin occupancy and responses to treatments in both the presence and absence of full-length AR.
METHODS: We used a cohort of patient-derived xenografts of metastatic prostate cancer with diverse AR alterations. Chromatin immunoprecipitation and RNA sequencing were used to compare the landscape of AR binding and transcriptomic features. We assessed responses to castration by castrating host mice and evaluated responses to bipolar androgen therapy by administering testosterone cypionate.
KEY FINDINGS AND LIMITATIONS: By profiling the AR cistrome, we identified a distinct group of tumours defined by ARv567es expression, a variant arising due to structural rearrangements of the AR gene. ARv567es-positive tumours also had a distinct epigenomic profile and altered transcriptional features, including loss of canonical AR-regulated gene signatures and elevated expression of AR-repressed genes. ARv567es-positive tumours were resistant to castration and bipolar androgen therapy. In tumours that coexpress full-length AR, this involves dampened transcriptional responses and disruption of the autoregulatory loop that modulates AR levels. Study limitations include the need for additional models of AR-driven prostate cancer.
The emergence of ARv567es via gene rearrangements causes transcriptional reprogramming and therapy resistance. This highlights ARv567es as a potential as a marker to guide treatment decisions.}, }
@article {pmid40216759, year = {2025}, author = {Zhang, X and Brody, JA and Graff, M and Highland, HM and Chami, N and Xu, H and Wang, Z and Ferrier, KR and Chittoor, G and Josyula, NS and Meyer, M and Gupta, S and Li, X and Li, Z and Allison, MA and Becker, DM and Bielak, LF and Bis, JC and Boorgula, MP and Bowden, DW and Broome, JG and Buth, EJ and Carlson, CS and Chang, KM and Chavan, S and Chiu, YF and Chuang, LM and Conomos, MP and DeMeo, DL and Du, M and Duggirala, R and Eng, C and Fohner, AE and Freedman, BI and Garrett, ME and Guo, X and Haiman, C and Heavner, BD and Hidalgo, B and Hixson, JE and Ho, YL and Hobbs, BD and Hu, D and Hui, Q and Hwu, CM and Jackson, RD and Jain, D and Kalyani, RR and Kardia, SLR and Kelly, TN and Lange, EM and LeNoir, M and Li, C and Le Marchand, L and McDonald, MN and McHugh, CP and Morrison, AC and Naseri, T and , and O'Connell, J and O'Donnell, CJ and Palmer, ND and Pankow, JS and Perry, JA and Peters, U and Preuss, MH and Rao, DC and Regan, EA and Reupena, SM and Roden, DM and Rodriguez-Santana, J and Sitlani, CM and Smith, JA and Tiwari, HK and Vasan, RS and Wang, Z and Weeks, DE and Wessel, J and Wiggins, KL and Wilkens, LR and Wilson, PWF and Yanek, LR and Yoneda, ZT and Zhao, W and Zöllner, S and Arnett, DK and Ashley-Koch, AE and Barnes, KC and Blangero, J and Boerwinkle, E and Burchard, EG and Carson, AP and Chasman, DI and Ida Chen, YD and Curran, JE and Fornage, M and Gordeuk, VR and He, J and Heckbert, SR and Hou, L and Irvin, MR and Kooperberg, C and Minster, RL and Mitchell, BD and Nouraie, M and Psaty, BM and Raffield, LM and Reiner, AP and Rich, SS and Rotter, JI and Benjamin Shoemaker, M and Smith, NL and Taylor, KD and Telen, MJ and Weiss, ST and Zhang, Y and Heard-Costa, N and Sun, YV and Lin, X and Cupples, LA and Lange, LA and Liu, CT and Loos, RJF and North, KE and Justice, AE}, title = {Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3470}, pmid = {40216759}, issn = {2041-1723}, support = {U01 HL054472/HL/NHLBI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; R01 DK075787/DK/NIDDK NIH HHS/United States ; F32 HL085989/HL/NHLBI NIH HHS/United States ; U01 HL072524/HL/NHLBI NIH HHS/United States ; I01 BX003340/BX/BLRD VA/United States ; P20 GM109036/GM/NIGMS NIH HHS/United States ; P01 CA134294/CA/NCI NIH HHS/United States ; U01 HG009088/HG/NHGRI NIH HHS/United States ; T32 HL007055/HL/NHLBI NIH HHS/United States ; R01 DK122503/DK/NIDDK NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; R01 HL104135/HL/NHLBI NIH HHS/United States ; I01 BX004821/BX/BLRD VA/United States ; R01 HL133040/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 AR048797/AR/NIAMS NIH HHS/United States ; U01 HG007416/HG/NHGRI NIH HHS/United States ; U01 HL054509/HL/NHLBI NIH HHS/United States ; R01 DK 122503//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 DK135938/DK/NIDDK NIH HHS/United States ; R01 AG058921/AG/NIA NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; R01 NS058700/NS/NINDS NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 AI114555/AI/NIAID NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; R01 HL067348/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 HL104608/HL/NHLBI NIH HHS/United States ; R01 AI132476/AI/NIAID NIH HHS/United States ; K08 HL136928/HL/NHLBI NIH HHS/United States ; M01 RR007122/RR/NCRR NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; R01 HL142825/HL/NHLBI NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; R01 HL093093/HL/NHLBI NIH HHS/United States ; I01 BX003362/BX/BLRD VA/United States ; R01 HL068959/HL/NHLBI NIH HHS/United States ; U01 HL072507/HL/NHLBI NIH HHS/United States ; R01 DK071891/DK/NIDDK NIH HHS/United States ; P01 HL132825/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 HL054495/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; R01 HL092301/HL/NHLBI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Alleles ; *Body Mass Index ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Obesity/genetics/ethnology ; Polymorphism, Single Nucleotide ; *Whole Genome Sequencing ; *African People/genetics ; Population Groups/genetics ; }, abstract = {Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10[-9]), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.}, }
@article {pmid40215224, year = {2025}, author = {Fisher, LH and Lazarus, E and Yu, C and Moodie, Z and Stieh, DJ and Yates, N and Zhang, L and Sawant, S and De Rosa, SC and Cohen, KW and Morris, D and Grant, S and Randhawa, A and Miner, MD and Hendriks, J and Wegmann, F and Gill, KM and Laher, F and Bekker, LG and Gray, GE and Corey, L and McElrath, MJ and Martin, T and Gilbert, PB and Tomaras, G and Walsh, SR and Baden, LR and , }, title = {ALVAC-prime and monomeric gp120 protein boost induces distinct HIV-1 specific humoral and cellular responses compared with adenovirus-prime and trimeric gp140 protein boost.}, journal = {PLOS global public health}, volume = {5}, number = {4}, pages = {e0004250}, pmid = {40215224}, issn = {2767-3375}, abstract = {Although clade-specific and cross-clade mosaic prime-boost HIV-1 vaccine regimens were advanced to the HVTN 702 and HVTN 705 efficacy trials, neither regimen prevented HIV acquisition. The respective Phase 1/2a studies, HVTN 100 (NCT02404311) and HVTN 117/HPX2004 (NCT02788045), provided rich immunological data, including previously identified correlates of risk, for comparing immune responses elicited by these vaccine regimens over time. We analyzed antibody responses measured by binding antibody multiplex assay, and CD4+ and CD8+ T-cell responses measured by intracellular cytokine staining in per-protocol vaccinees in HVTN 100 (n=186) vs. HVTN 117/HPX2004 (n=99) after the months 6 and 12 vaccinations (months 6.5/7 and 12.5/13), and 6 months after the last vaccination (month 18). At month 12.5/13, both regimens induced similarly high IgG breadth against gp120, gp140, and V1V2 antigens, and similar IgG responses to gp70-BCaseA V1V2. IgG V1V2 responses were more durable in HVTN 117/HPX2004, with the largest difference in the gp70-BCaseA V1V2 IgG response rate at month 18 (17.8% in HVTN 100 vs 61.9% in HVTN 117/HPX2004, p<0.001). IgG3 responses to consensus Env antigens were higher and more durable in HVTN117/HPX2004; for example, IgG3 response rate to the consensus gp140 antigen was 65.9% in HVTN 117/HPX2004 vs 6.3% in HVTN 100 at month 18 (TMLE p<0.0001). At month 18, both regimens induced similar IgG3 responses to gp70-BCaseA V1V2 (3.2% in HVTN 100 vs 1.1% in HVTN 117/HPX2004). Polyfunctional CD4+ Env was significantly higher in HVTN 100, and polyfunctional CD4+ Gag was higher in HVTN 117/HPX2004. CD8+ T-cell responses were not seen in HVTN 100, while CD8+ T-cell response rates in HVTN 117/HPX2004 reached up to 42%. Despite the distinct immune responses induced by the two HIV vaccine regimens, the lack of demonstrated efficacy suggests that broader, higher magnitude, and possibly qualitatively different immune responses are needed for protection against HIV acquisition. Trial registration: ClinicalTrials.gov NCT02404311 and NCT02788045; South African National Clinical Trials Registry (DOH-27-0215-4796).}, }
@article {pmid40214435, year = {2025}, author = {Ramani, H and Cleret-Buhot, A and Sylla, M and Bunet, R and Bertrand, F and Peet, MM and Chartrand-Lefebvre, C and Trottier, B and Thomas, R and Routy, JP and Fortin, C and Martel-Laferrière, V and Sadouni, M and Cloutier, G and Allard, L and Kizer, JR and Chomont, N and Ancuta, P and Hanna, DB and Kaplan, RC and Jenabian, MA and Landay, AL and Durand, M and El-Far, M and Tremblay, CL}, title = {Opposite Roles of IL-32α Versus IL-32β/γ Isoforms in Promoting Monocyte-Derived Osteoblast/Osteoclast Differentiation and Vascular Calcification in People with HIV.}, journal = {Cells}, volume = {14}, number = {7}, pages = {}, pmid = {40214435}, issn = {2073-4409}, support = {R01 AG054324/AG/NIA NIH HHS/United States ; 2R01AG054324-08A1/NH/NIH HHS/United States ; }, mesh = {Humans ; *Interleukins/metabolism ; *Monocytes/metabolism/pathology/cytology ; *Osteoblasts/metabolism/pathology ; *Cell Differentiation ; *HIV Infections/complications/pathology/metabolism ; *Vascular Calcification/metabolism/pathology/complications ; Protein Isoforms/metabolism ; *Osteoclasts/metabolism/pathology/cytology ; Male ; Calcium/metabolism ; Transforming Growth Factor beta/metabolism ; Middle Aged ; Female ; }, abstract = {People with HIV (PWH) have an increased risk of developing cardiovascular disease (CVD). Our recent data demonstrated that the multi-isoform proinflammatory cytokine IL-32 is upregulated in PWH and is associated with arterial stiffness and subclinical atherosclerosis. However, the mechanisms by which IL-32 contributes to the pathogenesis of these diseases remain unclear. Here, we show that while the less expressed IL-32α isoform induces the differentiation of human classical monocytes into the calcium-resorbing osteoclast cells, the dominantly expressed isoforms IL-32β and IL-32γ suppress this function through the inhibition of TGF-β and induce the differentiation of monocytes into the calcium-depositing osteocalcin+ osteoblasts. These results aligned with the increase in plasma levels of osteoprotegerin, a biomarker of vascular calcification, and its association with the presence of coronary artery subclinical atherosclerosis and calcium score in PWH. These findings support a novel role for the proinflammatory cytokine IL-32 in the pathophysiology of CVD by increasing vascular calcification in PWH.}, }
@article {pmid40212049, year = {2025}, author = {Onwuka, JU and Zahed, H and Feng, X and Alcala, K and Erhunmwunsee, L and Williams, RM and Aldrich, MC and Ahluwalia, JS and Albanes, D and Arslan, AA and Bassett, JK and Brennan, P and Cai, Q and Chen, C and Dimou, N and Ferrari, P and Freedman, ND and Huang, WY and Jones, ME and Jones, MR and Kaaks, R and Koh, WP and Langhammer, A and Liao, LM and Malekzadeh, R and Milne, RL and Rohan, TE and Sánchez, MJ and Sheikh, M and Sinha, R and Shu, XO and Stevens, VL and Tinker, LF and Visvanathan, K and Wang, Y and Wang, R and Weinstein, SJ and White, E and Yuan, JM and Zheng, W and Johansson, M and Robbins, HA}, title = {Association between socioeconomic position and lung cancer incidence in 16 countries: a prospective cohort consortium study.}, journal = {EClinicalMedicine}, volume = {82}, number = {}, pages = {103152}, pmid = {40212049}, issn = {2589-5370}, support = {001/WHO_/World Health Organization/International ; }, abstract = {BACKGROUND: Studies have reported higher lung cancer incidence among groups with lower socioeconomic position (SEP). However, it is not known how this difference in lung cancer incidence between SEP groups varies across different geographical settings. Furthermore, most prior studies that assessed the association between SEP and lung cancer incidence were conducted without detailed adjustment for smoking. Therefore, we aimed to assess this relationship across world regions.
METHODS: In this international prospective cohort consortium study, we used data from the Lung Cancer Cohort Consortium (LC3), which includes 20 prospective population cohorts from 16 countries in North America, Europe, Asia, and Australia. Participants were enrolled between 1985 and 2010 and followed for cancer outcomes using registry linkages and/or active follow-up. We estimated hazard ratios (HRs) for the association between educational level (our primary measure of SEP, in 4 categories) and incident lung cancer using Cox proportional hazards models separately for participants with and without a smoking history. The models were adjusted for age, sex, cohort (when multiple cohorts were included), smoking duration, cigarettes per day, and time since cessation.
FINDINGS: Among 2,487,511 participants, 53,830 developed lung cancer during a 13.5-year median follow-up (IQR = 6.5-15.0 years). Among participants with a smoking history, higher education was associated with decreased lung cancer incidence in nearly every cohort after detailed smoking adjustment. By world region, this association was observed in North America (HR per one-category increase in education [HRtrend] = 0.88, 95% CI = 0.87-0.89), Europe (HRtrend = 0.89, 95% CI = 0.88-0.91), and Asia (HRtrend = 0.91, 95% CI = 0.86-0.96), but not in the Australian study (HRtrend = 1.02, 95% CI = 0.95-1.09). By histological subtype, education associated most strongly with squamous cell carcinoma and more weakly with adenocarcinoma (p-heterogeneity < 0.0001). Among participants who never smoked, there was no association between education and lung cancer incidence in any cohort (all p-trend > 0.05), except the USA Southern Community Cohort Study (HRtrend = 0.75, 95% CI = 0.62-0.90).
INTERPRETATION: Based on longitudinal data from 2.5 million participants from 16 countries, our findings suggest that higher educational attainment was associated with lower lung cancer risk among participants with a smoking history, but not among participants who never smoked. Limitations of our study include that cohort participants cannot fully represent the general populations of the geographical regions included, and education was the only measure of SEP consistently available across our consortium.
FUNDING: This study was supported in part by the National Cancer Institute (NCI), the Lung Cancer Research Foundation (LCRF), and the World Cancer Research Fund (WCRF).}, }
@article {pmid40211539, year = {2025}, author = {Jennewein, MF and Schultz, MD and Beaver, S and Battisti, P and Bakken, J and Hanson, D and Akther, J and Zhou, F and Mohamath, R and Singh, J and Cross, N and Kasal, DN and Ykema, MR and Reed, S and Kalange, D and Cheatwood, IR and Tipper, JL and Foote, JB and King, RG and Silva-Sanchez, A and Harrod, KS and Botta, D and Gerhardt, A and Casper, C and Randall, TD and Lund, FE and Voigt, EA}, title = {Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {7}, pages = {3286-3306}, doi = {10.1016/j.ymthe.2025.04.007}, pmid = {40211539}, issn = {1525-0024}, mesh = {Animals ; Administration, Intranasal ; *SARS-CoV-2/immunology ; *COVID-19 Vaccines/immunology/administration & dosage ; *COVID-19/prevention & control/immunology/transmission/virology ; Antibodies, Viral/immunology/blood ; Antibodies, Neutralizing/immunology/blood ; Replicon/immunology ; Humans ; Cricetinae ; Immunity, Mucosal ; Viral Load ; Injections, Intramuscular ; Female ; Mice ; }, abstract = {While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident immunoglobulin G-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m.- and i.n.-administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This replicon-NLC vaccine's potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.}, }
@article {pmid40210677, year = {2025}, author = {Petty, LE and Chen, HH and Frankel, EG and Zhu, W and Downie, CG and Graff, M and Lin, P and Sharma, P and Zhang, X and Scartozzi, AC and Roshani, R and Landman, JM and Boehnke, M and Bowden, DW and Chambers, JC and Mahajan, A and McCarthy, MI and Ng, MCY and Sim, X and Spracklen, CN and Zhang, W and Preuss, M and Bottinger, EP and Nadkarni, GN and Loos, RJF and Chen, YI and Tan, J and Ipp, E and Genter, P and Emery, LS and Louie, T and Sofer, T and Stilp, AM and Taylor, KD and Xiang, AH and Buchanan, TA and Roll, K and Gao, C and Palmer, ND and Norris, JM and Wagenknecht, LE and Nousome, D and Varma, R and McKean-Cowdin, R and Guo, X and Hai, Y and Hsueh, W and Sandow, K and Parra, EJ and Cruz, M and Valladares-Salgado, A and Wacher-Rodarte, N and Rotter, JI and Goodarzi, MO and Rich, SS and Bertoni, A and Raffel, LJ and Nadler, JL and Kandeel, FR and Duggirala, R and Blangero, J and Lehman, DM and DeFronzo, RA and Thameem, F and Wang, Y and Gahagan, S and Blanco, E and Burrows, R and Huerta-Chagoya, A and Florez, JC and Tusie-Luna, T and González-Villalpando, C and Orozco, L and Haiman, CA and Hanis, CL and Rohde, R and Whitsel, EA and Reiner, AP and Kooperberg, C and Li, Y and Duan, Q and Lee, M and Correa-Burrows, P and Fried, SK and North, KE and McCormick, JB and Fisher-Hoch, SP and Gamazon, ER and Morris, AP and Mercader, JM and Highland, HM and Below, JE and , and , }, title = {Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3438}, pmid = {40210677}, issn = {2041-1723}, support = {R56 DK062370/DK/NIDDK NIH HHS/United States ; U01 HG007416/HG/NHGRI NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; R01 DK062370/DK/NIDDK NIH HHS/United States ; R56 HG010297/HG/NHGRI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; U01 DK062370/DK/NIDDK NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; R01 DK101855/DK/NIDDK NIH HHS/United States ; R01HL142302//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Female ; Humans ; Male ; Cholesterol, HDL/genetics/blood ; *Diabetes Mellitus, Type 2/genetics/ethnology/blood ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Hispanic or Latino/genetics ; Lipids/blood/genetics ; Membrane Proteins/genetics ; Mendelian Randomization Analysis ; Multiomics ; Polymorphism, Single Nucleotide ; Proteomics ; Quantitative Trait Loci ; Triglycerides/blood ; }, abstract = {Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.}, }
@article {pmid40208630, year = {2025}, author = {Zhao, Y and Gulati, R and Lange, J and Olivas-Martinez, A and Raoof, S and Zheng, Y and Feng, Z and Etzioni, R}, title = {Sensitivity Measures in Studies of Cancer Early Detection Biomarkers.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {6}, pages = {944-951}, pmid = {40208630}, issn = {1538-7755}, support = {UG1 CA286954/CA/NCI NIH HHS/United States ; R50 CA221836/CA/NCI NIH HHS/United States ; R50CA221836//National Cancer Institute (NCI)/ ; R35CA274442//National Cancer Institute (NCI)/ ; U24 CA086368/CA/NCI NIH HHS/United States ; UG1CA286954//National Cancer Institute (NCI)/ ; R35 CA274442/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods ; *Biomarkers, Tumor/analysis ; *Neoplasms/diagnosis ; Sensitivity and Specificity ; Prospective Studies ; }, abstract = {BACKGROUND: The sensitivity of a cancer screening biomarker to detect prevalent preclinical cancer drives screening benefit. Studies estimate sensitivity at different points in the biomarker development process. We examine how closely these estimates reflect the sensitivity to detect preclinical cancer (preclinical sensitivity).
METHODS: We posit that preclinical sensitivity is inversely proportional to the preclinical sojourn time. We simulate studies and estimates of sensitivity corresponding to the Early Detection Research Network's Phases of Biomarker Development. Sensitivity estimates based on clinically diagnosed cases (phase II, clinical sensitivity), archived-sample studies (phase III, archived-sample sensitivity), and prospectively screened cohorts (phases IV and V, prospective empirical sensitivity) are defined and compared against the corresponding expected preclinical sensitivity.
RESULTS: Clinical sensitivity is generally optimistic. Archived-sample sensitivity is optimistic near clinical diagnosis but may be pessimistic at longer look-back intervals, with bias also dependent on test specificity. Prospective empirical sensitivity is optimistic when the sojourn time is long relative to the screening interval. Bias in prospective empirical sensitivity also depends on the frequency and accuracy of confirmation testing following a positive screening test.
CONCLUSIONS: Sensitivity estimates from different phases of biomarker development should be distinguished and labeled accordingly to facilitate a realistic assessment of diagnostic performance and prediction of potential benefit.
IMPACT: Our study highlights the need for clearer terminology to describe the sensitivity of cancer early detection biomarkers. We introduce new labels, explain biases in sensitivity estimates, and advocate for improved communication to enhance understanding of diagnostic test performance.}, }
@article {pmid40207620, year = {2025}, author = {Gray, CN and Ashokkumar, M and Janssens, DH and Kirchherr, JL and Allard, B and Hsieh, E and Hafer, TL and Archin, NM and Browne, EP and Emerman, M}, title = {Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40207620}, issn = {2050-084X}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R61 DA047023/DA/NIDA NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; T32 AI 083203//National Institute of Allergy and Infectious Diseases/ ; R56 AI170226/AI/NIAID NIH HHS/United States ; 1UM1-A1-164567//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {*Virus Latency/drug effects/genetics ; Humans ; *HIV-1/physiology/drug effects/genetics ; Virus Activation/drug effects ; *HIV Infections/virology ; *Transcription, Genetic ; Gene Knockout Techniques ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; CD4-Positive T-Lymphocytes/virology ; }, abstract = {The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing toward inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells of people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 & I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo, and we detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout, suggesting that INTS12 prevents full-length HIV RNA production in primary T cells. Finally, we found that INTS12 more generally limits the efficacy of a variety of LRAs with different mechanisms of action.}, }
@article {pmid40205614, year = {2025}, author = {Villalobos, A and Lipman, PD and Beebe-Dimmer, J and Borrayo, EA and Briant, KJ and Bruegl, A and Dee, C and Chavez, S and Drake, B and Johnson, SS and Kikuchi, K and Leeman, J and Lowery, J and Mendoza, JA and Parker, M and Purvis, L and Wells Sittig, K and Thompson, HS and Wangen, M and Wheeler, SB}, title = {Synergies, partnership outcomes, and lessons learned: a qualitative evaluation of cancer center-coalition engagement.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {3}, pages = {}, pmid = {40205614}, issn = {2515-5091}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; 3P30CA091842-20S3, 3P30CA023108-42S3, 3P30CA015704-46S6, 3P30CA042014-32S5, 3P30CA069533-23S4, 3P30CA046934-32S5, 3P30CA022453-39S3, 3P30CA086862-21S5, 3P30CA016086-45S4, and 3P30CA022453-39S2/CA/NCI NIH HHS/United States ; P30 CA091842/CA/NCI NIH HHS/United States ; P30 CA022453/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; P30 CA069533/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; United States ; *Community-Institutional Relations ; National Cancer Institute (U.S.) ; *Cancer Care Facilities/organization & administration/economics ; *Neoplasms/prevention & control/therapy ; Centers for Disease Control and Prevention, U.S. ; Qualitative Research ; *Health Care Coalitions/organization & administration/economics ; Cooperative Behavior ; Artificial Intelligence ; Program Evaluation ; }, abstract = {BACKGROUND: Nine National Cancer Institute-Designated Cancer Centers received supplemental funding to expand community outreach and engagement activities through a partnership with Centers for Disease Control and Prevention-funded comprehensive cancer control coalitions. This article reports on an evaluation of these awards focused on organizational relationships and partnership outcomes.
METHODS: The National Cancer Institute, community outreach and engagement, and coalition representatives co-designed the evaluation, which involved document review and 18 semistructured interviews with 16 community outreach and engagement and 19 coalition representatives. Artificial intelligence-generated interview transcripts were dual-coded in NVivo, version 20/R1, software.
RESULTS: The funding generated a diverse collection of projects and partnerships. Community outreach and engagement-coalition synergies and lessons learned were evident in the following domains: infrastructure; community and partner engagement; data monitoring; and intervention implementation, evaluation, and dissemination. Outcomes of this funding initiative were evident in the following domains: strengthened partnerships, expanded knowledge, improved health or health-care programs and policies, and thriving communities.
CONCLUSIONS: Fostering community outreach and engagement-coalition partnerships created opportunities to use synergies and build capacity for engagement across multiple domains, contributing to enhanced trust and implementation of interventions across the cancer continuum. The findings provide examples and lessons on which cancer centers and coalitions can capitalize. Successful collaborative relationships were based on identifying shared goals and complementary expertise and roles, sharing financial and other resources, and a commitment to authentic and open dialogue. Although modest and short term, supplemental funding can strengthen organizational relationships and promote effective collaboration on community-facing activities; it can also lead to improved research engagement and translation of evidence to practice.}, }
@article {pmid40205312, year = {2025}, author = {Elbur, AI and Donnell, D and Hosek, S and Dye, B and Velloza, J and Delany-Moretlwe, S and Celum, C}, title = {The Association Between Use of Adherence Support Interventions and Adherence to HIV Preexposure Prophylaxis Among Young South African and Zimbabwean Women in HPTN 082.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {40205312}, issn = {1573-3254}, support = {UM1-AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068613//National Institute of Allergy and Infectious Diseases/ ; T32AI007433//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {We assessed the association between PrEP adherence support interventions and intracellular tenofovir-diphosphate (TFV-DP) levels, a biomarker for PrEP adherence, using data from 368 South African and Zimbabwean adolescent girls and young women enrolled in the HIV Prevention Trials Network 082 trial from 2016 to 2018. Group-based trajectory modeling identified trajectories of TFV-DP levels and adherence support interventions, including weekly two-way SMS and optional monthly adherence clubs. Two trajectories of TFV-DP levels were identified: a consistently low trajectory (N = 248, 67.4%, with consistent TFV-DP levels of 100 fmol/punch) and a high-decreasing trajectory (N = 120, 32.6%, with TFV-DP levels decreasing from approximately 900 to 500 fmol/punch). Two trajectories were also observed for adherence club attendance: consistently moderate (N = 249, 67.7%, attended approximately two out of three clubs in a three-month period) and low-increasing (N = 119, 32.3%). Similarly, SMS response patterns included a consistently high engagement group (N = 222, 66.1%), who responded to approximately 90% of messages, and a consistently low engagement group (N = 114, 33.9%). Women with consistently high SMS responses had higher odds of being in the high-decreasing TFV-DP levels trajectory group (Adjusted Odds Ratio [AOR]: 6.6; 95% CI 2.8-15.5; p < 0.001), while those with a consistently moderate adherence club attendance trajectory had an AOR of 1.3 (95% CI 0.5-3.3, p = 0.620) for being in the same group. Use of PrEP was aligned with the higher response trajectories of SMS responses but not with attendance to adherence support clubs.}, }
@article {pmid40203876, year = {2025}, author = {Gilligan, T and Lin, DW and Adra, N and Bagrodia, A and Feldman, DR and Yamoah, K and Aggarwal, R and Chandrasekar, T and Costa, D and Drakaki, A and Eggener, S and Emamekhoo, H and Geynisman, DM and Graham, L and Humphrey, P and Leuva, H and Levine, EG and Luckenbaugh, A and Maughan, BL and McGregor, B and Monk, P and Picus, J and Pierorazio, P and Rais-Bahrami, S and Reichert, Z and Rwigema, JC and Saylor, P and Shah, A and Shah, S and Singla, N and Sircar, K and VanderWeele, D and Zhumkhawala, A and Montgomery, S and Sliker, B}, title = {NCCN Guidelines® Insights: Testicular Cancer, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.0018}, pmid = {40203876}, issn = {1540-1413}, mesh = {Humans ; *Testicular Neoplasms/therapy/diagnosis ; Male ; *Neoplasms, Germ Cell and Embryonal/therapy/diagnosis ; Seminoma/therapy/diagnosis ; *Medical Oncology/standards ; Neoplasm Staging ; }, abstract = {The NCCN Guidelines for Testicular Cancer provide recommendations for the multidisciplinary approach to the diagnostic workup, treatment, and follow-up for testicular germ cell tumors, including both seminoma and nonseminoma. These NCCN Guidelines Insights discuss the current treatment recommendations and supporting clinical data for seminomas as presented in Version 2.2025 of the NCCN Guidelines for Testicular Cancer.}, }
@article {pmid40203873, year = {2025}, author = {Biermann, JS and Hirbe, A and Ahlawat, S and Bernthal, NM and Binitie, O and Boles, S and Brigman, B and Callan, AK and Cipriano, C and Cranmer, LD and Davis, J and Donnelly, E and Ferguson, M and Graham, A and Groundland, J and Hess, M and Hiniker, SM and Hoover-Regan, ML and Hornick, JL and Jonard, B and Kuechle, JB and Lindskog, D and Mayerson, JL and McGarry, SV and Morris, CD and Olson, D and Rose, PS and Santana, VM and Satcher, RL and Schwartz, H and Shulman, RM and Thorpe, SW and Wilky, BA and Wustrack, RL and Yoon, J and Hang, LE and Jones, F and Sansone, N and Lyons, M}, title = {Bone Cancer, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.0017}, pmid = {40203873}, issn = {1540-1413}, mesh = {Humans ; *Bone Neoplasms/therapy/diagnosis/mortality/pathology ; *Medical Oncology/standards/methods ; Combined Modality Therapy/methods ; *Sarcoma, Ewing/therapy/diagnosis ; *Osteosarcoma/therapy/diagnosis ; }, abstract = {Ewing sarcoma and osteosarcoma constitute 36% of all primary bone cancers. However, these 2 subtypes represent the most commonly diagnosed bone cancer types in the pediatric and adolescent population. Although still largely unknown, certain genetic mutations, rearrangements, and/or predisposition syndromes likely play a role in the pathogenesis of bone cancer. Osteosarcoma may also develop as a direct result of the long-term side effects of radiation therapy. With the implementation of a multimodality approach to treatment, including multiagent neoadjuvant and adjuvant chemotherapy regimens, targeted therapy options, surgery, and radiation, individuals with Ewing sarcoma and osteosarcoma are showing higher cure rates and improved overall survival. The NCCN Guidelines for Bone Cancer provide a consensus and evidence-based framework for the workup, management, and surveillance of local and recurrent/metastatic disease.}, }
@article {pmid40203872, year = {2025}, author = {Lerner, BA and Gupta, S and Burke, CA and Kupfer, S and Katona, BW and Grady, WM and Samadder, JJ and Yurgelun, MB and Kelly, KJ and Moreno Prats, M and Joseph, N and Idos, GE and Swanson, BJ and Kieber-Emmons, A and Weiss, JM and Llor, X}, title = {Advancing the Evaluation and Management of CDH1-Associated Gastric Cancer.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {4}, pages = {}, doi = {10.6004/jnccn.2025.7006}, pmid = {40203872}, issn = {1540-1413}, mesh = {Humans ; *Stomach Neoplasms/genetics/diagnosis/therapy/surgery/pathology ; Gastrectomy/methods ; *Cdh1 Proteins/genetics ; *Antigens, CD/genetics ; *Carcinoma, Signet Ring Cell/genetics/diagnosis/surgery/pathology ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Cadherins ; }, abstract = {Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent-or even eventual-progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.}, }
@article {pmid40203277, year = {2025}, author = {Shadman, M and Brown, JR and Mohseninejad, L and Yang, K and Burnett, H and Neupane, B and Williams, R and Lamanna, N and O'Brien, SM and Tedeschi, A and Tam, CS}, title = {Comparative efficacy of Bruton tyrosine kinase inhibitors in high-risk relapsed/refractory CLL: a network meta-analysis.}, journal = {Blood advances}, volume = {9}, number = {12}, pages = {2863-2870}, pmid = {40203277}, issn = {2473-9537}, mesh = {Humans ; Adenine/analogs & derivatives/therapeutic use/analogs & derivatives ; *Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; Piperidines/therapeutic use ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Pyrimidines/therapeutic use ; Recurrence ; Treatment Outcome ; Tyrosine Kinase Inhibitors ; Pyrazoles ; }, abstract = {Bruton tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), defined based on the presence of genetic mutations. Given the lack of head-to-head trials comparing next-generation BTKis used to treat high-risk R/R disease, a network meta-analysis (NMA) was performed to estimate their relative efficacy. High-risk populations were defined based on the prespecified definitions within each trial, including patients with del(17p) and/or TP53 mutations in the ALPINE (n = 150) and ASCEND (n = 86) trials, and del(17p)/del(11q) in the ELEVATE-RR (n = 533) trial. Bayesian NMAs found zanubrutinib to be the most efficacious treatment for high-risk patients, with significantly reduced risk of progression or death compared with ibrutinib (hazard ratio [HR], 0.49; 95% credible interval [CrI], 0.31-0.78), acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94), and bendamustine + rituximab or idelalisib + rituximab (BR/IR; HR, 0.12; 95% CrI, 0.05-0.26). Differences in overall survival demonstrated a numerical trend favoring zanubrutinib (probability better than ≥80%) compared with ibrutinib (HR, 0.59; 95% CrI, 0.31-1.11), acalabrutinib (HR, 0.72; 95% CrI, 0.35-1.50), and BR/IR (HR, 0.65; 95% CrI, 0.23-1.75). Rates of response also demonstrated trends favoring zanubrutinib compared with acalabrutinib, with significant results compared with ibrutinib. The NMA suggests that the most efficacious BTKi for patients with high-risk R/R CLL is zanubrutinib.}, }
@article {pmid40203192, year = {2025}, author = {Yegya-Raman, N and Plastaras, JP and Wright, CM and Chelius, M and Zhang, S and Baron, JA and Hubbeling, H and Sim, AJ and Robinson, TJ and Jain, MD and Imber, B and Fregonese, B and Yahalom, J and Ladbury, C and Dandapani, S and Pinnix, CC and Gunther, JR and Fang, PQ and Wu, SY and Dabaja, BS and Yang, JC and Chew, J and Braunstein, S and Sinha, S and Delinger, NM and Sun, S and Terezakis, SA and Sakthivel, G and Constine, LS and Chowdhry, AK and Reagan, PM and Burke, S and Tseng, YD and LaRiviere, MJ and Maity, A and Schuster, SJ and Chong, EA and Figura, NB}, title = {Bridging radiotherapy before chimeric antigen receptor T cells for B-cell lymphomas: an ILROG multicenter study.}, journal = {Blood advances}, volume = {9}, number = {13}, pages = {3293-3303}, doi = {10.1182/bloodadvances.2025015855}, pmid = {40203192}, issn = {2473-9537}, mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Immunotherapy, Adoptive/methods/adverse effects ; Adult ; *Lymphoma, B-Cell/therapy/mortality/radiotherapy ; *Receptors, Chimeric Antigen ; Retrospective Studies ; Aged, 80 and over ; Treatment Outcome ; Young Adult ; Cytokine Release Syndrome/etiology ; }, abstract = {Despite the increasing utilization of bridging radiotherapy (Br-RT), its impact on chimeric antigen receptor T-cell therapy (CAR-T) efficacy and toxicity remains poorly characterized. We retrospectively reviewed patients with relapsed/refractory B-cell lymphomas (BCLs) who received Br-RT followed by CAR-T from 2018 to 2020 across 10 institutions. Br-RT toxicities were graded per Common Terminology Criteria for Adverse Events version 5.0, and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy Consensus Guidelines. One hundred seventy-two patients (168 large BCL) received Br-RT before axicabtagene ciloleucel (73%), tisagenlecleucel (24%), or brexucabtagene autoleucel (2%). At leukapheresis, most patients (74%) had advanced-stage disease and 39% had bulky disease measuring ≥10cm. Comprehensive Br-RT was administered to 39% and bridging systemic therapy to 35%. Among all patients, grade ≥3 Br-RT toxicity occurred in 2% (1 grade 5 toxicity), grade ≥3 CRS in 9%, and grade ≥3 ICANS in 24%. Median follow-up was 31.3 months. Two-year progression-free survival (PFS) and overall survival (OS) were 38% and 53%, respectively. On multivariable analysis, comprehensive Br-RT was associated with superior PFS (hazard ratio [HR], 0.38; P < .001) and OS (HR, 0.48; P = .011). Patients with lactate dehydrogenase (LDH) normalization after Br-RT (high pre-Br-RT LDH, normal post-Br-RT LDH) had superior PFS and OS compared with those with high post-Br-RT LDH and similar PFS and OS compared with those with normal baseline LDH. In this particularly high-risk cohort, Br-RT before CAR-T demonstrates an acceptable toxicity profile with favorable clinical outcomes compared with historical controls. Comprehensive Br-RT and LDH normalization after Br-RT may be associated with superior PFS and OS.}, }
@article {pmid40203190, year = {2025}, author = {Kampouri, E and Flaherty, P and Xie, H and Sekhon, MK and Chalal, C and Stevens-Ayers, TL and Green, DJ and Gauthier, J and Shadman, M and Pérez-Osorio, AC and Jerome, KR and Leisenring, WM and Boeckh, MJ and Hill, JA}, title = {The impact of CMV reactivation on mortality after chimeric antigen receptor T-cell therapy.}, journal = {Blood advances}, volume = {9}, number = {12}, pages = {2997-3001}, pmid = {40203190}, issn = {2473-9537}, }
@article {pmid40202852, year = {2025}, author = {McQuoid, J and Blackwell, M and Bradley, D and Durazo, A and Frank-Pearce, SG and Heffner, JL and Islam, S and Le, M and Ling, PM and Pan, S and Raye, T and Tan, ASL and Vogel, EA and Wilson, M and Kendzor, DE}, title = {"It took me on a journey other than just to stop smoking": Pilot trial outcomes of an Empowerment Theory-based smoking cessation intervention for sexual and/or gender minoritized people in Oklahoma.}, journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntaf080}, pmid = {40202852}, issn = {1469-994X}, abstract = {INTRODUCTION: Sexual and/or gender minoritized (SGM) people are more likely to smoke if they live where SGM stigma is high, and existing SGM-tailored cessation interventions do not address unique challenges of these environments. This paper reports outcomes from a single-arm pilot trial of an Empowerment Theory-based smoking cessation intervention for SGM people living in high-stigma environments.
METHODS: SGM adults willing to quit smoking (N=20; Oklahoma) participated in a 12-week intervention comprised of online SGM-serving volunteer activity sessions concurrent with remotely-delivered smoking cessation support (i.e., behavioral support plus combination nicotine replacement therapy [NRT]). Baseline and exit surveys and in-depth exit interviews addressed retention, acceptability, engagement, and adherence.
RESULTS: Study retention was 80.0% (16/20). Most exit survey respondents attended ≥4 volunteer activity sessions (62.5%; 10/16) and ≥4 cessation counseling sessions (87.5%; 14/16), had moderate/high NRT adherence (patch 84.6%; 11/13 and gum/lozenge 76.9%; 10/13), and would recommend the intervention (81.3%; 13/16). At exit, 7-day point prevalence abstinence was self-reported by 45.0% (9/20; missing=smoking) of all participants and 56.3% (9/16) of exit survey respondents. At least half of participants reported pre-post intervention increases in perceived assertiveness and/or decreases in sexual identity acceptance concerns, concealment concerns, and internalized transphobia. Interviews identified intervention endorsement reasons, including experiencing greater belonging and hope.
CONCLUSION: A novel approach to SGM-tailored smoking cessation treatment that leveraged Empowerment Theory was feasible and acceptable. Future work should refine and adapt this intervention for other high-stigma places, test its efficacy and treatment mechanisms, and measure organizational and individual-level outcomes.
IMPLICATIONS: This study adds to the literature on culturally tailored smoking cessation interventions as the first tobacco intervention tailored for SGM people in high-stigma environments. It used a novel application of Empowerment Theory to advance SGM smoking cessation and resilience in the face of minority stress. Findings from this pilot study in Oklahoma indicate promising feasibility and acceptability and will inform future interventions to address tobacco use disparities among SGM people in high-stigma environments.}, }
@article {pmid40201647, year = {2025}, author = {Dickson, E and Kuhlemeier, A and Adsul, P and Sanchez-Youngman, S and Myers, K and Akintobi, TH and Rosas, LG and Mendoza, JA and Oetzel, J and Castro-Reyes, P and Alaniz, C and Jacquez, B and Wallerstein, N}, title = {Developing the engage for equity institutional multi-sector survey: Assessing academic institutional culture and climate for community-based participatory research (CBPR).}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e44}, pmid = {40201647}, issn = {2059-8661}, abstract = {INTRODUCTION: Community-engaged research/community-based participatory research/patient-engaged research (CEnR/CBPR/PEnR) are increasingly recognized as important approaches for addressing health equity. However, there is limited support for CEnR/CBPR/PEnR within Academic Health Centers (AHCs). It is important for AHCs to measure and monitor the context, process, and policies in support for CEnR/CBPR/PEnR. The Engage for Equity (E2) team developed the first Institutional Multi-Sector Survey (IMSS) instrument to assess and explore CEnR/CBPR/PEnR-related practices at three AHCs.
METHODS: Working with "champion teams" consisting of academic leaders, researchers, and patient/community partners at each AHC, we developed the IMSS to assess the following domains: institutional mission, vision, and values; CEnR/CBPR/PEnR policies/practices; community processes/structures; function of formal community advisory boards; climate/culture for CEnR/CBPR; perceptions of institutional leadership for CEnR/CBPR/PEnR. The survey was piloted to a convenience sample of CEnR/CBPR/PEnR participants at each AHC site.
RESULTS: A sample aggregated across all sites consisting of community (n = 49) and academic (n = 50) participants perceived high levels of advocacy for CEnR/CBPR/PEnR among their AHC research teams. Participants indicated that institutional leadership supported CEnR/CBPR/PEnR in principle, but resources to build CEnR/CBPR/PEnR capacity at their respective institutions were lacking. Differences in responses from community and academic partners are summarized.
CONCLUSIONS: While limited by survey length and question adaptation, the findings contribute to identification of institutional barriers and facilitators to CEnR/CBPR/PEnR in AHCs. These findings are critically important to support and improve CEnR/CBPR/PEnR practice in academic institutions and to elevate community partner voices and needs for advancing community and patient partners' research.}, }
@article {pmid40201643, year = {2025}, author = {Aschbrenner, KA and Walsh-Bailey, C and Brown, MC and Khan, T and Baggett, TP and Jones, SMW and Levy, DE and Pace, LE and Winickoff, JP}, title = {Practical considerations for engaging staff in resource-constrained healthcare settings in implementation research: A qualitative focus group and consensus building study.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e65}, pmid = {40201643}, issn = {2059-8661}, abstract = {BACKGROUND: The primary purpose of this study was to assess perceived burdens and benefits of participating in implementation research among staff employed in resource-constrained healthcare settings. Another objective was to use findings to generate considerations for engaging staff in research across different phases of implementation research.
METHODS: This qualitative focus group and consensus building study involved researchers affiliated with the National Cancer Institute Implementation Science Centers in Cancer Control program and nine Community Health Centers (CHCs) in Massachusetts. Six focus groups (n = 3 with CHC staff; n = 3 with researchers) assessed barriers and facilitators to staff participation in implementation research. During consensus discussions, we used findings to develop considerations for engaging staff as participants and partners throughout phases of implementation research.
RESULTS: Sixteen researchers and 14 staff participated in separate focus groups; nine researchers and seven staff participated in separate consensus discussions. Themes emerged across participant groups in three domains: (1) influences on research participation; (2) research burdens and benefits; and (3) ways to facilitate staff participation in research. Practical considerations included: (a) aligning research with organizational and staff values and priorities; (b) applying user-centered design to research methods; (c) building organizational and individual research capacity; and (d) offering equitable incentives for staff participation.
CONCLUSIONS: Engaging staff as participants and partners across different phases of implementation research requires knowledge about what contributes to research burden and benefits and addressing context-specific burdens and benefits.}, }
@article {pmid40201639, year = {2025}, author = {Briant, KJ and Adsul, P and Carosso, EA and Chakoian, M and Mapes, D and Coutee, T and Hempstead, B and Hassell, L and Law, W and Mendoza, JA}, title = {Adoption of E2PLUS tools and resources to promote the development of institutional capacity for patient-centered and community-engaged research at a cancer center.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e72}, pmid = {40201639}, issn = {2059-8661}, abstract = {INTRODUCTION: The Fred Hutch/University of Washington/Seattle Children's Cancer Consortium's (Consortium) Office of Community Outreach & Engagement (OCOE) joined Stanford Medicine and Morehouse School of Medicine in implementing Engage for Equity Plus (E2PLUS), a multi-institutional community of practice to learn and share patient-centered and community-engaged research (P/CEnR) practices. University of New Mexico (UNM) facilitated this collaboration.
METHODS: The Consortium formed a Champion Team of 12 people who participated in two virtual workshops facilitated by UNM. Consortium executive leadership (n = 4) participated in interviews, and investigators (n = 4) and community members/patient advocates (n = 8) participated in focus groups to provide institutional context regarding P/CEnR. This is a paper on the process and findings.
RESULTS: Through E2PLUS engagement, the Champion Team identified four strategies to address institutional health inequities: 1) increase participation of underrepresented groups at all levels of institutional leadership and advisory boards; 2) create an Office of Patient Engagement to train and support patients who participate in institutional initiatives and advise research teams; 3) expand community engagement training, resources, and institutional commitment to focus on community-identified social and health needs; and 4) establish an umbrella entity for health equity efforts across the Consortium.
CONCLUSION: While the Consortium had longstanding community advisory boards and faculty and staff with P/CEnR expertise, it did not have centralized and institutionally supported P/CEnR resources, policies, and infrastructure. By participating in E2PLUS, the Champion Team received technical assistance to leverage qualitative data to influence strategies to guide the development of Consortium health equity infrastructure and capacity for P/CEnR in Washington.}, }
@article {pmid40200765, year = {2025}, author = {Macris, PC and McMillen, K}, title = {Nutrition issues in adult hematopoietic cell transplantation: A narrative review of latest advances.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {40}, number = {3}, pages = {518-533}, doi = {10.1002/ncp.11288}, pmid = {40200765}, issn = {1941-2452}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Nutritional Status ; Adult ; Enteral Nutrition/methods ; Parenteral Nutrition/methods ; Nutrition Assessment ; *Nutritional Support/methods ; Nutritional Requirements ; Transplantation Conditioning/adverse effects ; Graft vs Host Disease ; Immunocompromised Host ; }, abstract = {Patients undergoing hematopoietic cell transplantation (HCT) are a highly heterogenous population with respect to their unique nutrient requirements and need for nutrition support. Dose-intensive conditioning regimens in addition to the debilitating effects of graft-vs-host disease impact and adversely affect the transplant recipient's nutrition status. Decreased oral intake, increased nutrient requirements, and impaired nutrient absorption and utilization often necessitate specialized nutrition support. The use of parenteral nutrition and enteral nutrition support, as well as dietary intervention strategies for immunocompromised patients, have varied over the past five decades and are highly dependent on the type of transplant used. This review highlights adult nutrition assessment components, nutrition support practices, and management of complex nutrition consequences associated with HCT.}, }
@article {pmid40199861, year = {2025}, author = {Chunara, F and Lugo, C and Osinski, K and Shah, MR and Shah, N and Kent, J and Mohyuddin, GR and Radhakrishnan, SV and Kaur, G and Chakraborty, R and Banerjee, R and Rasche, L and Schinke, C and D'Souza, A and Szabo, A and Mohan, M}, title = {Real-world treatment patterns for teclistamab and talquetamab in multiple myeloma (MM): experience from 609 patients.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {61}, pmid = {40199861}, issn = {2044-5385}, }
@article {pmid40198924, year = {2025}, author = {Chen, Y and Montaño, MA and Naik, P and Thuo, N and Kiptinness, C and Rafferty, M and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Incremental cost of pre- and post-exposure prophylaxis service provision via an online pharmacy in Kenya.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000003680}, pmid = {40198924}, issn = {1944-7884}, abstract = {BACKGROUND: Online pharmacy HIV pre- and post-exposure prophylaxis (PrEP/PEP) provision is a novel strategy to expand HIV prevention coverage. In the ePrEP pilot study, we found online pharmacy PrEP/PEP was feasible and reached populations at HIV risk in Kenya. However, program costs data are lacking.
METHODS: We conducted a costing within the ePrEP pilot study in Nairobi from 11/01/2022-12/29/2023. We obtained costs from expense reports and conducted time-and-motion observations and staff interviews. We estimated total and unit costs in the first year of implementation, cost per client and per PrEP client-month (2023 US Dollars (USD)).
RESULTS: Overall, 229 clients initiated PrEP (507 months of PrEP coverage) and 1320 initiated PEP. Based on observed program volume, annual financial cost was $109,945 USD (PrEP: $19,456; PEP: $90,489). Cost per client was higher for PrEP than PEP ($85 vs $68.6), and cost per PrEP client-month was $38 (mean duration: 2.2 months). Main drivers of financial costs were courier-delivery of HIV testing kits and drugs (PrEP: 50.6%; PEP: 40.5%), demand generation (PrEP: 25.9%; PEP: 32.1%), and equipment, system development, and utilities (PrEP: 9.3%; PEP: 9.8%). Assuming a scaled-up client volume of 2500 (PrEP: 370; PEP: 2130) reduced per-client financial costs for PrEP ($65.5) and PEP ($56) and cost per PrEP client-month ($29.6).
CONCLUSIONS: Costs of online PrEP/PEP provision is likely higher than clinic-based PrEP. Implementing cost sharing models including charging clients for HIV testing and optimizing courier delivery routes can increase program efficiencies. Our cost estimates can inform economic evaluations of online PrEP/PEP delivery.}, }
@article {pmid40198877, year = {2025}, author = {Tuazon, SA and Portuguese, AJ and Pont, MJ and Cowan, AJ and Cole, GO and Sather, BD and Song, X and Thomas, S and Wood, BL and Blake, ML and Works, MG and Shadman, M and Liang, EC and Wu, Q and Voutsinas, JM and Gooley, TA and Turtle, CJ and Till, BG and Coffey, DG and Maloney, DG and Riddell, SR and Green, DJ}, title = {A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024027681}, pmid = {40198877}, issn = {1528-0020}, abstract = {FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow (BM) plasma cell involvement (10-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T cell doses (50×106 to 450×106). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Among 28 enrolled patients, all underwent leukapheresis and successful CAR-T manufacturing, though three (11%) did not proceed to infusion. The 25 treated patients (median age 64 years) had a median of eight prior therapies, 80% were triple-class refractory, and 44% had extramedullary disease (EMD). Cytokine release syndrome (CRS) occurred in 84% (8% grade 3-4, no grade 5), and neurotoxicity in 24% (12% grade 3, no grade 4-5). No treatment-related deaths occurred. At a median follow-up of 67.3 months, treated patients had an ORR of 100%, including a stringent complete response in 64%. Median PFS and overall survival (OS) were 15.5 and 32.1 months, respectively. In an intention-to-treat analysis (median follow-up 69.6 months), the ORR was 89.3%, and OS was 30.2 months. FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted.}, }
@article {pmid40198850, year = {2025}, author = {Li, YL and Langley, C and Emerman, M and Gross, JD}, title = {APOBEC3G Antagonism by Vif, or When Structure Meets Biological and Evolutionary Studies.}, journal = {Annual review of virology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-virology-092623-091351}, pmid = {40198850}, issn = {2327-0578}, abstract = {Restriction factors serve as innate host defenses against viruses and act as critical barriers to cross-species transmission. In response, viruses have evolved accessory proteins to counteract restriction factors, enabling evasion of innate immune responses. The interplay between primate APOBEC3G (A3G) and lentiviral virion infectivity factor (Vif) exemplifies a molecular arms race between a restriction factor and its viral antagonist. This review integrates evolutionary and functional analyses of this system, showing how genetic signatures of molecular arms races map onto high-resolution cryo-electron microscopy structures. However, A3G's interaction with Vif is not limited to the evolutionary dynamic interface, characterized by rapidly evolving residues under selective pressure, but also involves a conserved interface mediated by RNA binding that positions A3G for antagonism by Vif. These findings propose a model wherein Vif and potentially other viral antagonists target functional complexes using a dual strategy: leveraging both adaptive interfaces subject to evolutionary pressures and conserved interfaces that constrain host escape mechanisms.}, }
@article {pmid40198766, year = {2025}, author = {Dima, D and Afrough, A and Goel, U and Grajales-Cruz, A and Khouri, J and Julian, K and Pasvolsky, O and Banerjee, R and Razzo, B and Ferreri, CJ and Vazquez Martinez, MA and Davis, JA and Sannareddy, A and Castaneda Puglianini, O and Raza, S and Portuguese, AJ and Gaballa, MR and Rana, M and Lieberman-Cribbin, A and DeJarnette, S and Gonzalez, R and Chen, A and Herr, MM and Mikkilineni, L and Hosoya, H and Ouchveridze, E and Kaur, G and Rossi, AC and Shune, L and Anwer, F and Lin, Y and Richard, S and Sborov, DW and Baz, RC and Garfall, A and Lee, HC and Anderson, LD and Cowan, AJ and Patel, KK and Voorhees, PM and Sidana, S and Hansen, DK and Atrash, S and Susanibar-Adaniya, SP}, title = {Teclistamab for Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma and Renal Impairment.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016059}, pmid = {40198766}, issn = {2473-9537}, abstract = {Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well-characterized given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40mL/min. CrCl <30mL/min or dialysis dependence were defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age 71 vs. 67 years, p=0.002), and have a higher median number of prior lines of therapy (7 vs. 6, p=0.04). Rates and severity of cytokine release syndrome (51% vs. 59%, grade ≥3: 1.2% vs. 1%) and immune effector cell-associated neurotoxicity syndrome (16% vs. 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day-30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in patients with RI outside of the context of disease progression. Overall response rate (52% vs. 56%, p=0.61) and survival outcomes (median progression-free survival: 4.6 vs. 6.5 months; p=0.62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI including those on dialysis, with a similar safety and efficacy profile to patients without RI.}, }
@article {pmid40198713, year = {2025}, author = {Ashokkumar, M and Hafer, TL and Felton, A and Archin, NM and Margolis, DM and Emerman, M and Browne, EP}, title = {A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency.}, journal = {PLoS pathogens}, volume = {21}, number = {4}, pages = {e1012467}, pmid = {40198713}, issn = {1553-7374}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; UM1 AI164567/AI/NIAID NIH HHS/United States ; }, mesh = {*Proto-Oncogene Protein c-ets-1/genetics/metabolism ; *HIV-1/physiology/genetics ; Humans ; *Virus Latency/physiology/genetics ; *CD4-Positive T-Lymphocytes/virology/metabolism ; *HIV Infections/virology/genetics/metabolism ; CRISPR-Cas Systems ; Gene Expression Regulation, Viral ; Clustered Regularly Interspaced Short Palindromic Repeats ; }, abstract = {Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV-1 latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV-1 expression. We further investigated one of the identified factors - the transcription factor ETS1, and found that it is required for maintenance of HIV-1 latency in both latently infected cell lines and in a primary CD4 T cell latency model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV-1 expression in actively infected cells, but increased HIV-1 expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV-1 expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV-1 (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV-1 reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV-1 expression. Furthermore, the impact of ETS1 depletion on HIV-1 expression in latently infected cells was partially dependent on MALAT1. Additionally, we demonstrate that ETS1 knockout resulted in enhanced abundance of activating modifications (H3K9Ac, H3K27Ac, H3K4me3) on histones located at the HIV-1 long terminal repeat (LTR), indicating that ETS1 regulates the activity of chromatin-targeting complexes at the HIV-1 LTR. Overall, these data demonstrate that ETS1 is an important regulator of HIV-1 latency that impacts HIV-1 expression through repressing MALAT1 expression and by regulating modification of proviral histones.}, }
@article {pmid40198382, year = {2025}, author = {Jones, MK and Nicklawsky, A and Shortt, J and Pattee, J and Kennerley, V and Eule, CJ and Candelario, N and , and O'Donnell, PH and Flaig, TW}, title = {Pharmacogenomics of chemotherapy induced peripheral neuropathy using an electronic health record-derived definition: a genome-wide association study.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {5}, pages = {362}, pmid = {40198382}, issn = {1433-7339}, support = {University of Colorado Cancer Center Support Grant P30CA04934//University of Colorado/ ; }, mesh = {Humans ; Genome-Wide Association Study ; *Peripheral Nervous System Diseases/chemically induced/genetics ; Female ; Male ; Electronic Health Records ; Middle Aged ; *Antineoplastic Agents/adverse effects/administration & dosage ; Aged ; Pharmacogenetics ; Genetic Predisposition to Disease ; Bridged-Ring Compounds/adverse effects/administration & dosage ; Taxoids/adverse effects/administration & dosage ; Adult ; *Neoplasms/drug therapy ; Polymorphism, Single Nucleotide ; Vinca Alkaloids/adverse effects/administration & dosage ; }, abstract = {PURPOSE: Prior studies evaluating the genetic predisposition to chemotherapy induced peripheral neuropathy (CIPN) have been limited by small populations due to difficulty with real-world data extraction. This genome-wide association study (GWAS) evaluates the genetic differences between patients who developed CIPN against those unaffected, using an electronic health record (EHR) definition of CIPN.
METHODS: This study included all patients who received chemotherapy associated with CIPN and had germline genetic data within the biobank at the Colorado Center for Personalized Medicine. CIPN was defined by a new neuropathic pain medication or an ICD-diagnosis of neuropathy after specified chemotherapy initiation. GWAS were stratified by (1) total population, (2) platinum chemotherapy, (3) taxane chemotherapy, and (4) vinca alkaloid chemotherapy. Genes previously associated with CIPN were analyzed within each GWAS.
RESULTS: Nine hundred fifteen patients received chemotherapy associated with CIPN, with 528 patients (57%) developing CIPN. Median age at chemotherapy initiation was 60.5 years; female sex (n = 517, 56.5%) and White or Caucasian race (n = 822, 89.8%) were most common. Among single nucleotide polymorphisms (SNPs) that reached suggestive levels of genome-wide significance (p < 1 × 10[-5]), 60 SNPs occurred within 11 genes that may play a role in the development of or protection against CIPN, including RCOR1, CLDN14, TRIM5, and TMC2. No SNPs previously associated with CIPN achieved genome-wide significance in this population.
CONCLUSION: This pharmacogenomic study suggests several genomic loci that may modulate the development of CIPN. This EHR-definition may allow for increased sample sizes and improved statistical power in future genetic studies of CIPN.}, }
@article {pmid40197896, year = {2025}, author = {Kantarjian, H and Zhai, Y and Oehler, VG and Jamy, O and Koller, PB and Haddad, FG and Sasaki, K and Jabbour, EJ}, title = {Olverembatinib in chronic myeloid leukemia-Review of historical development, current status, and future research.}, journal = {Cancer}, volume = {131}, number = {8}, pages = {e35832}, doi = {10.1002/cncr.35832}, pmid = {40197896}, issn = {1097-0142}, support = {//Ascentage Pharma Group Corp Ltd. (Hong Kong)/ ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Drug Resistance, Neoplasm/genetics/drug effects ; Fusion Proteins, bcr-abl/genetics/antagonists & inhibitors ; Mutation ; *Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; }, abstract = {Once considered an incurable disease with a poor prognosis (median survival, 3-6 years), chronic myeloid leukemia (CML) is now managed with a diverse clinical armamentarium that includes BCR::ABL1 tyrosine kinase inhibitors (TKIs), which have largely normalized life expectancy in most patients in the chronic phase of the disease (CML-CP). Clinical challenges remain, including ABL1 mutation-driven treatment resistance (under the selection pressures exerted by TKIs), as well as treatment intolerance, which can involve potentially serious arterial occlusive events. Olverembatinib is a third-generation TKI approved in China for TKI-resistant CML-CP and accelerated-phase CML with the T135I mutation, as well as for CML-CP resistant to or intolerant of first- and/or second-generation TKIs. Olverembatinib exhibits a broad coverage of ABL1 mutants, including the gatekeeper T315I variant and compound mutations. In preclinical models, olverembatinib inhibited multiple downstream protein kinases, which has potentially opened avenues for future management of other malignancies, including acute myeloid and lymphoid leukemias, gastrointestinal tumors, and others. The pharmacokinetic profile of olverembatinib is compatible with alternate-day dosing. In clinical trials, olverembatinib exerted potent antileukemic effects in heavily pretreated patients with CML, including those with ponatinib or asciminib resistance or intolerance, and was well tolerated. Future studies include the phase 3 registrational POLARIS-1 (NCT06051409; in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia), POLARIS-2 (NCT06423911; in patients with CML with or without the T315I mutation), and POLARIS-3 (NCT06640361; in patients with succinate dehydrogenase-deficient gastrointestinal stromal tumors) clinical trials.}, }
@article {pmid40196517, year = {2025}, author = {Readshaw, JJ and Doyle, LA and Puiu, M and Kelly, A and Nelson, A and Kaiser, AJ and McGuire, S and Peralta-Acosta, J and Smith, DL and Stoddard, BL and Kaiser, BK and Blower, TR}, title = {PglZ from Type I BREX phage defence systems is a metal-dependent nuclease that forms a sub-complex with BrxB.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40196517}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; R15 GM140375/GM/NIGMS NIH HHS/United States ; }, abstract = {BREX (Bacteriophage Exclusion) systems, identified through shared identity with Pgl (Phage Growth Limitation) systems, are a widespread, highly diverse group of phage defence systems found throughout bacteria and archaea. The varied BREX Types harbour multiple protein subunits (between four and eight) and all encode a conserved putative phosphatase (PglZ aka BrxZ) and an equally conserved, putative ATPase (BrxC). Almost all BREX systems also contain a site-specific methyltransferase (PglX aka BrxX). Despite having determined the structure and fundamental biophysical and biochemical behaviours for the PglX methyltransferase, the BrxL effector, the BrxA DNA-binding protein and the BrxR transcriptional regulator, the mechanism by which BREX impedes phage replication remains largely undetermined. In this study, we identify a stable BREX sub-complex of PglZ:BrxB, validate the structure and dynamic behaviour of that sub-complex, and assess the biochemical activity of PglZ, revealing it to be a metal-dependent nuclease. PglZ can cleave cyclic oligonucleotides, linear oligonucleotides, plasmid DNA and both non-modified and modified linear phage genomes. PglZ nuclease activity has no obvious role in BREX-dependent methylation, but does contribute to BREX phage defence. BrxB binding does not impact PglZ nuclease activity. These data contribute to our growing understanding of the BREX phage defence mechanism.}, }
@article {pmid40195998, year = {2025}, author = {Kareithi, T and D Roche, S and Omollo, V and Ong'wen, PA and Kiptinness, C and Otieno, P and Juma, L and Malen, RC and Harkey, K and Anyona, MO and Curran, K and Banerjee, P and Gichuru, E and Asewe, M and Yu, K and Pintye, J and Mugambi, M and Shah, PD and Sharma, M and Meisner, A and Were, D and Ngure, K and Bukusi, EA and Ortblad, KF}, title = {Testing different models of pharmacy-based HIV pre- and post-exposure prophylaxis initiation and management in Kenya: protocol for a cluster-randomized controlled trial.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40195998}, issn = {2693-5015}, support = {INV-033052/GATES/Gates Foundation/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; }, abstract = {BACKGROUND: In Kenya, as in many African countries, private pharmacies are ubiquitous, frequently accessed, and underutilized for the delivery of HIV prevention services. Whether enabling private pharmacies to initiate and manage clients on HIV pre- and post-exposure prophylaxis (PrEP and PEP) leads to greater uptake and continuation than the current standard-pharmacy referral to clinic-based PrEP/PEP-is unknown. To address this gap and inform how private pharmacies might partner with the public sector, we are testing several models of pharmacy-delivered PrEP/PEP in comparison to the current standard.
METHODS: The Pharm PrEP cRCT is a 60-pharmacy, four-arm cluster-randomized controlled trial ongoing in Central and Western Kenya (first enrollment: 26 June 2023). Eligible pharmacies were licensed by the government, had a private room, and were willing to complete research activities (including a three-day provider training). Study pharmacies were randomized 1:1:1:1 to: 1) client-sustained delivery, in which clients pay pharmacies 250 KES (~$2 USD) per PrEP/PEP visit, 2) implementor-sustained delivery, in which clients pay nothing and implementors pay pharmacies 250 KES per PrEP/PEP visit, 3) implementor-sustained + counselor-supported delivery, in which clients pay nothing, delivery is supported by an HIV testing services (HTS) counselor, and implementors pay pharmacies 100 KES (~$1 USD) per PrEP/PEP visit, or 4) referral (control), in which clients pay nothing and implementors pay pharmacies 100 KES per referral to clinic-based PrEP/PEP. Pharmacies delivering PrEP/PEP receive supporting commodities free from government stock. Primary outcomes are PrEP initiation and continuation (any refilling) reported by clients 60 days post-enrollment; secondary outcomes include PEP initiation, PEP-to-PrEP transition, repeat PEP use, PrEP/PEP initiation, and PrEP/PEP continuation at 60 and 270 days post-enrollment. Primary analyses will compare each intervention arm to the control; secondary analyses will compare intervention arms to one another. We will additionally assess implementation outcomes (e.g., acceptability, feasibility, cost) from client and provider perspectives.
DISCUSSION: This trial will generate evidence on the potential benefits of leveraging private pharmacies for delivery of PrEP and PEP and the relative effectiveness of pharmacy delivery when subsidized by clients, implementors, and/or supported by HTS counselors. The findings may inform enabling policy and approaches for scale-up.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT05842122.}, }
@article {pmid40195984, year = {2025}, author = {Fredericks, MN and Kolodner, Z and Waalkes, A and Sawatzki, K and Hao, L and Long, DR and Penewit, K and Midkiff, CC and McCormick, CJ and Beraki, S and Edlefsen, PT and Barrow, J and Greninger, AL and Gale, M and Blair, RV and Salipante, SJ and Fuller, DH and O'Connor, MA}, title = {SIV/SARS-CoV-2 co-infection in rhesus macaques impacts viral shedding, host immunity, the microbiome, and viral evolution.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40195984}, issn = {2693-5015}, support = {K01 MH123258/MH/NIMH NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; S10 OD030347/OD/NIH HHS/United States ; }, abstract = {People living with HIV (PLWH) have an increased risk of severe COVID-19, including prolonged viral shedding and emergence of mutations. To investigate the simian immunodeficiency virus (SIV) macaque model for HIV/SARS-CoV-2 co-infection, seven SIV+ rhesus macaques were co-infected with SARS-CoV-2. COVID-19 in all macaques was mild. SARS-CoV-2 replication persisted in the upper, but not the lower respiratory tract for 14 days post-infection. Animals showed impaired generation of anti-SARS-CoV-2 antibodies and T-cells. Animals also displayed transient changes in microbial communities in the upper airway and gastrointestinal tract. Evidence of SARS-CoV-2 evolution was observed in the upper respiratory tract. This study demonstrates that SIV/SARS-CoV-2 co-infection in rhesus macaques recapitulates aspects of COVID-19 in PLWH. We show that SIV impairs anti-SARS-CoV-2 immunity, potentially leading to prolonged viral shedding, altered pathogenesis, and viral evolution. This highlights the importance of HIV status in COVID-19 and supports the use of this model for HIV/SARS-CoV-2 co-infection.}, }
@article {pmid40195948, year = {2025}, author = {Sandfort, TGM and Szydlo, D and Fogel, JM and Chimwaza, Y and Rinnooy Kan, CE and Hamilton, EL and Mudhune, V and Panchia, R and Reynolds, D}, title = {Gaps in HIV Treatment and Care Cascade Among Men and Transfeminine Persons Who Have Sex with Men in Kenya, Malawi, and South Africa: Findings from the HIV Prevention Trials Network 075 Study (2015-2017).}, journal = {AIDS patient care and STDs}, volume = {39}, number = {6}, pages = {224-232}, doi = {10.1089/apc.2025.0028}, pmid = {40195948}, issn = {1557-7449}, mesh = {Humans ; Male ; *HIV Infections/drug therapy/prevention & control/diagnosis/epidemiology ; *Homosexuality, Male/statistics & numerical data/psychology ; Adult ; Prospective Studies ; South Africa/epidemiology ; *Anti-HIV Agents/therapeutic use ; *Transgender Persons/statistics & numerical data/psychology ; Kenya/epidemiology ; *Patient Acceptance of Health Care/statistics & numerical data ; Young Adult ; Malawi/epidemiology ; Middle Aged ; Medication Adherence ; Sexual and Gender Minorities ; Adolescent ; }, abstract = {Improving HIV outcomes for men who have sex with men (MSM) in sub-Saharan Africa requires addressing gaps in the HIV treatment cascade. This study examined these gaps among 71 treatment-naive MSM with HIV in the HIV Prevention Trials Network 075, a 1-year prospective biobehavioral cohort study (2015-2017) across four sub-Saharan African sites. Following a positive diagnosis, 86% of participants sought HIV care. Reasons for not having sought care or delays included a lack of perceived health issues and practical challenges. Most participants (80%) who engaged in care were prescribed antiretroviral therapy (ART). Although self-reported adherence was high, over one-third of those prescribed ART had no detectable antiretroviral drugs (ARVs) at the study's conclusion. ARV detection was significantly associated with study site, higher income, and experienced homophobia. The highest adherence rates were observed at the site offering direct, integrated treatment, underscoring the potential of "one-stop shop" services to mitigate intra-, interpersonal, and structural barriers. Despite a supportive study environment, gaps remain in linking MSM and transfeminine individuals to sustained HIV care and ART adherence. Given the urgency of addressing HIV among these populations, targeted interventions that promote engagement in care and adherence to treatment are critical.}, }
@article {pmid40193202, year = {2025}, author = {Zhang, X and Scadden, AW and Marthi, A and Buchanan, VL and Qu, Y and Ferrier, KR and Chen, BD and Graff, M and Avila, J and Boerwinkle, E and Buyske, S and Clish, CB and Cruz, D and Fornage, M and Gerzsten, RE and Gignoux, CR and Glover, L and Hou, L and Justice, AE and Kooperberg, C and Kramer, H and Lange, L and Loos, RJF and Matise, T and Mychaleckyj, JC and Olabisi, OA and Peters, U and Raffield, LM and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Yu, B and Zheng, Y and North, KE and Mottl, AK and Highland, HM and Stanislawski, MA}, title = {Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {}, number = {}, pages = {}, pmid = {40193202}, issn = {1533-3450}, support = {R01HG010297/HG/NHGRI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; R01HL087641/HL/NHLBI NIH HHS/United States ; R01HL086694/HL/NHLBI NIH HHS/United States ; U01HG004402/HG/NHGRI NIH HHS/United States ; HHSN268200625226C/NH/NIH HHS/United States ; UL1RR025005/RR/NCRR NIH HHS/United States ; 5RC2HL102419/HL/NHLBI NIH HHS/United States ; R01NS087541/NS/NINDS NIH HHS/United States ; 3U01HG004402-02S1/HG/NHGRI NIH HHS/United States ; 75N92023D00002/HL/NHLBI NIH HHS/United States ; 75N92023D00005/HL/NHLBI NIH HHS/United States ; 75N92023D00004/HL/NHLBI NIH HHS/United States ; 75N92023D00006/HL/NHLBI NIH HHS/United States ; 75N92023D00003/HL/NHLBI NIH HHS/United States ; HHSN268201300001I/N01-HC-65233/HL/NHLBI NIH HHS/United States ; HHSN268201300004I/N01-HC-65234/HL/NHLBI NIH HHS/United States ; HHSN268201300002I/N01-HC-65235/HL/NHLBI NIH HHS/United States ; HHSN268201300003I/N01- HC-65236/HL/NHLBI NIH HHS/United States ; HHSN268201300005I/N01-HC-65237/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HL/NHLBI NIH HHS/United States ; HHSN268201800011I/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; HHSN268201100037C/HL/NHLBI NIH HHS/United States ; 3U54HG003067-13S1/HG/NHGRI NIH HHS/United States ; HHSN268201600038I/HL/NHLBI NIH HHS/United States ; HHSN268201600034I/HL/NHLBI NIH HHS/United States ; 3R01HL-117626-02S1/HL/NHLBI NIH HHS/United States ; HHSN268201800002I/HL/NHLBI NIH HHS/United States ; R01HL-120393/HL/NHLBI NIH HHS/United States ; U01HL-120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001I/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01-HC-95159/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01-HC-95160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; N01-HC-95161/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; N01-HC-95162/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01-HC-95163/HL/NHLBI NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01-HC-95164/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01-HC-95165/HL/NHLBI NIH HHS/United States ; N01-HC-95166/HL/NHLBI NIH HHS/United States ; N01-HC-95167/HL/NHLBI NIH HHS/United States ; N01-HC-95168/HL/NHLBI NIH HHS/United States ; N01-HC-95169/HL/NHLBI NIH HHS/United States ; UL1-TR-000040/HL/NHLBI NIH HHS/United States ; UL1-TR-001079/HL/NHLBI NIH HHS/United States ; UL1-TR-001420/HL/NHLBI NIH HHS/United States ; UL1TR001881/TR/NCATS NIH HHS/United States ; DK063491/DK/NIDDK NIH HHS/United States ; R01HL105756/HL/NHLBI NIH HHS/United States ; N02-HL-64278/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid40191562, year = {2024}, author = {Chintsanya, M and Talham, C and Zhang, B and Taylor, TE and Seydel, KB}, title = {Vital Sign alterations within 24 hours prior to death in children with retinopathy-positive Cerebral Malaria at Queen Elizabeth Central Hospital Malawi.}, journal = {Malawi medical journal : the journal of Medical Association of Malawi}, volume = {36}, number = {2}, pages = {128-133}, pmid = {40191562}, issn = {1995-7270}, mesh = {Humans ; *Malaria, Cerebral/mortality/complications/diagnosis/physiopathology ; Male ; Female ; Malawi/epidemiology ; Retrospective Studies ; Case-Control Studies ; Child, Preschool ; *Vital Signs ; Infant ; Child ; *Malaria, Falciparum/mortality/complications ; *Retinal Diseases/parasitology/mortality ; Coma ; }, abstract = {BACKGROUND: Malaria is a significant obstacle to child health and survival. Plasmodium falciparum infections, especially in children under five, lead to high morbidity and mortality. Cerebral malaria (CM) is a life-threatening complication characterized by coma, and its diagnosis can be improved by observing malarial retinopathy in children. Monitoring vital signs is essential for managing patients with CM.
OBJECTIVES: To determine if changes in vital signs predict death in children with retinopathy positive cerebral malaria (RPCM).
METHODS: This was a retrospective case-control study using data collected from children admitted to the Paediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre between 1997 and 2020. Patients who died 24 hours or more after admission were matched with control patients who survived. Linear regression analyses were used to assess the differential time trends of each vital sign in the survivor group and death group. Classification models were used to quantify various vital signs' predictive power of death.
RESULTS: Among the population that died, the estimated change in average respiratory rate per hour approaching death was 0.02 breaths per minute compared to -0.25 breaths per minute among those who survive (p < 0.001), and the estimated change in average BCS per hour approaching death was -0.01 compared to 0.06 among the survivors (p < 0.001). Changes in temperature and heart rate were not associated with clinical deterioration. Three models were developed, and the best receiver operating characteristic curve was 100% sensitive, the corresponding false positive rate was 75%.
CONCLUSION: Changes in respiratory rate and BCS have prognostic significance in the final 24 hours before death in children with cerebral malaria. Extra attention should be paid to these two vital signs as they may help to identify children who are at increased risk of deteriorating.}, }
@article {pmid40190112, year = {2025}, author = {Moodie, Z and Li, SS and Giorgi, EE and Williams, LD and Dintwe, O and Carpp, LN and Chen, S and Seaton, KE and Sawant, SS and Zhang, L and Heptinstall, J and Liu, S and Grunenberg, N and Tomaka, F and Rerks-Ngarm, S and Pitisuttithum, P and Nitayaphan, S and Ake, JA and Vasan, S and Pantaleo, G and Frank, I and Baden, LR and Goepfert, PA and Keefer, M and Chirenje, M and Hosseinipour, MC and Mngadi, K and Laher, F and Garrett, N and Bekker, LG and De Rosa, S and Andersen-Nissen, E and Kublin, JG and Lu, S and Gilbert, PB and Gray, GE and Corey, L and McElrath, MJ and Tomaras, GD}, title = {A polyvalent DNA prime with matched polyvalent protein/GLA-SE boost regimen elicited the most robust and broad IgG and IgG3 V1V2 binding antibody and CD4+ T cell responses among 13 HIV vaccine trials.}, journal = {Emerging microbes & infections}, volume = {14}, number = {1}, pages = {2485317}, pmid = {40190112}, issn = {2222-1751}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *AIDS Vaccines/immunology/administration & dosage ; *CD4-Positive T-Lymphocytes/immunology ; *HIV Antibodies/immunology/blood ; *HIV Infections/prevention & control/immunology/virology ; *HIV-1/immunology ; Immunization, Secondary ; Immunogenicity, Vaccine ; *Immunoglobulin G/immunology/blood ; Vaccines, DNA/immunology/administration & dosage ; Clinical Trials as Topic ; }, abstract = {Developing an effective HIV vaccine is a momentous challenge. An exceptionally wide range of candidate HIV vaccines have been tested, yet many were poorly immunogenic, and of the select few that advanced into efficacy trials, only one demonstrated any efficacy. Here we report the results of the largest-scale cross-protocol immunogenicity comparison to date: 13 HIV vaccine trials (including 36 vaccine regimens) conducted across nine countries worldwide, strengthened by standardized trial designs, validated assays in centralized laboratories, and harmonized immunogenicity endpoints - providing an objective approach to identify the HIV vaccine candidate(s) with the best immunogenicity. A polyvalent DNA prime + protein boost regimen (HVTN 124) including Env immunogens of four subtypes, matched between prime and boost, achieved the best anti-V1V2 antibody responses by a large margin and also induced high CD4+ T-cell responses - two key immune responses implicated in HIV vaccine protection. Our results provide strong support to test this promising HIV vaccine design in more advanced phase clinical trials and will also guide the future design of additional HIV vaccines.Trial registration: ClinicalTrials.gov identifier: NCT01799954..Trial registration: ClinicalTrials.gov identifier: NCT02109354..Trial registration: ClinicalTrials.gov identifier: NCT02404311..Trial registration: ClinicalTrials.gov identifier: NCT02207920..Trial registration: ClinicalTrials.gov identifier: NCT02296541..Trial registration: ClinicalTrials.gov identifier: NCT03284710..Trial registration: ClinicalTrials.gov identifier: NCT02915016..Trial registration: ClinicalTrials.gov identifier: NCT02997969..Trial registration: ClinicalTrials.gov identifier: NCT03122223..Trial registration: ClinicalTrials.gov identifier: NCT03409276..Trial registration: ClinicalTrials.gov identifier: NCT02968849..Trial registration: ClinicalTrials.gov identifier: NCT03060629..Trial registration: ClinicalTrials.gov identifier: NCT00223080..}, }
@article {pmid40190065, year = {2025}, author = {Osei-Assibey, BA and Lewis, FM}, title = {Helping Her Heal-Ghana: A pilot feasibility study of a culturally adapted educational counseling intervention for spouse caregivers of women with breast cancer.}, journal = {Palliative & supportive care}, volume = {23}, number = {}, pages = {e88}, doi = {10.1017/S1478951524002153}, pmid = {40190065}, issn = {1478-9523}, mesh = {Humans ; Female ; Ghana ; *Breast Neoplasms/psychology/complications/therapy ; Middle Aged ; Feasibility Studies ; Pilot Projects ; *Caregivers/psychology/education ; Adult ; *Counseling/methods/standards ; *Spouses/psychology ; Aged ; Male ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Breast cancer is the leading cancer in Ghana, Africa, accounting for 31% of all cancers in women. The effects of breast cancer are not limited to the woman but also impact the spouse's anxiety, depressed mood, and coping behavior. Helping Her Heal (HHH)-Ghana is a culturally adapted evidenced-based intervention with potential to improve health outcomes of spouse caregivers.
OBJECTIVES: The purpose of the study was to ascertain the feasibility, acceptability, and short-term impact of HHH-Ghana, a culturally adapted evidenced-based intervention for spouses of women with breast cancer in Ghana.
METHODS: The study used a single group pre-post design. Participants (n = 14) were recruited from medical care providers and were eligible if they were spouse caregivers of wives with Stage I, II, or III breast cancer, were 18 years or older, and had been living with their wives for at least 6 months. Data were obtained by spouse self-report on standardized measures of depressed mood, anxiety, self-care skills, self-efficacy to support their wife, self-efficacy to carry out their own self-care, and the quality of marital communication about breast cancer. Exit interviews were additionally obtained to describe the gains spouses attributed to their participation in the study.
RESULTS: The HHH-Ghana study was feasible and acceptable. Spouses actively engaged in each intervention session and completed the at-home assignments; retention was 87.5%. Spouses significantly improved on standardized measures of anxiety (p = 0.010), depressed mood (p = 0.002), self-care skills (p = 0.006), and their self-efficacy in supporting their wife (p = 0.001) and in carrying out their own self-care (p = 0.011). Although there was no statistically significant change in marital communication, spouses reported in their exit interviews that the intervention enabled them to communicate better and be more attentive listeners to their wives.
SIGNIFICANCE OF RESULTS: Results warrant a larger clinical trial in Ghana.}, }
@article {pmid40188457, year = {2025}, author = {Sarchi, M and Clough, CA and Gallì, A and Picone, C and Ferrari, B and Crosse, EI and Baquero Galvis, LD and Fiducioso, C and Aydinyan, N and Creamer, JP and Pozzi, S and Molteni, E and Elena, C and Bradley, RK and Malcovati, L and Doulatov, S}, title = {Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.}, journal = {Blood advances}, volume = {9}, number = {12}, pages = {3044-3055}, pmid = {40188457}, issn = {2473-9537}, mesh = {Humans ; *RNA Splicing Factors/genetics ; *Myelodysplastic Syndromes/genetics/pathology ; *Mutation ; *Phosphoproteins/genetics ; Disease Progression ; Hematopoietic Stem Cells/metabolism ; Core Binding Factor Alpha 2 Subunit/genetics ; }, abstract = {Myelodysplastic syndromes (MDS) are clonal stem cell disorders driven by heterogeneous genetic alterations leading to variable clinical course. MDS with splicing factor SF3B1 mutations is a distinct subtype with a favorable outcome. However, selected comutations induce poor prognosis and how these genetic lesions cooperate in human hematopoietic stem and progenitor cells (HSPCs) during disease progression is still unclear. Here, we integrated clinical and molecular profiling of patients with SF3B1 mutations with gene editing of primary and induced pluripotent stem cell-derived human HSPCs to show that high-risk comutations impart distinct effects on lineage programs of SF3B1-mutant HSPCs. Secondary RUNX1 or STAG2 mutations were clinically associated with advanced disease and reduced survival. However, RUNX1 and STAG2 mutations induced opposing regulation of myeloid transcriptional programs and differentiation in SF3B1-mutant HSPCs. Moreover, high-risk RUNX1 and STAG2, but not low-risk TET2, mutations expanded distinct SF3B1-mutant HSPC subpopulations. These findings provide evidence that progression from low- to high-risk MDS involves distinct molecular and cellular routes depending on comutation patterns.}, }
@article {pmid40187495, year = {2025}, author = {Guo, M and Keane, EP and Baliousis, M and Gudenkauf, LM and Mate-Kole, MN and Boardman, AC and Larizza, IS and Song, MT and Wolfe, ED and Schaefer, DA and Cutler, C and Jim, HS and Lee, SJ and El-Jawahri, A and Amonoo, HL}, title = {A Structured Peer Support Intervention for Patients With Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation: Peer Support Interventionists' Perspectives.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {6}, pages = {390.e1-390.e13}, pmid = {40187495}, issn = {2666-6367}, support = {K08 CA251654/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/psychology ; Male ; *Hematologic Neoplasms/therapy/psychology ; Middle Aged ; Female ; *Peer Group ; Adult ; *Social Support ; Qualitative Research ; Aged ; }, abstract = {BACKGROUND: Peer support is emerging as an important component of supportive care for patients with hematologic malignancies, but it has not been robustly implemented in patients undergoing hematopoietic stem cell transplantation (HSCT).
OBJECTIVES: This qualitative study aimed to explore the experiences of peer support interventionists (participants) delivering a structured, 5-session, phone-delivered peer support intervention, the Supporting Transplant Experiences with Peer Program (STEPP) for patients undergoing HSCT.
METHODS: Adult patients who underwent allogeneic or autologous HSCT for the treatment of a hematologic malignancy within the past 3 years were eligible to volunteer in this study as trained STEPP interventionists. Semi-structured qualitative interviews were conducted to explore participants' experiences, including their motivations for volunteering, reflections on intervention delivery and on the impact of peer support, and challenges faced while serving in this role. Interviews were deductively analyzed by 2 coders using framework-guided rapid analysis.
RESULTS: Twenty STEPP interventionists participated in this study. Participants were 65% men, with a median age of 63.5 years. Most (75%) had undergone allogeneic HSCT. Emerging themes from the qualitative interviews highlighted that participants were motivated to serve as interventionists by a sense of gratitude for their transplant care and a desire to share their transplant experiences with others. The impact of the STEPP intervention on interventionists included opportunities to process their transplant journey while also providing support to their peers. Interventionists reported a preference for free-flowing conversations, which were still guided by the structured manual. Challenges included terminating the interventionist-patient relationship at the conclusion of STEPP.
CONCLUSION: Peer support interventions for patients undergoing HSCT have the potential to enhance well-being and provide meaning for both patients preparing to undergo HSCT and HSCT survivors who serve as interventionists. Large-scale randomized clinical trials are needed to test the efficacy of peer support interventions for improving health-related outcomes among patients undergoing HSCT and HSCT survivors serving as interventionists for these interventions.}, }
@article {pmid40187050, year = {2025}, author = {Rajan, A and Karpac, J}, title = {Inter-organ communication in Drosophila: Lipoproteins, adipokines, and immune-metabolic coordination.}, journal = {Current opinion in cell biology}, volume = {94}, number = {}, pages = {102508}, pmid = {40187050}, issn = {1879-0410}, support = {R01 DK133294/DK/NIDDK NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Adipokines/metabolism ; *Lipoproteins/metabolism ; *Drosophila melanogaster/metabolism/immunology ; Signal Transduction ; Drosophila Proteins/metabolism ; }, abstract = {Inter-organ communication networks are essential for maintaining systemic homeostasis in multicellular organisms. In Drosophila melanogaster, studies of adipokines and lipoproteins reveal evolutionarily conserved mechanisms coordinating metabolism, immunity, and behavior. This mini-review focuses on two key pathways: the adipokine Unpaired 2 (Upd2) and lipoprotein-mediated signaling. Upd2, a leptin analog, mediates fat-brain communication to regulate insulin secretion, sleep, and feeding behavior. Recent work has uncovered an LC3/Atg8-dependent secretion mechanism for Upd2, linking nutrient sensing to systemic adaptation. Lipoproteins, particularly ApoLpp and LTP, function beyond lipid transport, orchestrating neural maintenance and immune responses. During infection, macrophage-derived signals trigger lipoprotein-mediated lipid redistribution to support host defense. Additionally, muscle tissue emerges as an unexpected mediator of immune-metabolic coordination through inter-organ signaling. These findings highlight the intricate cross-talk between organs required for organismal survival and suggest therapeutic strategies for metabolic disorders.}, }
@article {pmid40186724, year = {2025}, author = {Hopkins, T and Bell-Brown, A and Martinez-Pinto, P and Henderson, V and Ko, LK and Isler, A and Issaka, RB}, title = {A Video Decision Aid Decreases Fear of Colonoscopy After an Abnormal Fecal Immunochemical Test Result: A Pilot Study.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40186724}, issn = {1543-0154}, support = {2022 Health Equity Research Award//American College of Gastroenterology/ ; K08CA241296/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {Colonoscopy completion after abnormal fecal immunochemical test (FIT) results is inadequate, and patient fear is a commonly reported barrier. We developed and piloted a video decision aid that addresses fear of colonoscopy among patients with abnormal FIT results. We developed a video decision aid and, in a pilot study, randomized patients in a safety-net healthcare system with abnormal FIT results and no follow-up colonoscopy to the intervention or usual care. Both groups completed a baseline survey that measured fear of colonoscopy, knowledge about colorectal cancer (CRC), self-efficacy, and intent to complete a colonoscopy, and the intervention group repeated the survey after watching the video. Sixty patients were enrolled in the study. Participants that watched the video reported a 17.7% decrease in fear of colonoscopy (p < 0.01) across six domains, including fear of the bowel prep (p < 0.01), the actual colonoscopy procedure (p < 0.01), and possible complications from the procedure (p = 0.04). Participant CRC knowledge also increased across several measures, including a 43.5% decrease in the belief that it is difficult to know which CRC prevention recommendations to follow. Overall, 78.3% of participants found the video to be helpful, and 90.6% would recommend the video to other patients with abnormal FIT results. In a safety-net population with abnormal FIT results, a video decision aid decreased fear of colonoscopy and increased knowledge about CRC. The video decision aid was acceptable to participants and can be considered an additional tool to improve follow-up of abnormal FIT results.}, }
@article {pmid40186355, year = {2025}, author = {Choe, M and Einav, T and Phillips, R and Titov, DV}, title = {Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.}, journal = {Biophysical journal}, volume = {124}, number = {10}, pages = {1562-1586}, doi = {10.1016/j.bpj.2025.03.037}, pmid = {40186355}, issn = {1542-0086}, mesh = {*Adenosine Triphosphate/metabolism ; *Glycolysis ; Allosteric Regulation ; Humans ; *Models, Biological ; Hexokinase/metabolism ; Kinetics ; Hydrolysis ; Phosphofructokinases/metabolism ; }, abstract = {Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase and phosphofructokinase by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining hexokinase and phosphofructokinase enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.}, }
@article {pmid40184567, year = {2025}, author = {Menon, MP and Ddungu, H and Mubiru, KR and Adams, SV and Asea, J and Namagembe, R and Namuli, P and Kambugu, J and Towlerton, AMH and Puronen, C and Uldrick, TS and Orem, J and Warren, EH}, title = {Phase I Study of Subcutaneous Rituximab Hyaluronidase Combined With CHOP Chemotherapy for the Treatment of Diffuse Large B-Cell Lymphoma in Uganda.}, journal = {JCO global oncology}, volume = {11}, number = {}, pages = {e2400489}, doi = {10.1200/GO-24-00489}, pmid = {40184567}, issn = {2687-8941}, mesh = {Humans ; *Rituximab/administration & dosage/therapeutic use/pharmacology ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology/mortality ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology/administration & dosage ; Female ; Adult ; Uganda ; Vincristine/therapeutic use/administration & dosage/pharmacology ; Cyclophosphamide/therapeutic use/administration & dosage/pharmacology ; Doxorubicin/therapeutic use/administration & dosage ; Prednisone/therapeutic use/administration & dosage/pharmacology ; Middle Aged ; *Hyaluronoglucosaminidase/administration & dosage/therapeutic use ; Young Adult ; }, abstract = {PURPOSE: Patients with diffuse large B-cell lymphoma (DLBCL) who are treated in low-resource settings have inferior outcomes compared with those in high-resource settings. Rituximab, an anti-CD20 monoclonal antibody, when combined with chemotherapy, improves overall survival (OS) for DLBCL. However, in part due to the limited availability of infusion centers in low-resource countries, rituximab is rarely used. Subcutaneous rituximab (sqR) is a potential solution; however, its safety and efficacy have not been tested in low-income countries.
METHODS: This open-label phase I study enrolled patients 18 years or older with newly diagnosed DLBCL. The first cohort (n = 6) received intravenous rituximab plus CHOP. This cohort received sqR for subsequent cycles. The second cohort (n = 12) received sqR plus CHOP for all cycles. Safety and tolerability were evaluated; secondary outcomes included response rates and treatment completion.
RESULTS: Between October 25, 2019, and October 7, 2022, 18 patients, with a median age of 36.5 years, were enrolled; 10 were male, and 10 presented with advanced-stage disease. The most common hematologic toxicity was neutropenia (n = 9, 50%). Fifteen of the 18 participants completed treatment; 14 (93.3%) patients achieved a complete response, and one patient (6.7%) had a partial response. The OS and progression-free survival (PFS) at 12 months were 83% (95% CI, 68 to 100) and 67% (95% CI, 48 to 92), respectively. The OS and PFS at 24 months were 66% (95% CI, 47 to 92) and 67% (95% CI, 48 to 92), respectively.
CONCLUSION: As demonstrated in other parts of the world, sqR together with CHOP was safe, well-tolerated, and efficacious among Ugandan patients with DLBCL. The very high OS rates are nearly double those of historical controls and comparable with outcomes expected in resource-rich settings. This study demonstrated the feasibility, safety, and efficacy of sqR-CHOP, increased the research infrastructure in Uganda, and will improve care in other resource-limited settings.}, }
@article {pmid40184428, year = {2025}, author = {Reeves, DB and Litchford, M and Fish, CS and Farrell-Sherman, A and Poindexter, M and Ahmed, N and Cassidy, NAJ and Neary, J and Wamalwa, D and Langat, A and Chebet, D and Moraa, H and Antar, AAR and Slyker, J and Benki-Nugent, S and Cohn, LB and Schiffer, JT and Overbaugh, J and John-Stewart, G and Lehman, DA}, title = {Intact HIV DNA decays in children with and without complete viral load suppression.}, journal = {PLoS pathogens}, volume = {21}, number = {4}, pages = {e1013003}, pmid = {40184428}, issn = {1553-7374}, support = {K25 AI155224/AI/NIAID NIH HHS/United States ; UM1 AI164565/AI/NIAID NIH HHS/United States ; R01 HD094718/HD/NICHD NIH HHS/United States ; R01 AI186721/AI/NIAID NIH HHS/United States ; R01 HD023412/HD/NICHD NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Viral Load/drug effects ; *HIV Infections/drug therapy/virology/immunology ; *DNA, Viral/genetics ; Male ; *HIV-1/genetics/drug effects ; Female ; Infant ; Child ; Child, Preschool ; RNA, Viral/blood ; CD4 Lymphocyte Count ; Proviruses/genetics ; CD4-Positive T-Lymphocytes/virology/immunology ; Anti-HIV Agents/therapeutic use ; Kenya ; }, abstract = {To inform cure in children living with HIV (CWH), we elucidated the dynamics and mechanisms underlying HIV persistence during antiretroviral therapy (ART). In 120 Kenyan CWH who initiated ART between 1-12 months of age, 55 had durable viral load suppression, and 65 experienced ART interruptions. We measured plasma HIV RNA levels, CD4+ T cell count, and levels of intact and defective HIV DNA proviruses via the cross-subtype intact proviral DNA assay (CS-IPDA). By modeling data from the durably suppressed subset, we found that during early ART (year 0-1 on ART), plasma RNA levels decayed rapidly and biphasically and intact and defective HIV DNA decayed with mean 3 and 9 month half-lives, respectively. After viral suppression was achieved (years 1-8 on ART), intact HIV DNA decay slowed to a mean 22 month half-life, whilst defective HIV DNA no longer decayed. In five CWH, we found individual CD4+ TCRβ clones wax and wane, but average kinetics resembled those of defective DNA and CD4 count, suggesting that differential decay of intact HIV DNA arises from selective pressures overlaying normal CD4+ T cell kinetics. Finally, by modeling HIV RNA and DNA in CWH with treatment interruptions, we linked temporary viremia to transient rises in HIV DNA, but long-term intact reservoirs were not strongly influenced, suggesting brief treatment interruptions may not significantly increase HIV reservoirs in children.}, }
@article {pmid40184422, year = {2025}, author = {Nelson, CR and Mallett, DR and Biggins, S}, title = {Spindle integrity is regulated by a phospho-dependent interaction between the Ndc80 and Dam1 kinetochore complexes.}, journal = {PLoS genetics}, volume = {21}, number = {4}, pages = {e1011645}, pmid = {40184422}, issn = {1553-7404}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, mesh = {*Kinetochores/metabolism ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; Phosphorylation ; *Microtubule-Associated Proteins/genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; *Spindle Apparatus/metabolism/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Chromosome Segregation/genetics ; Microtubules/genetics/metabolism ; *Nuclear Proteins/metabolism/genetics ; Protein Serine-Threonine Kinases/genetics/metabolism ; Anaphase/genetics ; }, abstract = {Faithful chromosome segregation depends upon kinetochores, large protein complexes that anchor chromosomes to dynamic microtubules, allowing for their movement at anaphase. Critical microtubule-coupling components of the budding yeast kinetochore, the Dam1 (Dam1c) and Ndc80 (Ndc80c) complexes, work cooperatively to ensure that kinetochores track with the plus-ends of microtubules. Additionally, the Dam1 complex plays a distinct role in ensuring the integrity of the mitotic spindle. However, the events required to orchestrate these diverse functions of Dam1c remain unclear. To identify regulatory events on kinetochores, we performed phosphoproteomics on purified kinetochore proteins and identified many previously unknown phosphorylation events. We demonstrate that Ndc80 is phosphorylated at Thr-248 and Thr-252 to promote the interaction between Ndc80 and the Dam1c. The phosphorylation of T248 is cell cycle regulated and depends on Mps1. Ndc80 phosphorylation at T248 and T252 does not appear to regulate kinetochore function and instead contributes to Dam1c localization to the anaphase spindle. A ndc80 phospho-deficient mutant exhibited a genetic interaction and altered spindle morphology when combined with dam1 mutant alleles. Taken together, we propose that Mps1-dependent phosphorylation of Ndc80 at T248 and T252 is removed at anaphase to allow Dam1c to help organize and stabilize the spindle.}, }
@article {pmid40180499, year = {2025}, author = {Porter, J and Ward, LC and Nguo, K and Davidson, Z and Gibson, S and Prentice, R and Neuhouser, ML and Truby, H}, title = {Investigating the impact of body composition on the estimation of resting metabolic rate: new equations for adults aged ≥65 years developed using cross-sectional data.}, journal = {The American journal of clinical nutrition}, volume = {121}, number = {4}, pages = {795-803}, doi = {10.1016/j.ajcnut.2024.12.023}, pmid = {40180499}, issn = {1938-3207}, mesh = {Humans ; *Basal Metabolism ; *Body Composition ; Aged ; Male ; Female ; Cross-Sectional Studies ; Aged, 80 and over ; }, abstract = {BACKGROUND: Due to changes in body composition during aging, the inclusion of body composition measures as a variable within equations to predict resting metabolic rate (RMR) may improve their predictive accuracy.
OBJECTIVES: This analysis of cross-sectional data aimed to develop and validate new RMR equations for older adults (≥65 y) incorporating variables for body composition, to predict performance and accuracy, and to explore the relative contribution of body composition variables acting directly or potentially via fat-free mass (FFM) to RMR.
METHODS: Analyses were conducted utilizing a unique international dataset of gold standard measures developed for this purpose. RMR was predicted from potential predictive variables using stepwise multiple regression. Predictive performance of the final model was assessed using double cross-validation. The new prediction equation was compared with published prediction equations for similar populations and with previously published RMR prediction equations that did not include FFM. Direct associations between the determined predictor variables and RMR with indirect effects mediated via FFM were examined using mediation final (or pathway) analysis.
RESULTS: The dataset contained 1238 participants. The predictive equations {utilizing either FFM (Equation 1) or lean body weight [LBW](Equation 2)} follow. Equation 1: RMR = 8.645 × height + 23.684 × weight - 29.717 × age + 38.213 × FFM + 209.637 × sex + 2693.223; Equation 2: RMR = -30.570 × age + 80.736 × LBW - 186.825 × sex + 3956.822 where RMR (kJ/d); height (cm); weight (kg); age (y); FFM (kg); LBW (kg); sex (M = 1, F = 0). The equation performed similarly to some anthropometric-based prediction equations. Predictors using FFM performed marginally better than those using LBW. All variables had significant (P < 0.001) direct effects upon RMR and significant (P < 0.001) indirect effects for sex, weight, and height.
CONCLUSIONS: New prediction equations predict RMR at the population level with minimal bias; however, the difference in performance with anthropometry-based equations is minimal. This may be explained by the contribution of FFM to weight, whereby equations that include weight are already accounting for FFM.}, }
@article {pmid40180419, year = {2025}, author = {Arias-Badia, M and Pai, CS and Lwin, YM and Chen, P and Srinath, A and Tanaka, M and Musser, E and Goodearl, A and Gorman, JV and Ritacco, W and Fong, L}, title = {Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {4}, pages = {}, pmid = {40180419}, issn = {2051-1426}, support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *CTLA-4 Antigen/antagonists & inhibitors ; Humans ; *Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Male ; Cell Line, Tumor ; *Neoplasms/immunology/drug therapy ; *Immunotherapy/methods ; }, abstract = {BACKGROUND: Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.
METHODS: We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.
RESULTS: Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic "non-exhausted" antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.
CONCLUSIONS: These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases.}, }
@article {pmid40180180, year = {2025}, author = {Diacova, T and Cifelli, CJ and Davis, CD and Holscher, HD and Kable, ME and Lampe, JW and Latulippe, ME and Swanson, KS and Karl, JP}, title = {Best Practices and Considerations for Conducting Research on Diet-Gut Microbiome Interactions and Their Impact on Health in Adult Populations: An Umbrella Review.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {16}, number = {5}, pages = {100419}, pmid = {40180180}, issn = {2156-5376}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Diet ; Adult ; *Research Design ; }, abstract = {Diet modulates gut microbiome composition and function. However, determining causal links between diet-gut microbiome interactions and human health is complicated by inconsistencies in the evidence, arising partially from variability in research methods and reporting. Widespread adoption of standardized best practices would advance the field but require those practices to be identified, consolidated, and discussed. This umbrella review aimed to identify recommended best practices, define existing gaps, and collate considerations for conducting research on diet-gut microbiome interactions and their impact on human health outcomes. Reviews meeting inclusion criteria and published after 2013 were identified using a systematic search. Recommendations, considerations, and gaps relating to the best practices associated with study design, participant selection, dietary intervention/assessment, biological sample collection, and data analysis and reporting were extracted and consolidated. Eight narrative reviews were included. Several general points of agreement were identified, and a recurring theme was that best practices are dependent upon the research aims, outcomes, and feasibility. Multiple gaps were also identified. Some, such as suboptimal diet assessment methods and lack of validated dietary intake biomarkers, are particularly relevant to nutrition science. Others, including defining a "healthy" gut microbiome and the absence of standardized sample and data collection/analysis protocols, were relevant specifically to gut microbiome research. Gaps specific to diet-gut microbiome research include the underrepresentation of microbiome-modulating dietary components in food databases, lack of knowledge regarding interventions eliciting changes in the gut microbiome to confer health benefits, lack of in situ measurement methods, and the need to further develop and refine statistical approaches for integrating diet and gut microbiome data. Future research and cross-disciplinary exchange will address these gaps and evolve the best practices. In the interim, the best practices and considerations discussed herein, and the publications from which that information was extracted provide a roadmap for conducting diet-gut microbiome research. This trial was registered at PROSPERO as CRD42023437645.}, }
@article {pmid40179338, year = {2025}, author = {Wu, M and Russell, K and Shaw, CM and Halpern, AB and Ghiuzeli, C and Appelbaum, JS and Hendrie, P and Walter, RB and Percival, MM}, title = {Predictors of Cardiac Recovery in Adults With AML Who Develop Heart Failure During Treatment.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400734}, doi = {10.1200/OP-24-00734}, pmid = {40179338}, issn = {2688-1535}, abstract = {PURPOSE: Heart failure is a leading cause of death in patients with AML, who face higher risks of cardiac complications than nonleukemic cancer patients treated with anthracyclines. This study examines factors associated with myocardial dysfunction and recovery occurring during treatment of AML.
METHODS: We retrospectively analyzed patients with AML who sustained reduced left ventricular ejection fraction (LVEF) during induction therapy at the University of Washington/Fred Hutchinson Cancer Center (2008-2022). Multivariable analysis compared characteristics between patients who eventually recovered LVEF and those who did not, with survival analysis performed by landmark censoring.
RESULTS: Of 86 patients with AML diagnosed with systolic dysfunction, 41 (48%) failed to recover LVEF. These patients were more frequently male, older than 60 years, had preexisting cardiovascular risk factors, and leukemias of higher risk. Ischemia-related systolic failure was associated with nonrecovery (B = -2.89, P = .005), whereas chemotherapy-related dysfunction was associated with eventual recovery (B = 1.15, P = .014). Frequent use and higher doses of guideline-directed medical therapy (GDMT) were found among patients who recovered LVEF. Failure to recover cardiac function was associated with a greater incidence of cardiac-specific mortality (51% v 23%, P = .042), although impact on overall survival was unclear.
CONCLUSION: Our retrospective single-center analysis suggests that approximately half of the patients with AML who experience LVEF decline during induction will not recover. Ischemic events during treatment were predictive of nonrecovery. The use of GDMT may improve prognosis for some patients. Given the impact of recovery, we propose the prospective verification and establishment of cardiac management algorithms in patients with AML.}, }
@article {pmid40178906, year = {2025}, author = {Violari, A and Otwombe, K and Hahn, W and Chen, S and Josipovic, D and Baba, V and Angelidou, A and Smolen, KK and Levy, O and Mkhize, NN and Woodward Davis, AS and Martin, TM and Haynes, BF and Williams, WB and Sagawa, ZK and Kublin, JG and Polakowski, L and Brewinski Isaacs, M and Yen, C and Tomaras, G and Corey, L and Janes, H and Gray, GE}, title = {Safety and implementation of phase I randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {11}, pages = {}, pmid = {40178906}, issn = {1558-8238}, support = {K08 AI168487/AI/NIAID NIH HHS/United States ; U19 AI168643/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; HHSN272201800047C/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology/adverse effects/administration & dosage ; Female ; *HIV Envelope Protein gp120/immunology/administration & dosage ; Infant, Newborn ; *HIV Infections/prevention & control/immunology ; Male ; *Adjuvants, Immunologic/administration & dosage/adverse effects ; *Lipid A/analogs & derivatives/administration & dosage/adverse effects ; *HIV-1/immunology ; HIV Antibodies/immunology ; Infant ; Glucosides ; }, abstract = {BACKGROUNDThe neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs), and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a new-in-infants glucopyranosyl lipid A-stable emulsion (GLA-SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.METHODSHIV Vaccine Trials Network 135 is a phase I randomized, placebo-controlled trial of CH505TF plus GLA-SE or placebo. Healthy infants aged ≤5 days, born to mothers living with HIV but HIV nucleic acid-negative at birth, were randomized to 5 doses of CH505TF plus GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.RESULTSThirty-eight infants (median age 4 days; interquartile range 4-4.75 days) were enrolled November 2020 to January 2022. Among 28 infants assigned to receive CH505TF plus GLA-SE and 10 assigned to receive placebo, most completed the 5-dose immunization series (32/38) and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) versus placebo recipients (1, 10% local, P = 0.25; 4, 40.0% systemic, P = 0.38). All events were grade 1 except 2 grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.CONCLUSIONThis study illustrates the feasibility of conducting trials of new-in-infants adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF plus GLA-SE vaccine was reassuring.TRIAL REGISTRATIONClinicalTrials.gov NCT04607408.FUNDINGNational Institute of Allergy and Infectious Diseases of the NIH under grants UM1AI068614, UM1AI068635, and UM1AI068618.}, }
@article {pmid40176173, year = {2025}, author = {Hu, Y and Haessler, J and Lundin, JI and Darst, BF and Whitsel, EA and Grove, M and Guan, W and Xia, R and Szeto, M and Raffield, LM and Ratliff, S and Wang, Y and Wang, X and Fohner, AE and Lynch, MT and Patel, YM and Lani Park, S and Xu, H and Mitchell, BD and Bis, JC and Sotoodehnia, N and Brody, JA and Psaty, BM and Peloso, GM and Tsai, MY and Rich, SS and Rotter, JI and Smith, JA and Kardia, SLR and Reiner, AP and Lange, L and Fornage, M and Pankow, JS and Graff, M and North, KE and Kooperberg, C and Peters, U}, title = {Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants.}, journal = {Clinical epigenetics}, volume = {17}, number = {1}, pages = {54}, pmid = {40176173}, issn = {1868-7083}, support = {N01 HC095168/HL/NHLBI NIH HHS/United States ; 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005, and S10OD028685/NH/NIH HHS/United States ; 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, HL148610, and R01HL105756/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; U01HG007397/HG/NHGRI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01HL054457, RC1HL100185, R01HL087660, R01HL119443, R01HL133221/HL/NHLBI NIH HHS/United States ; 75N92022D00001/NH/NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; DK063491//National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center/ ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; U01CA164973/CA/NCI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; R01 HL087660/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; K08 HL116640/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; RC1 HL100185/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; UL1TR000124/TR/NCATS NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I, HHSN268201800014I, HHSN268201800015I, HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I/MD/NIMHD NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01HL105756, HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, R01AG023629, 75N92021D00006, U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL111089, R01HL116747 and R01HL120393/HL/NHLBI NIH HHS/United States ; R01 HL133221/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; R01HG010297/HG/NHGRI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; R01 HL111089/HL/NHLBI NIH HHS/United States ; R01 HL116747/HL/NHLBI NIH HHS/United States ; R01 HL092111/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study/methods ; Female ; Male ; *DNA Methylation/genetics ; Middle Aged ; CpG Islands ; Adult ; Alcohol Drinking/genetics ; *Lipids/blood/genetics ; Ethnicity/genetics ; Racial Groups/genetics ; Smoking/genetics ; White People/genetics ; Aged ; }, abstract = {Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.}, }
@article {pmid40175263, year = {2025}, author = {Chari, A and Bal, S and Ailawadhi, S and Krishnan, A and Patel, KK and Berdeja, JG and Garfall, A and Callander, N and Banerjee, R and Alsina, M and Nooka, AK and Dhakal, B and Gasparetto, C and Costello, C}, title = {Expert Perspectives on Current Challenges and Emerging Approaches for Multiple Myeloma: Narrative Review of an Inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2025.03.008}, pmid = {40175263}, issn = {2152-2669}, abstract = {PURPOSE: The management of multiple myeloma (MM) is becoming increasingly more complex. The approval of novel treatment approaches provides much-needed opportunities but also raises questions and controversies about how to optimally sequence therapies and select treatments for individual patients.
METHODS AND RESULTS: A panel of experts assembled to discuss current controversies in the care of patients with MM across the disease continuum. Workshop topics included: management of smoldering MM; treatment selection for transplant-eligible and transplant-ineligible patients; risk assessment and the possibility of risk-adapted treatment; use of measurable residual disease (MRD) as a clinical trial end point and to guide treatment decisions; management of early relapse; management of triple class-refractory MM; treatment sequencing; and novel therapies.
CONCLUSION: Many controversies remain regarding the management of patients with MM related to risk assessment, treatment selection and sequencing, and the optimal use of current therapies while balancing efficacy, toxicity, patient considerations, and treatment logistics. Ongoing research efforts are needed to further define the optimal use of current therapies and to develop more efficacious therapies for all patients and for particular subset populations with unmet need.}, }
@article {pmid40173015, year = {2025}, author = {Russell, ML and Trofimov, A and Bradley, P and Matsen Iv, FA}, title = {Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination.}, journal = {Nucleic acids research}, volume = {53}, number = {6}, pages = {}, pmid = {40173015}, issn = {1362-4962}, support = {//Mahan Fellowship/ ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/GF/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, mesh = {*V(D)J Recombination ; Humans ; High-Throughput Nucleotide Sequencing ; Sequence Homology, Nucleic Acid ; }, abstract = {V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology-short stretches of sequence homology between gene ends-can bias the recombination process, the extent of microhomology's impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously published high-throughput TCRα repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across other receptor loci and sequence types. Further, we demonstrate that accounting for germline microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how germline-encoded microhomologous nucleotides shape the human V(D)J recombination process.}, }
@article {pmid40172323, year = {2025}, author = {Milch, HS and Lee, CI}, title = {Establishing the Evidence Needed for AI-driven Mammography Screening.}, journal = {Radiology. Artificial intelligence}, volume = {7}, number = {3}, pages = {e250152}, pmid = {40172323}, issn = {2638-6100}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; R01 CA262023/CA/NCI NIH HHS/United States ; R01 CA266377/CA/NCI NIH HHS/United States ; R37 CA240403/CA/NCI NIH HHS/United States ; }, }
@article {pmid40171709, year = {2025}, author = {Nakamura, M and Parkhurst, SM}, title = {Septin complexes: Ahead of the curve.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {82}, number = {4}, pages = {229-233}, pmid = {40171709}, issn = {1949-3592}, support = {R01 GM111635/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Actin Cytoskeleton/metabolism ; Actins/metabolism ; Actomyosin/metabolism ; Drosophila/metabolism ; *Drosophila Proteins/metabolism ; *Septins/metabolism ; }, abstract = {Individual cells have robust repair systems to survive cell cortex damage caused by mechanical and chemical stresses, allowing them to maintain the integrity of tissues and organs. The contraction of an actomyosin ring at the wound edge is a major mechanism for physically closing the cell wound. In contrast to polymerization and bundling of actin filaments, little is known about how linear actin filaments are bent to be integrated into the actin ring structure encircling the wound edge. We recently found that the five Drosophila Septins function simultaneously in the regulation of actomyosin ring assembly, contraction, and disassembly during cell wound repair. These Septins form two distinct complexes-Sep1-Sep2-Pnut and Sep4-Sep5-Pnut-composed of different subunits from the same groups. Strikingly, these two distinct Septin complexes have different degrees of F-actin bending activities that are consistent with their spatial recruitment: different degrees of curved actin filaments are required for the robust formation of different regions of the actomyosin ring. In addition, we found that the two Septin complexes are regulated by different molecular pathways as a loss of Anillin only affects Sep1-Sep2-Pnut complex recruitment. These findings open new directions for how individual Septin subunits form complexes and function differentially in cellular and developmental processes.}, }
@article {pmid40170549, year = {2025}, author = {Hoffman, RM and Wolf, AMD and Raoof, S and Guerra, CE and Church, TR and Elkin, EB and Etzioni, RD and Shih, YT and Skates, SJ and Manassaram-Baptiste, D and Smith, RA}, title = {Multicancer early detection testing: Guidance for primary care discussions with patients.}, journal = {Cancer}, volume = {131}, number = {7}, pages = {e35823}, pmid = {40170549}, issn = {1097-0142}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; *Primary Health Care ; Practice Guidelines as Topic ; }, abstract = {Multicancer early detection (MCED) tests are an emerging technology for cancer screening. MCED tests can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. Some tests can suggest the most likely cancer origin, whereas others report cancer detected somewhere in the body. Although some MCED tests are currently commercially available, none are approved by the Food and Drug Administration or endorsed by any clinical practice guideline or recommendation. Most insurance companies do not currently cover MCED testing. MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials. Because patients already are asking for MCED test prescriptions or for interpretation of results from tests acquired elsewhere, clinicians should be prepared to discuss what is known about the benefits, risks, and uncertainties of MCED testing, including performance characteristics in screening populations and preferred follow-up strategies for positive test results. At this time, clinicians should not feel obligated to initiate discussions about MCED testing with their patients. However, clinicians should engage patients who inquire about getting tested or previous MCED test results in shared decision-making, and take the opportunity to offer and help patients complete age- and sex-appropriate guideline-recommended cancer screenings. In this article, the current evidence and issues around MCED testing are summarized, and a framework for shared decision-making discussions is provided.}, }
@article {pmid40170460, year = {2025}, author = {Griffin, SP and Signorelli, J and Raheem, F and Adler, K and Benitez, LL and Cheng, RM and Dotson, E and Fares, M and Ganti, BR and Hickey Zacholski, E and Lasko, AR and Lewallen, AB and Lynch, AC and Paulic, N and Quach, D and Vogel, V and Yacobucci, M and Riebandt, G}, title = {Time to complete oncology pharmacist tasks: A joint opinion of the Hematology/Oncology Pharmacy Association and American College of Clinical Pharmacy's Hematology/Oncology Practice and Research Network.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251330252}, doi = {10.1177/10781552251330252}, pmid = {40170460}, issn = {1477-092X}, abstract = {PurposeThe time to complete oncology pharmacist tasks is needed to determine workload and productivity. The Hematology/Oncology Pharmacy Association (HOPA) and the Hematology/Oncology Practice and Research Network (PRN) of the American College of Clinical Pharmacy (ACCP) partnered with the aim of establishing consensus on the time required to complete oncology pharmacy tasks.MethodsFifteen patient care tasks and 9 non-patient care tasks, commonly completed by oncology pharmacists were each assigned an average amount of time to be completed. This list was then converted into 24 statements and the Delphi survey method was utilized with an expert panel to arrive at consensus between December 2023 and February 2024. Consensus was defined as at least 75% agreement. The complete manuscript was endorsed by HOPA and ACCP Hematology/Oncology PRN.ResultsThirty-three pharmacist-experts agreed to participate in this survey with all participating in round 1, and 29 (87.9%) participating in round 2. In round 1, 9 tasks achieved consensus, with 7 of these being classified as patient care associated. Seven statements reaching 65% but less than 75% agreement were deemed to reach borderline consensus. Eight statements failed to achieve at least 65% agreement and were modified based on respondent feedback. In round 2, 15 statements were included with all achieving consensus. At the completion of round 2, all 24 statements reached consensus, and the survey was deemed complete.ConclusionThis project produced the first comprehensive consensus statements for the average time for a US-based oncology pharmacist to complete common patient and non-patient care-related tasks.}, }
@article {pmid40169355, year = {2025}, author = {Zhang, X and Perrigue, M and Schenk, JM and Drewnowski, A and Wang, CY and Beatty, SJ and Neuhouser, ML}, title = {Objective and subjective appetite measures: high versus low eating frequency in a randomized crossover clinical trial.}, journal = {Obesity (Silver Spring, Md.)}, volume = {33}, number = {5}, pages = {879-891}, pmid = {40169355}, issn = {1930-739X}, support = {R01 DK103674/DK/NIDDK NIH HHS/United States ; K00CA253745/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Appetite/physiology ; Cross-Over Studies ; Energy Intake ; *Feeding Behavior ; *Ghrelin/blood ; Hunger ; Meals ; *Peptide YY/blood ; Postprandial Period ; Satiation ; }, abstract = {OBJECTIVE: The objective of this study was to examine objective (ghrelin and peptide YY [PYY]) and subjective appetite measures following 21-day high and low eating frequency (EF) interventions among healthy adults.
METHODS: In the randomized crossover trial (Frequency of Eating and Satiety Hormones [FRESH] study), participants completed two eucaloric 21-day study periods of low (3 meals/day) and high (6 meals/day) EF with a 14-day washout period. Self-selected foods and total energy consumed were identical in both arms. On day 21 of each period, participants completed a 7-h clinic visit with meals provided according to assigned EF. Postprandial plasma ghrelin and PYY concentrations were assessed through serial blood draws (hourly), and self-reported appetite ratings were collected every 30 min.
RESULTS: Fifty participants were recruited and completed the trial (mean age, 32 years, 78% women, and 60% non-Hispanic White). High EF resulted in smaller changes in postprandial ghrelin and PYY concentrations compared to low EF, with significant area under the curve differences between groups (p value for ghrelin = 0.03; p value for PYY < 0.001). Similar patterns were found in self-reported hunger, desire to eat, and fullness. Differences in postprandial PYY were greater among participants with overweight/obesity or high body fat percentage.
CONCLUSIONS: High EF led to smaller changes in objective and subjective appetite measures, suggesting that small frequent meals may lead to blunted satiety and less optimal appetite regulation.}, }
@article {pmid40167599, year = {2025}, author = {Tanaka, M and Lum, L and Hu, KH and Chaudhary, P and Hughes, S and Ledezma-Soto, C and Samad, B and Superville, D and Ng, K and Chumber, A and Benson, C and Adams, ZN and Kersten, K and Aguilar, OA and Fong, L and Combes, AJ and Krummel, MF and Reeves, MQ}, title = {Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {6}, pages = {}, pmid = {40167599}, issn = {1540-9538}, support = {//Five For The Fight/ ; //Cancer League/ ; IRG-21-131-01//American Cancer Society/ ; V2024-002//V Foundation/ ; //University of Texas/ ; //University of California, San Francisco/ ; S10 OD021644/OD/NIH HHS/United States ; //Parker Institute for Cancer Immunotherapy/ ; //Sanford Burnham Prebys/ ; R21 CA264599/CA/NCI NIH HHS/United States ; RR230012//Cancer Prevention and Research Institute of Texas/ ; R21CA264599/CA/NCI NIH HHS/United States ; 1S10OD021644-01A1/NH/NIH HHS/United States ; P30CA040214//Huntsman Cancer Institute Cancer Center/ ; }, mesh = {Animals ; *Tumor Microenvironment/immunology ; Mice ; Chemokine CX3CL1/metabolism/immunology ; Mice, Inbred C57BL ; Macrophages/immunology ; Immunotherapy ; *Neoplasms/immunology/pathology ; T-Lymphocytes/immunology ; Humans ; Cell Line, Tumor ; }, abstract = {Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.}, }
@article {pmid40167119, year = {2025}, author = {Sharifi, MN and Sperger, JM and Taylor, AK and Tippins, KE and Reese, SR and Carreno, V and Kaufmann, KR and Chang, AH and Nunamaker, LA and Linebarger, C and Mora-Rodriguez, L and Schehr, JL and Krause, HM and Helzer, KT and Bootsma, ML and Blitzer, GC and Floberg, JM and Kyriakopoulos, CE and Emamekhoo, H and Heath, EI and Wells, M and Tagawa, ST and Sjöström, M and Choudhury, AD and Yu, M and Armstrong, AJ and Rathkopf, DE and Beltran, H and Nelson, PS and Feng, FY and Dehm, SM and Kosoff, D and Wei, XX and McKay, RR and Zhao, SG and Lang, JM}, title = {High-Purity CTC RNA Sequencing Identifies Prostate Cancer Lineage Phenotypes Prognostic for Clinical Outcomes.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1-OF19}, doi = {10.1158/2159-8290.CD-24-1509}, pmid = {40167119}, issn = {2159-8290}, support = {DP2 OD030734/NH/NIH HHS/United States ; PC190039//Department of Defense/ ; 2024 TACTICAL Award//Prostate Cancer Foundation/ ; PICI//University of Wisconsin Office of the Vice Chancellor for Research and Graduate Education/ ; }, abstract = {Treatment resistance remains a universal driver of lethal metastatic prostate cancer, associated with acquired genomic alterations and lineage transitions. Using a novel high-purity CTC isolation approach for CTC transcriptional profiling, we identified four lineage phenotypes differentially associated with prognosis in metastatic prostate cancer.}, }
@article {pmid40166810, year = {2025}, author = {Chandra, AA and Duran Luciano, P and Swett, K and Kaplan, R and Talavera, GA and Lamar, M and Tarraf, W and Marquez, F and Joshi, PH and Gallo, L and Sotres-Alvarez, D and Gianola, M and Daviglus, ML and Labovitz, DL and Gonzalez, H and DeCarli, C and Rodriguez, CJ}, title = {Association of Lp(a) With Stroke and Cerebral Injury on MRI: Insights From the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) and Investigation of Neurocognitive Aging MRI (SOL-INCA MRI).}, journal = {Stroke}, volume = {56}, number = {6}, pages = {1492-1504}, pmid = {40166810}, issn = {1524-4628}, support = {N01 HC065233/HL/NHLBI NIH HHS/United States ; N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; RF1 AG054548/AG/NIA NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Magnetic Resonance Imaging ; *Lipoprotein(a)/blood ; Middle Aged ; Hispanic or Latino ; *Stroke/blood/diagnostic imaging/epidemiology/ethnology ; Adult ; *Ischemic Attack, Transient/blood/diagnostic imaging ; Cohort Studies ; *Aging ; Aged ; White Matter ; Brain/diagnostic imaging ; White ; }, abstract = {BACKGROUND: Lp(a) (lipoprotein[a]) is a risk factor for cardiovascular disease; however, its association with cerebrovascular disease is not as well established.
METHODS: Data from a population-based cohort of Hispanics/Latinos included 16 333 individuals with baseline Lp(a) levels (nmol/L) and self-reported prevalent stroke or transient ischemic attack (TIA). A subset of 2642 individuals with brain magnetic resonance imaging was also included. Linear and multivariate logistic regression assessed the association of Lp(a) with (1) self-reported stroke or TIA, (2) cerebral injury defined as self-reported stroke or TIA or evidence of a stroke on brain magnetic resonance imaging, (3) white matter hyperintensity volume, and (4) silent brain infarcts. Sampling weights were utilized given the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) complex sample design.
RESULTS: Mean age±SE was 41.1±0.3 years, 52.0% women, and median interquartile range (Q1, Q3) Lp(a) level of 19.7 (7.3-60.6) nmol/L; brain magnetic resonance imaging subset mean age±SE was 49.9±0.4 years, 56.4% women, and median (interquartile range) Lp(a) level of 21.7 (8.1-62.9) nmol/L. Each unit increase in log-transformed Lp(a) was associated with higher odds of self-reported stroke or TIA (odds ratio, 1.13 [95% CI, 1.01-1.27]; P=0.03). Lp(a) levels in the highest quintile (>77 nmol/L) were significantly associated with higher odds of prevalent stroke or TIA compared with Lp(a) <6 nmol/L (first quintile: odds ratio, 1.74 [95% CI, 1.09-2.77]; P=0.02). The highest proportion of cerebral injury was noted in Q5, while the lowest proportion was noted in Q2. When comparing Lp(a) >77 nmol/L with Lp(a) of 6 to <13 nmol/L (second quintile), a significant association was found between Lp(a) and cerebral injury that persisted after fully adjusted models (odds ratio, 2.03 [95% CI, 1.05-3.93]; P=0.03). Each unit increase in log-Lp(a) was associated with a 0.10 increase in log-white matter hyperintensity (β, 0.10; P=0.005). No significant association was found between Lp(a) and silent brain infarcts.
CONCLUSIONS: Lp(a) is independently and significantly associated with prevalent stroke/TIA, and white matter hyperintensity, in a large diverse population of Hispanics/Latinos.}, }
@article {pmid40166161, year = {2025}, author = {Wang, K and Saniei, S and Poddar, N and Autar, S and Carcamo, S and Sreenath, M and Peplinski, JH and Ries, RE and Martinez, IG and Chao, C and Mei, AH and Rahman, N and Mekerishvili, L and Quijada-Álamo, M and Freed, G and Zhang, M and Lachman, K and Diaz, Z and Gonzalez, MM and Zhang, J and Pham, G and Filipescu, D and Berisa, M and Balestra, T and Reisz, JA and D'Alessandro, A and Puleston, DJ and Bernstein, E and Chipuk, JE and Wunderlich, M and Tasian, SK and Marcellino, BK and Glass, IA and , and Sturgeon, CM and Landau, DA and Chen, Z and Papapetrou, EP and Izzo, F and Meshinchi, S and Hasson, D and Wagenblast, E}, title = {Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40166161}, issn = {2692-8205}, support = {S10 OD026880/OD/NIH HHS/United States ; R01 CA290681/CA/NCI NIH HHS/United States ; R01 CA292503/CA/NCI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; P30 CA196521/CA/NCI NIH HHS/United States ; }, abstract = {Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98∷NSD1-driven pediatric acute myeloid leukemia, that is particularly aggressive with WT1 co-mutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses, despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.}, }
@article {pmid40166020, year = {2025}, author = {Peluso, MJ and Sandel, DA and Deitchman, AN and Kim, SJ and Dalhuisen, T and Tummala, HP and Tibúrcio, R and Zemelko, L and Borgo, GM and Singh, SS and Schwartz, K and Deswal, M and Williams, MC and Hoh, R and Shimoda, M and Narpala, S and Serebryannyy, L and Khalili, M and Vendrame, E and SenGupta, D and Whitmore, LS and Tisoncik-Go, J and Gale, M and Koup, RA and Mullins, JI and Felber, BK and Pavlakis, GN and Reeves, JD and Petropoulos, CJ and Glidden, DV and Spitzer, MH and Gama, L and Caskey, M and Nussenzweig, MC and Chew, KW and Henrich, TJ and Yukl, SA and Cohn, LB and Deeks, SG and Rutishauser, RL}, title = {Combination immunotherapy induces post-intervention control of HIV.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40166020}, issn = {2693-5015}, support = {R01 DE032033/DE/NIDCR NIH HHS/United States ; K23 AI162249/AI/NIAID NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; INV-002707/GATES/Gates Foundation/United States ; R01 AI170239/AI/NIAID NIH HHS/United States ; P30 AI152501/AI/NIAID NIH HHS/United States ; P01 AI169606/AI/NIAID NIH HHS/United States ; T32 GM136547/GM/NIGMS NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; K24 AA022523/AA/NIAAA NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; T32 AI060530/AI/NIAID NIH HHS/United States ; P01 AI178375/AI/NIAID NIH HHS/United States ; }, abstract = {The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority.[1] Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models,[2-7] but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.}, }
@article {pmid40164700, year = {2025}, author = {Feng, EM and Vo-Phamhi, J and Subramanian, AN and Dias, M and Foye, A and Vinson, J and Hong, JC and Freedland, SJ and Alumkal, JJ and Beltran, H and Morrissey, C and Nelson, PS and Chinnaiyan, AM and Aggarwal, R and Small, EJ and Quigley, DA and Sjöström, M and Zhao, SG and Chen, WS}, title = {Racial variation in the advanced prostate cancer genome.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {40164700}, issn = {1476-5608}, abstract = {BACKGROUND: Racial differences in metastatic castration-resistant prostate cancer (mCRPC) genomes have not yet been fully studied. We aimed to investigate transcriptomic, mutational, and clinical differences by race in a large multi-institutional cohort of men with mCRPC.
METHODS: Genomic and clinicopathologic data from four mCRPC tumor biopsy cohorts were obtained and aggregated. Gene set enrichment analyses were performed to assess pathway-level differences in gene expression by patient race. DNA alteration frequencies of known prostate cancer driver genes and clinical outcomes were compared across racial groups.
RESULTS: In our cohort of 445 men with mCRPC, tumors from African American patients (N = 26) demonstrated higher expression of MYC pathway genes (FDR q = 0.03) and lower expression of IFN-γ, IL-6/JAK/STAT3, and inflammatory pathway genes (FDR q < 0.001) compared to tumors from European American patients. TMPRSS2:ERG gene fusions were observed more frequently in tumors from European American compared to African American patients (41% vs. 11%, P = 0.015). Asian patients (N = 9) and other racial groups comprised a small minority of our cohort. No differences in overall survival were noted across racial groups.
CONCLUSIONS: Despite demonstrating similar clinical outcomes, cancers from African Americans display distinct tumor biology. Specifically, we observed racial differences in expression of prostate cancer driver gene pathways (including potential clinically actionable pathways of IFN-γ and JAK/STAT) and DNA alterations, including TMPRSS2:ERG gene fusion. Our findings highlight the importance of racial diversity in future genomic profiling and clinical trials efforts.}, }
@article {pmid40163891, year = {2025}, author = {Shasha, C and Glass, DR and Moelhman, E and Islas, L and Tian, Y and Chour, T and Xu, G and Szeto, GL and Peng, T and Song, X and Wurscher, M and Cowan, AJ and Bumol, TF and Torgerson, TR and Greenberg, PD and Green, DJ and Newell, EW}, title = {Hallmarks of T-cell exhaustion and antigen experience are absent in multiple myeloma from diagnosis to maintenance therapy.}, journal = {Blood}, volume = {145}, number = {26}, pages = {3113-3123}, doi = {10.1182/blood.2024025655}, pmid = {40163891}, issn = {1528-0020}, mesh = {Humans ; *Multiple Myeloma/immunology/therapy/diagnosis/pathology ; *CD8-Positive T-Lymphocytes/immunology/pathology ; Lymphocyte Activation ; Male ; Female ; Middle Aged ; *Antigens, Neoplasm/immunology ; Aged ; T-Cell Exhaustion ; }, abstract = {Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding antitumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T-cell exhaustion is not well characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8+ T-cell compartment of patients with newly diagnosed MM (NDMM) for evidence of T-cell activation and exhaustion. We applied single-cell multiomic sequencing and mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from time points spanning from diagnosis to induction therapy, autologous stem cell transplant, and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in patients with NDMM, and consisted of small, nonpersistent clonotypes. We also observed an activated population with increased frequency in the PB of patients with NDMM exhibiting phenotypic and clonal features consistent with homeostatic, cytokine-driven activation. As an orthogonal measurement of T-cell exhaustion, we performed intracellular cytokine staining and found that patients with NDMM lacked functionally exhausted T cells. In summary, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or antigen-driven activation/expansion in patients with NDMM at any time point.}, }
@article {pmid40163754, year = {2025}, author = {Zähringer, A and Morgado, I and Erny, D and Ingelfinger, F and Gawron, J and Chatterjee, S and Wenger, V and Schmidt, D and Schwöbel, L and Adams, RC and Langenbach, M and Hartmann, A and Osswald, N and Wolf, J and Schlunck, G and Briquez, PS and Grueter, K and Ruess, DA and Frew, I and Burk, AC and Holzmüller, V and Grimbacher, B and Michonneau, D and Andrieux, G and Socié, G and Kolter, J and Boerries, M and Follo, M and Blaeschke, F and Sevenich, L and Prinz, M and Zeiser, R and Vinnakota, JM}, title = {AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.}, journal = {Blood advances}, volume = {9}, number = {12}, pages = {2935-2952}, pmid = {40163754}, issn = {2473-9537}, mesh = {*Receptors, Aryl Hydrocarbon/metabolism/agonists ; *Microglia/metabolism/pathology/drug effects ; Animals ; *Graft vs Host Disease/metabolism/etiology/pathology ; *NF-kappa B/metabolism ; Mice ; *Signal Transduction/drug effects ; Humans ; Hematopoietic Stem Cell Transplantation/adverse effects ; *Central Nervous System/metabolism/pathology ; Male ; Disease Models, Animal ; Female ; }, abstract = {Acute graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). Most patients who have undergone allo-HCT receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglial morphology shifted toward a highly branched phenotype. Consistent with a proinflammatory phenotype, the microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived aryl hydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of the primary microglia with the AhR ligand 6-formylindolo(3,2-b)carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR ligand FICZ treatment. Moreover, the AhR ligand indole-3-acetate was also reduced in the CNS of patients who developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR ligands resulted in increased microglial activation in CNS GVHD. FICZ treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS GVHD in vivo.}, }
@article {pmid40163689, year = {2025}, author = {Punie, K and Kurian, AW and Ntalla, I and Sjekloca, N and Estrin, A and Dabrowski, EC and Lai, C and Hurvitz, S}, title = {Unmet need for previously untreated metastatic triple-negative breast cancer: a real-world study of patients diagnosed from 2011 to 2022 in the United States.}, journal = {The oncologist}, volume = {30}, number = {3}, pages = {}, pmid = {40163689}, issn = {1549-490X}, support = {//Gilead Sciences/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy/pathology/mortality/epidemiology ; Female ; Middle Aged ; United States/epidemiology ; Retrospective Studies ; Aged ; Adult ; Neoplasm Metastasis ; }, abstract = {BACKGROUND: This real-world study describes the treatment landscape evolution after targeted therapy approval and associated survival outcomes for previously untreated metastatic triple-negative breast cancer (mTNBC) in the United States.
PATIENTS AND METHODS: This retrospective analysis used de-identified electronic health record-derived data of patients diagnosed with mTNBC (January 2011-July 2022; index date was first-line [1L] treatment start date). Patient characteristics, treatment patterns, real-world overall survival (rwOS), and time to next treatment or death (TTNTD) were determined. Outcomes before (2011-2017, early cohort) and after (2018-2022, late cohort) targeted therapy approval were evaluated.
RESULTS: Among 2004 eligible patients, 21% were classified as Black, 13% had Eastern Cooperative Oncology Group performance status ≥2, and 63% were diagnosed with recurrent disease; median age was 60 years. First-line chemotherapy-only (single- and multiple-agent chemotherapy) use decreased with the introduction of targeted therapies from 96% before 2018 to 65% between 2019 and 2022. From 2019, 33% of patients received programmed death-(ligand) 1 inhibitor-based regimen; ~2% received poly (ADP-ribose) polymerase inhibitors. Median 1L treatment duration was 2.6 months and this did not change over time. Of all 1L patients, 34% died before second-line (2L) and 51% subsequently received 2L treatment. Median (95% CI) 1L rwOS and TTNTD were 11.3 (10.7-12.0) months and 4.3 (4.1-4.6) months, respectively. Median 1L 5-year survival [95% CI] showed statistically significant but small improvement from the early (10.9 [10.3-11.6] months) to late cohort (11.9 [10.7-13.1] months; HR [95% CI], 0.87 [0.78-0.96]).
CONCLUSION: This analysis demonstrated that, despite changes in care over time, survival improvements were not clinically meaningful; thus, a substantial unmet need for more efficacious treatments in previously untreated patients with mTNBC remains.}, }
@article {pmid40163550, year = {2025}, author = {Shinde, P and Willemsen, L and Anderson, M and Aoki, M and Basu, S and Burel, JG and Cheng, P and Ghosh Dastidar, S and Dunleavy, A and Einav, T and Forschmiedt, J and Fourati, S and Garcia, J and Gibson, W and Greenbaum, JA and Guan, L and Guan, W and Gygi, JP and Ha, B and Hou, J and Hsiao, J and Huang, Y and Jansen, R and Kakoty, B and Kang, Z and Kobie, JJ and Kojima, M and Konstorum, A and Lee, J and Lewis, SA and Li, A and Lock, EF and Mahita, J and Mendes, M and Meng, H and Neher, A and Nili, S and Olsen, LR and Orfield, S and Overton, JA and Pai, N and Parker, C and Qian, B and Rasmussen, M and Reyna, J and Richardson, E and Safo, S and Sorenson, J and Srinivasan, A and Thrupp, N and Tippalagama, R and Trevizani, R and Ventz, S and Wang, J and Wu, CC and Ay, F and Grant, B and Kleinstein, SH and Peters, B}, title = {Putting computational models of immunity to the test-An invited challenge to predict B.pertussis vaccination responses.}, journal = {PLoS computational biology}, volume = {21}, number = {3}, pages = {e1012927}, pmid = {40163550}, issn = {1553-7358}, support = {U01 AI141995/AI/NIAID NIH HHS/United States ; U01 AI150753/AI/NIAID NIH HHS/United States ; U01 AI187062/AI/NIAID NIH HHS/United States ; U19 AI142742/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Pertussis Vaccine/immunology ; *Whooping Cough/prevention & control/immunology ; *Bordetella pertussis/immunology ; Computer Simulation ; Computational Biology/methods ; Vaccination ; Algorithms ; *Models, Immunological ; }, abstract = {Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.}, }
@article {pmid40162984, year = {2025}, author = {Lin, LY and Ferte, T and Chachage, M and Casteano, C and Laumond, G and Schmidt, S and Tahar, O and Carapito, R and Bekker, LG and Churchyard, G and Keefer, M and Moodie, Z and Viegas, E and Geldmacher, C and Lhomme, E and Moog, C}, title = {Deciphering HIV vaccine-induced antibody response according to ethnicity.}, journal = {AIDS (London, England)}, volume = {39}, number = {8}, pages = {957-963}, pmid = {40162984}, issn = {1473-5571}, mesh = {Humans ; *AIDS Vaccines/immunology/administration & dosage ; Male ; Female ; South Africa ; *HIV Infections/prevention & control/immunology ; *HIV Antibodies/blood ; Adult ; Immunoglobulin G/blood ; United States ; Young Adult ; Ethnicity ; Adolescent ; *Antibody Formation ; Middle Aged ; }, abstract = {OBJECTIVE: One recurrent question is whether an HIV-1 preventive vaccine requires adaptation to geographic and/or ethnicity background. A recent attempt to improve the Thai RV144 vaccine efficacy in South Africa resulted in nonefficacy. The potential reasons for this disappointing outcome are probably multifactorial; the role of ethnicity could not be investigated given the trials' demographics.
DESIGN: To assess the role of ethnicity in the immune responses induced in HIV vaccine trials, we considered the HVTN 204 vaccine trial, which was conducted in the USA and South Africa.
METHODS: Univariate and multivariate analysis of antibody responses were conducted to assess ethnicity, geographic location, Fc-receptor polymorphism, sex at birth, age and geographic location.
RESULTS: We found that Black South Africans displayed higher total immunoglobulins compared to White Americans. Noteworthy, Black South Africans showed lower HIV-specific binding immunoglobulin G (IgG) following vaccination. As they also showed lower background at baseline, differences between ethnic groups were narrowed after baseline background subtraction, referred to as delta values for the vaccine response outcome.
CONCLUSION: The observed modifications of HIV-specific antibody immune responses to the HVTN 204 vaccine according to genetic, geographic location and ethnic background warrants further investigation. Additional studies of immunological differences, especially with vaccine platforms inducing high HIV-specific antibodies that correlate with vaccine efficacy may help decipher the impact of ethnicity on HIV-vaccine efficacy.}, }
@article {pmid40162676, year = {2025}, author = {Wang, HH and Ono, Y and Paulson, TG and Grady, WM and Odze, RD}, title = {Gastric (Foveolar) Dysplasia in Barrett's Esophagus: A Clinical, Molecular and Long-Term Outcome Study.}, journal = {The American journal of gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.14309/ajg.0000000000003450}, pmid = {40162676}, issn = {1572-0241}, abstract = {BACKGROUND AND AIMS: The aim of this long-term progression study was to evaluate the clinical and pathologic features of gastric type dysplasia in Barrett's esophagus (BE).
METHODS: Baseline biopsies from 208 BE patients from the Seattle prospective cohort were evaluated for the type and grade of dysplasia (gastric or intestinal). Twenty-seven patients progressed to cancer and 181 did not over the long term follow up period. Patients with gastric or intestinal dysplasia were compared to each other with regard to their flow cytometric DNA content abnormalities and progression rates to cancer.
RESULTS: Of the 59 patients with dysplasia at baseline, 12 (20%) had gastric dysplasia only, 24 (41%) had mixed gastric and intestinal dysplasia, and 23 (39%) had intestinal dysplasia only. Patients with any gastric dysplasia component (alone or mixed with intestinal dysplasia) showed a significantly higher rate of high-grade dysplasia (72% vs 23%, P < 0.001) at baseline and cancer development (47% versus 22%, P = 0.05), and a significantly shorter time frame to cancer development (32 versus 64 months, P = 0.008), as well as a longer BE segment length (P = 0.05), and higher rate of aneuploidy (P = 0.04), compared to patients with pure intestinal dysplasia. By multivariable analysis, gastric dysplasia showed a higher hazard ratio of progression to cancer compared to intestinal dysplasia patients.
CONCLUSION: Gastric type dysplasia is common in BE. Our study suggests that this type of dysplasia may represent a more aggressive form of neoplastic precursor than conventional intestinal type dysplasia.}, }
@article {pmid40161829, year = {2025}, author = {Agrawal, P and Khechaduri, A and Salladay, KR and MacCamy, A and Ralph, DK and Riker, A and Stuart, AB and Siddaramaiah, LK and Shen, X and Matsen, FA and Montefiori, D and Stamatatos, L}, title = {Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-class antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161829}, issn = {2692-8205}, support = {HHSN272201800004C/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI143370/AI/NIAID NIH HHS/United States ; P01 AI138212/AI/NIAID NIH HHS/United States ; R01 AI177095/AI/NIAID NIH HHS/United States ; }, abstract = {Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be a key component of an effective HIV-1 vaccine. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-class antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.}, }
@article {pmid40161767, year = {2025}, author = {Vinueza, JL and Salisbury, NJH and Dye, KN and Roman, A and Galloway, DA}, title = {Delta-catenin is required for cell proliferation in virus positive Merkel cell carcinoma cell lines but not in human fibroblasts.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161767}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast, cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that LSD1 (KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.}, }
@article {pmid40161760, year = {2025}, author = {Simonich, CAL and McMahon, TE and Ju, X and Yu, TC and Brunette, N and Stevens-Ayers, T and Boeckh, MJ and King, NP and Greninger, AL and Bloom, JD}, title = {RSV F evolution escapes some monoclonal antibodies but does not strongly erode neutralization by human polyclonal sera.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161760}, issn = {2692-8205}, support = {K12 HD000850/HD/NICHD NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI181767/AI/NIAID NIH HHS/United States ; }, abstract = {Vaccines and monoclonal antibodies targeting the respiratory syncytial virus (RSV) fusion protein (F) have recently begun to be widely used to protect infants and high-risk adults. Some other viral proteins evolve to erode polyclonal antibody neutralization and escape individual monoclonal antibodies. However, little is known about how RSV F evolution affects antibodies. Here we develop an experimental system for measuring neutralization titers against RSV F using pseudotyped lentiviral particles. This system is easily adaptable to evaluate neutralization of relevant clinical strains. We apply this system to demonstrate that natural evolution of RSV F leads to escape from some monoclonal antibodies, but at most modestly affects neutralization by polyclonal serum antibodies. Overall, our work sheds light on RSV antigenic evolution and describes a tool to measure the ability of antibodies and sera to neutralize contemporary RSV strains.}, }
@article {pmid40161702, year = {2025}, author = {Kikawa, C and Loes, AN and Huddleston, J and Figgins, MD and Steinberg, P and Griffiths, T and Drapeau, EM and Peck, H and Barr, IG and Englund, JA and Hensley, SE and Bedford, T and Bloom, JD}, title = {High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40161702}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ~10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.}, }
@article {pmid40161544, year = {2025}, author = {Safyan, RA and Zhang, K and Apisarnthanarax, S and Sham, JG and Pillarisetty, VG and Kugel, S and Dubard-Gault, M and Pritchard, CC and Konnick, EQ and Sahani, D and Chiorean, EG}, title = {Long-Term Survival Following Chemoradiation in Locoregional Recurrent Germline ATM Mutated Pancreatic Ductal Adenocarcinoma.}, journal = {Advances in radiation oncology}, volume = {10}, number = {4}, pages = {101742}, pmid = {40161544}, issn = {2452-1094}, }
@article {pmid40161439, year = {2025}, author = {Andrade Latino, A and Biggins, S}, title = {Analysis of a cancer-associated mutation in the budding yeast Nuf2 kinetochore protein.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40161439}, issn = {2578-9430}, abstract = {The kinetochore is a highly conserved megadalton protein complex that ensures proper chromosome segregation via microtubule attachments. The NDC80 complex is one of the major conserved microtubule binding complexes in the kinetochore. NUF2, a protein within the NDC80 complex, has been identified as a cancer gene candidate because missense mutations, found across different tumor samples, cluster within NUF2's calponin homology domain. In this study, we examined a NUF2 cancer-associated mutation in a simple and well-studied organism, Saccharomyces cerevisiae , to elucidate its effects on cell division. We studied the budding yeast nuf2 [Q21A] mutation with the intention of extrapolating our results to the homologous cancer associated mutation in Homo sapiens NUF2 [R19H] (HsNUF2 [R19H]). Our studies demonstrate that the nuf2 [Q21A] mutant does not exhibit any growth defects or disrupt kinetochore composition. Additionally, it does not affect the Ndc80 complex's interactions with the Dam1 complex or with the Mps1 kinase. These results indicate that the yeast nuf2 [Q21A] mutant does not cause a significant defect in kinetochore function, and that the role of HsNUF2 [R19H] in cancer will need to be further investigated by directly studying the cancer-associated mutation in human cells.}, }
@article {pmid40160342, year = {2025}, author = {Haas, AL and Ma, A and Pham, J and Verma, P and Malhotra, U and Church, EC and Narita, M and Escuyer, V and Shakir, SM}, title = {Limitations of the MTB/RIF Assay: An Xpert Review of 4 Clinical Cases.}, journal = {Open forum infectious diseases}, volume = {12}, number = {4}, pages = {ofaf132}, pmid = {40160342}, issn = {2328-8957}, abstract = {Current U.S. Centers for Disease Control and Prevention tuberculosis (TB) guidelines recommend molecular testing for initial diagnosis of TB and detection of rifampin resistance to expedite initiation of proper treatment. The Cepheid Xpert MTB/RIF assay can detect members of the Mycobacterium tuberculosis complex and rifampin resistance by evaluating for mutations in the rpoB gene. However, false-positive and false-negative detection of M tuberculosis and rifampin resistance results can lead to incorrect treatment of patients, including overuse of second-line anti-TB drugs, and may result in patient harm and increased healthcare cost. We present a series of 4 cases to demonstrate the limitations of the Xpert MTB/RIF assay in the diagnosis of TB, emphasizing the importance of follow-up confirmatory testing and laboratory oversight in reporting accurate results.}, }
@article {pmid40159249, year = {2025}, author = {Fest, SN and Farland, LV and Doody, DR and Eliassen, AH and Rosner, BA and Fung, TT and Hankinson, SE and Kensler, TW and Willett, WC and Harris, HR}, title = {Hormone-associated dietary patterns and premenopausal breast cancer risk.}, journal = {Breast cancer research and treatment}, volume = {212}, number = {1}, pages = {23-35}, pmid = {40159249}, issn = {1573-7217}, support = {U01 CA176726/NH/NIH HHS/United States ; R01 CA67262/NH/NIH HHS/United States ; U01 CA176726/NH/NIH HHS/United States ; R01 CA67262/NH/NIH HHS/United States ; U01 CA176726/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/etiology/blood ; *Premenopause/blood ; Adult ; Risk Factors ; Middle Aged ; *Diet ; *Gonadal Steroid Hormones/blood ; Proportional Hazards Models ; }, abstract = {PURPOSE: Circulating levels of sex steroid hormones have previously been associated with premenopausal breast cancer risk. Few studies have considered the association between dietary patterns and premenopausal hormone levels. Our objective was to derive dietary patterns associated with premenopausal hormone levels and investigate the association between pattern scores and premenopausal breast cancer risk.
METHODS: Using reduced rank regression among a subset of participants from the Nurses' Health Study II (NHSII) (n = 8,962), we identified dietary patterns correlated with premenopausal levels of five sex steroid hormones measured in the follicular and luteal phases. Then, in the full NHSII cohort (n = 90,341), we used Cox proportional hazards models to calculate hazard ratios (HRs) for breast cancer risk associated with each dietary pattern score.
RESULTS: Dietary patterns were identified for luteal estradiol, luteal free estradiol, follicular estrone, luteal estrone, and free testosterone. However, these patterns explained a low percent variation in individual hormone levels, ranging from 2.5-4.1%. During 24 years of follow-up, 1,956 premenopausal breast cancer cases were ascertained. Dietary patterns associated with luteal free estradiol (HR for fifth versus first quintile = 1.29; 95% CI = 1.11-1.49; Ptrend < 0.01) and follicular estrone (HR for fifth versus first quintile = 1.28; 95% CI = 1.10-1.49; Ptrend < 0.01) were positively associated with premenopausal breast cancer risk.
CONCLUSION: Our findings indicate that while some dietary factors may marginally influence premenopausal hormone levels, the relation between sex steroid hormones and premenopausal breast cancer risk is likely not driven by diet. Future studies should consider other mechanisms through which diet may impact breast cancer risk, including inflammatory processes.}, }
@article {pmid40155649, year = {2025}, author = {Dong, S and Banerjee, R and Khan, AM and Wang, M and Wang, X and Afghahi, A and Afrough, A and Janakiram, M and Wang, B and Cowan, AJ and Sperling, AS and Anderson, LD and Rajkumar, SV and Kaur, G}, title = {Carfilzomib prescribing patterns and outcomes for relapsed or refractory multiple myeloma: a real-world analysis.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {48}, pmid = {40155649}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; *Oligopeptides/therapeutic use/administration & dosage/adverse effects ; Male ; Female ; Aged ; Middle Aged ; *Practice Patterns, Physicians' ; Aged, 80 and over ; Adult ; Treatment Outcome ; }, abstract = {Despite the widespread use of carfilzomib (K) in relapsed/refractory multiple myeloma (RRMM), there is no consensus on optimal K dose in milligrams per square meter (mg/m2) or dosing schedule. We assessed three modern K prescribing patterns in RRMM using a large United States electronic health record-derived database. Our final cohort (n = 486) included 136 patients (28.0%) who received K 56 mg/m2 once weekly (K56-1x), 86 (17.7%) who received 56 mg/m2 twice weekly (K56-2x), and 264 (54.3%) who received 70 mg/m2 once weekly (K70-1x). Between 2016 and 2023, once-weekly dosing became more common: K70-1x proportions changed from 21.1% in 2016 to 50.6% in 2023, K56-1x from 15.8% to 37.0%, and K56-2x from 63.2% to 12.3%. Median progression-free survival was 13.0 months [95% confidence interval (CI) 11.2-20.7] for K56-1x, 13.2 months (95% CI 9.0-28.1 months) for K56-2x, and 10.9 months (95% CI 9.9-15.3 months) for K70-1x; these differences were not statistically significant (log-rank p = 0.46). Rates of heart failure was comparable (<5% in all cohorts). In summary, our findings do not support improved outcomes with twice-weekly carfilzomib in RRMM. K56-1x may provide the best balance of efficacy, safety, and avoidance of time toxicity from frequent infusions.}, }
@article {pmid40155326, year = {2025}, author = {Saeed, A and Colby, S and Oberstein, PE and Duda, DG and Park, R and Agarwal, R and Figueroa-Moseley, C and Vaidya, R and Unger, JM and Guthrie, KA and Rocha, FG and Senthil, M and Safyan, RA and Wainberg, ZA and Iqbal, S and Chiorean, EG and Philip, PA}, title = {S2303: phase II/III trial of paclitaxel + ramucirumab ± nivolumab in gastric and esophageal adenocarcinoma (PARAMUNE).}, journal = {Future oncology (London, England)}, volume = {21}, number = {11}, pages = {1325-1331}, pmid = {40155326}, issn = {1744-8301}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Adenocarcinoma/drug therapy/mortality/pathology ; Antibodies, Monoclonal, Humanized/administration & dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; *Esophageal Neoplasms/drug therapy/mortality/pathology ; Nivolumab/administration & dosage ; Paclitaxel/administration & dosage/adverse effects ; Ramucirumab ; *Stomach Neoplasms/drug therapy/mortality/pathology ; }, abstract = {NCT06203600.}, }
@article {pmid40154445, year = {2025}, author = {Pierce, AL and Okcu, I and Nowakowski, G and Tolu, S and Amengual, J and Ross, C and Graber, J and Bock, A and Hu, B and Ermann, D}, title = {HSR25-185: A Multicenter Retrospective Study of Treatment and Survival Outcomes of Patients With Secondary CNS Relapsed DLBCL in the Modern Era.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3.5}, pages = {}, doi = {10.6004/jnccn.2024.7347}, pmid = {40154445}, issn = {1540-1413}, }
@article {pmid40153499, year = {2025}, author = {Page, CK and Shepard, JD and Ray, SD and Ferguson, JA and Rodriguez, AJ and Han, J and Jacob, JC and Rowe-Haas, DK and Akinpelu, JY and Friedman, LM and Hertz, T and Ward, AB and Tompkins, SM}, title = {Neuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineages.}, journal = {Science advances}, volume = {11}, number = {13}, pages = {eadu3344}, pmid = {40153499}, issn = {2375-2548}, mesh = {*Neuraminidase/immunology ; Animals ; *Antibodies, Viral/immunology ; *Cross Protection/immunology ; *Influenza B virus/immunology/classification/genetics ; Humans ; *Orthomyxoviridae Infections/immunology/virology/prevention & control ; Influenza, Human/immunology/virology ; Cross Reactions ; Mice ; }, abstract = {The two influenza B virus (FLUBV) lineages have continuously diverged from each other since the 1980s, with recent (post-2015) viruses exhibiting accelerated evolutionary rates. Emerging data from human studies and epidemiological models suggest that increased divergence in contemporary viruses may drive differential cross-protection, where infection with Yamagata lineage viruses provides limited immunity against Victoria lineage viruses. Here, we developed animal models to investigate the mechanisms behind asymmetric cross-protection between contemporary FLUBV lineages. Our results show that contemporary Victoria immunity provides robust cross-protection against the Yamagata lineage, whereas Yamagata immunity offers limited protection against the Victoria lineage. This differential cross-protection is driven by Victoria-elicited neuraminidase (NA)-specific antibodies, which show cross-lineage reactivity, unlike those from Yamagata infections. These findings identify a phenomenon in contemporary FLUBV that may help explain the recent disappearance of the Yamagata lineage from circulation, highlighting the crucial role of targeting NA in vaccination strategies to enhance cross-lineage FLUBV protection.}, }
@article {pmid40153422, year = {2025}, author = {Smibert, OC and Vogrin, S and Sinclair, M and Majumdar, A and Nasra, M and Pandey, D and Jahanabadi, H and Trubiano, JA and Markey, KA and Slavin, MA and Testro, A and Kwong, JC}, title = {Antibiotic Exposure and Risk of Allograft Rejection and Survival After Liver Transplant: An Observational Cohort Study From a Tertiary Referral Centre.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {27}, number = {3}, pages = {e70026}, pmid = {40153422}, issn = {1399-3062}, support = {1191571//National Health and Medical Research Council/ ; #1173791//National Health and Medical Research Council Leadership Investigator/ ; }, abstract = {INTRODUCTION: Our goal is to understand whether there is an association between Abx exposure-and the inferred downstream damage to the intestinal microbiome-and the key patient outcomes of overall survival and rejection following liver transplant.
METHODS: We conducted a retrospective cohort study of 462 liver transplant recipients treated at a multistate liver transplant (LTx) service during a 7-year period. The association between antibiotic exposure and outcome was tested across models that addressed antibiotic spectrum, duration, and timing relative to transplant. Cox proportional hazard regression was used to evaluate the relationship between antibiotics with survival and rejection.
RESULTS: The observed 1-year survival in this cohort was 95% (95% CI: 93%, 97%), and 20.8% of patients (96/462) experienced rejection at 1 year. In multivariable analyses, exposure to anaerobe-targeting antibiotics for longer than 14 days pretransplant (p = 0.055) or posttransplant (p = 0.040) was significantly associated with reduced 1-year survival. In multivariable analyses, exposure to any anaerobe-targeting Abx posttransplant was significantly associated with an increased risk of rejection (p = 0.001).
CONCLUSIONS: Exposure to anaerobic spectrum antibiotics either before or after LTx was associated with poor outcomes during the first year posttransplant and provides an impetus to further characterize the relationship between antibiotic use, microbiota disruption, and cellular immunity in liver transplantation.}, }
@article {pmid40153356, year = {2025}, author = {Suger, AH and Chen, H and Haas, CB and Fan, S and Scott, CG and Bolla, MK and Dennis, J and Dunning, AM and Michailidou, K and Wang, Q and Fasching, PA and Haeberle, L and Stone, J and Gago-Dominguez, M and Castelao, JE and Murphy, RA and Aronson, K and Couch, FJ and Yadav, S and Milne, RL and Hopper, JL and Norman, A and Eliassen, AH and Tapper, WJ and Eccles, DM and Evans, DG and Astley, S and Hall, P and Czene, K and Pharoah, PDP and Antoniou, AC and García-Closas, M and Berrington, A and Easton, DF and Gierach, GL and Tamimi, RM and Vachon, CM and Lindström, S and Harrison, TA}, title = {Interactions Between Genetic and Epidemiological Factors Influencing Mammographic Density.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaf067}, pmid = {40153356}, issn = {1476-6256}, abstract = {Studies have identified genetic and epidemiological factors associated with mammographic density (MD) phenotypes. However, MD-associated genetic variants only account for a small proportion of the total estimated heritability. Interrogating interactions between genetic and epidemiological factors could potentially identify additional MD-associated loci, expand our understanding of the genetic basis of MD phenotypes, and clarify how epidemiological factors modulate relationships between genetic variants and MD. We conducted six separate genome-wide, gene-environment (GxE) interaction analyses, applying 2 degrees of freedom (df) and 1df interaction tests, for each of three MD phenotypes (percent density (PD), dense area (DA), and non-dense area (NDA)). The six epidemiological factors considered were height, ever parous, parity, ever menopausal hormone therapy (MHT), ever breastfeeding, and months of breastfeeding. We included European ancestry participants from multiple studies within the Markers of Density (MODE) consortium and the Breast Cancer Association Consortium (BCAC) (n = 4,895 - 16,218 depending on specific analyses). We identified 11 loci with genome-wide significant (P < 5 × 10-8) interaction tests including two novel common genetic signals interacting with parity (8p21.2) and ever breastfeeding (19p13.2) for NDA. Our results suggest that epidemiological risk factors might influence relationships between common genetic variants and MD phenotypes at particular genomic loci.}, }
@article {pmid40152978, year = {2025}, author = {Orenduff, MC and Pieper, CF and Allott, EH and Coleman, MF and Jung, SY and Vitolins, MZ and Fenton, JI and Chen, C and Kroenke, CH and Tabung, FK and Barac, A and Paskett, ED and Pollak, MN and Hays-Grudo, J and Chang, S and Hursting, SD}, title = {Plasma Insulin-like Growth Factor-Binding Protein-7 Is Positively Associated with Age, Obesity, Mortality, and Cancer in Postmenopausal Women.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {6}, pages = {922-932}, doi = {10.1158/1055-9965.EPI-24-1644}, pmid = {40152978}, issn = {1538-7755}, support = {R35CA197627//National Cancer Institute (NCI)/ ; R21CA086036//National Cancer Institute (NCI)/ ; P30AG028716//National Institute on Aging (NIA)/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Obesity/blood/mortality/complications ; *Postmenopause/blood ; Middle Aged ; Aged ; *Insulin-Like Growth Factor Binding Proteins/blood ; Insulin-Like Growth Factor I/analysis/metabolism ; *Neoplasms/blood/mortality ; Longitudinal Studies ; Age Factors ; Risk Factors ; Biomarkers, Tumor/blood ; Body Mass Index ; Insulin-Like Peptides ; }, abstract = {BACKGROUND: Predictors of premature death and cancer development are needed to more precisely identify individuals who may warrant preventive intervention. Circulating insulin-like growth factor (IGF)-binding protein-7 (IGFBP7) and, to a lesser extent, the IGFBP7/IGF-1 ratio are emerging biomarkers of renal and cardiovascular morbidity. However, their relationships with aging, obesity, mortality, and cancer risk remain unclear.
METHODS: This hypothesis-generating study investigated plasma IGFBP7, IGF-1, and their ratio as predictors of all-cause mortality and the incidence of any cancer (excluding nonmelanoma skin cancer), obesity-related cancer (composite of 13 cancer types), and breast cancer in a large longitudinal cohort of postmenopausal women. We assessed the relationships of each biomarker with age, body mass index, and each outcome (bivariately and controlling for age, body mass index, race, physical activity, education, income, marital status, alcohol intake, smoking, diabetes, and hormone therapy) in 793 Women's Health Initiative Observational Study participants (mean, 19.4-year follow-up).
RESULTS: In adjusted analyses, IGFBP7 increased with age and obesity and was positively associated with risks of all-cause mortality [HR = 2.42 (95% confidence interval, 1.37-4.26); P = 0.002], any cancer [HR = 2.04 (1.05-3.94); P = 0.035], and obesity-related cancer [HR = 1.58 (0.99-2.51); P = 0.053]. Also in adjusted analyses, the IGFBP7/IGF-1 ratio increased with age and was positively associated with all-cause mortality [HR = 1.51 (1.14-1.99); P = 0.004] and any cancer incidence [HR = 5.44 (1.13-26.1); P = 0.034].
CONCLUSIONS: Plasma IGFBP7 and the IGFBP7/IGF-1 ratio are positively associated with age, obesity (IGFBP7 only), mortality, and cancer in postmenopausal women.
IMPACT: Plasma IGFBP7 may represent an age- and obesity-sensitive biomarker of increased risk of developing cancer and/or dying prematurely.}, }
@article {pmid40151933, year = {2025}, author = {Wang, X and Singh, P and Cejas, RB and Zhou, L and Sharafeldin, N and Trainor, PJ and Landier, W and Cheng, C and Hageman, L and Wang, F and Sapkota, Y and Yasui, Y and Hudson, MM and Chow, EJ and Armenian, SH and Neglia, JP and Hawkins, DS and Ginsberg, JP and Burridge, PW and Armstrong, GT and Bhatia, S}, title = {DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children's Oncology Group and the Childhood Cancer Survivor Study.}, journal = {Circulation. Genomic and precision medicine}, volume = {18}, number = {2}, pages = {e004813}, pmid = {40151933}, issn = {2574-8300}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; UG3 HG013615/HG/NHGRI NIH HHS/United States ; R01 CA139633/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; R35 CA220502/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U10 CA095861/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Anthracyclines/adverse effects ; Child ; Female ; Male ; *Cancer Survivors ; *DNA Repair/genetics ; *Cardiomyopathies/chemically induced/genetics/pathology ; Adolescent ; *DNA Damage ; Child, Preschool ; Case-Control Studies ; *Neoplasms/drug therapy/genetics ; Myocytes, Cardiac/drug effects/metabolism ; }, abstract = {BACKGROUND: Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.
METHODS: We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.
RESULTS: Successfully replicated DDR genes demonstrating main-effect association included FANCC (P=0.037) and XRCC5 (P=0.001) and demonstrated gene-anthracycline interaction included MGMT (P=0.041). Knockouts of FANCC and MGMT in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (P=2.7×10[-4]); role of BRCA1 in DDR (P=9.2×10[-5]); p53 signaling (P<1×10[-16]); role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10[-16]); mismatch repair (P<10[-16]); and double-strand break repair by homologous recombination (P<1×10[-16]). Successfully replicated DDR pathways demonstrating significant interaction effects included role of BRCA1 in DDR (P=1.4×10[-4]); p53 signaling (P<1×10[-16]); the role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10[-16]); mismatch repair (P<1×10[-16]); cell cycle: G2/M DNA damage checkpoint regulation (P=0.002); double-strand break repair by homologous recombination (P=0.009); GADD45 signaling (P=4.8×10[-4]); and cell cycle control of chromosomal replication (P=4.5×10[-4]).
CONCLUSIONS: These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.}, }
@article {pmid40147465, year = {2025}, author = {Luetkemeyer, AF and Donnell, D and Cohen, SE and Dombrowski, JC and Grabow, C and Haser, G and Brown, C and Cannon, C and Malinski, C and Perkins, R and Nasser, M and Lopez, C and Suchland, RJ and Vittinghoff, E and Buchbinder, SP and Scott, H and Charlebois, ED and Havlir, DV and Soge, OO and Celum, C}, title = {Doxycycline to prevent bacterial sexually transmitted infections in the USA: final results from the DoxyPEP multicentre, open-label, randomised controlled trial and open-label extension.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(25)00085-4}, pmid = {40147465}, issn = {1474-4457}, abstract = {BACKGROUND: Doxycycline post-exposure prophylaxis (doxy-PEP) is a promising intervention to reduce bacterial sexually transmitted infections (STIs). We evaluated the effect of doxy-PEP on STI incidence and antimicrobial resistance in men who have sex with men and transgender women for up to 12 months of follow-up, inlcuding an open-label extension.
METHODS: DoxyPEP, an open-label trial in Seattle (WA, USA) and San Francisco (CA, USA) among men who have sex with men and transgender women with at least one bacterial STI in the past year, randomly assigned participants by clinic (with computer-generated variable block sizes) 2:1 to doxy-PEP (200 mg doxycycline delayed-release tablets 24-72 h after condomless sex) or standard care. The independent endpoint adjudication committee was masked to group assignment. The primary outcome was presence of one or more bacterial STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, or early syphilis) each quarter. This outcome was assessed in the modified intention-to-treat cohort, which included participants with at least one follow-up quarter (ie, ∼3 months) in their as-randomised assignment. After early termination of the randomised phase for efficacy, all participants still enrolled were offered doxy-PEP in an open-label extension (OLE). We report quarterly incidence of bacterial STIs for the as-randomised and OLE periods. Safety was assessed in all participants with any follow-up data. The trial was registered with ClinicalTrials.gov (NCT03980223) and is completed.
FINDINGS: From Aug 19, 2020, to May 13, 2022, we enrolled 637 participants; 592 participants completed at least one follow-up quarter in the randomised phase (411 in the doxy-PEP group and 181 in the standard-care group) and 282 in the OLE phase (207 in the doxy-PEP group and 82 in the standard-care group). STIs were present in 129 (12·0%) of 1077 quarters in the doxy-PEP group versus 139 (30·5%) of 455 quarters in the standard-care group during the as-randomised period, showing an absolute difference of 19 percentage points and a relative risk of 0·39 (95% CI 0·31-0·49, p<0·0001). During the OLE, STIs were diagnosed in 51 (13%) of 388 quarters among those continuing doxy-PEP and 25 (17%) of 145 quarters among standard-care participants who initiated doxy-PEP. Throughout all quarters for participants on doxy-PEP, there was one grade 2 laboratory abnormality and five grade 3 adverse events that were possibly or probably related to doxy-PEP. No serious adverse events were attributed by site investigators to doxycycline. Of participants with positive gonorrhoea cultures during the study, eight (27%) of 29 taking doxy-PEP versus five (24%) of 21 not taking doxy-PEP had tetracycline resistance (minimum inhibitory concentration ≥2 μg/mL).
INTERPRETATION: Doxy-PEP was effective in reducing bacterial STIs in this population of men who have sex with men and transgender women, including during an open-label extension when doxy-PEP efficacy was known. Doxy-PEP was well tolerated, highly acceptable, and with no new safety signals.
FUNDING: US National Institutes of Health.}, }
@article {pmid40147439, year = {2025}, author = {Dubocanin, D and Hartley, GA and Sedeño Cortés, AE and Mao, Y and Hedouin, S and Ranchalis, J and Agarwal, A and Logsdon, GA and Munson, KM and Real, T and Mallory, BJ and Eichler, EE and Biggins, S and O'Neill, RJ and Stergachis, AB}, title = {Conservation of dichromatin organization along regional centromeres.}, journal = {Cell genomics}, volume = {5}, number = {4}, pages = {100819}, pmid = {40147439}, issn = {2666-979X}, mesh = {*Centromere/metabolism/genetics ; Humans ; *Chromatin/metabolism/genetics ; Kinetochores/metabolism ; Animals ; Centromere Protein B/metabolism/genetics ; Nucleosomes/metabolism/genetics ; DNA, Satellite/genetics ; }, abstract = {The attachment of the kinetochore to the centromere is essential for genome maintenance, yet the highly repetitive nature of satellite regional centromeres limits our understanding of their chromatin organization. We demonstrate that single-molecule chromatin fiber sequencing (Fiber-seq) can uniquely co-resolve kinetochore and surrounding chromatin architectures along point centromeres, revealing largely homogeneous single-molecule kinetochore occupancy. In contrast, the application of Fiber-seq to regional centromeres exposed marked per-molecule heterogeneity in their chromatin organization. Regional centromere cores uniquely contain a dichotomous chromatin organization (dichromatin) composed of compacted nucleosome arrays punctuated with highly accessible chromatin patches. CENP-B occupancy phases dichromatin to the underlying alpha-satellite repeat within centromere cores but is not necessary for dichromatin formation. Centromere core dichromatin is conserved between humans and primates, including along regional centromeres lacking satellite repeats. Overall, the chromatin organization of regional centromeres is defined by marked per-molecule heterogeneity, buffering kinetochore attachment against sequence and structural variability within regional centromeres.}, }
@article {pmid40146127, year = {2025}, author = {Lee, CI and Lowry, KP}, title = {Identifying Who Is at Risk of Interval Breast Cancers.}, journal = {JAMA oncology}, volume = {11}, number = {5}, pages = {527-528}, doi = {10.1001/jamaoncol.2025.0101}, pmid = {40146127}, issn = {2374-2445}, }
@article {pmid40146038, year = {2025}, author = {Unger, JM and McAneny, BL and Osarogiagbon, RU}, title = {Cancer in rural America: Improving access to clinical trials and quality of oncologic care.}, journal = {CA: a cancer journal for clinicians}, volume = {75}, number = {4}, pages = {341-361}, pmid = {40146038}, issn = {1542-4863}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; UG1CA189974//National Institutes of Health, National Cancer Institute/ ; 5U10CA180819//National Institutes of Health, National Cancer Institute/ ; }, mesh = {Humans ; *Health Services Accessibility ; *Neoplasms/therapy/epidemiology ; United States/epidemiology ; *Quality of Health Care ; *Rural Population ; *Clinical Trials as Topic ; *Rural Health Services ; Healthcare Disparities ; *Medical Oncology/standards ; Socioeconomic Factors ; }, abstract = {Individuals from rural areas in the United States suffer higher rates of morbidity and mortality from cancer than their urban counterparts. This review is based on the idea that equity-the elimination of unnecessary and preventable differences between groups of individuals-should underlie access to cancer care resources for patients from rural areas. Access to cancer clinical trials serves as the framework for identifying and understanding barriers in access to quality oncologic care. The authors discuss the interplay between rural living, socioeconomic status, culture, and health; and they highlight how economic considerations in rural areas often limit access to clinical trials and oncologic care because economies of scale do not apply in these regions given the requirement for high-quality oncology care even with lower patient volumes. The authors propose solutions to enhance access to clinical trials and improve the quality of oncologic care in rural areas, viewing these aims as ethical and moral imperatives.}, }
@article {pmid40141440, year = {2025}, author = {Germain, A and Jaycox, JR and Emig, CJ and Ring, AM and Hanson, MR}, title = {An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141440}, issn = {1422-0067}, support = {U54NS105541/GF/NIH HHS/United States ; U54AI178855/GF/NIH HHS/United States ; UL1 TR 002384/GF/NIH HHS/United States ; 3P30CA016359-40S4//Yale Cancer Center Support/ ; DP5OD023088/GF/NIH HHS/United States ; T32GM007205//Yale Medical Scientist Training Program/ ; }, mesh = {Humans ; *Autoantibodies/immunology/blood ; Female ; Male ; *Fatigue Syndrome, Chronic/immunology ; Adult ; Middle Aged ; *Autoantigens/immunology ; }, abstract = {Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology. Expanding on previous studies, we analyzed 7542 antibody-antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins. Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration.}, }
@article {pmid40140386, year = {2025}, author = {Beddows, I and Djirackor, S and Omran, DK and Jung, E and Shih, NN and Roy, R and Hechmer, A and Olshen, A and Adelmant, G and Tom, A and Morrison, J and Adams, M and Rohrer, DC and Schwartz, LE and Pearce, CL and Auman, H and Marto, JA and Drescher, CW and Drapkin, R and Shen, H}, title = {Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2981}, pmid = {40140386}, issn = {2041-1723}, mesh = {Humans ; Female ; *Fallopian Tubes/metabolism/surgery/pathology ; *BRCA1 Protein/genetics/metabolism ; *BRCA2 Protein/genetics ; Middle Aged ; Ovarian Neoplasms/genetics/surgery/pathology ; Adult ; Phenotype ; *Fallopian Tube Neoplasms/genetics/surgery/pathology/metabolism ; Epigenesis, Genetic ; Age Factors ; Germ-Line Mutation ; Mutation ; Aged ; Proteomics ; }, abstract = {The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer.}, }
@article {pmid40139185, year = {2025}, author = {Tenthorey, JL and Del Banco, S and Ramzan, I and Klingenberg, H and Liu, C and Emerman, M and Malik, HS}, title = {Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations.}, journal = {Cell genomics}, volume = {5}, number = {6}, pages = {100818}, pmid = {40139185}, issn = {2666-979X}, mesh = {*Mutation, Missense/genetics ; Humans ; Animals ; *INDEL Mutation/genetics ; *Simian Immunodeficiency Virus/genetics/immunology ; *Evolution, Molecular ; Tripartite Motif Proteins/genetics ; Ubiquitin-Protein Ligases ; *Antiviral Agents/metabolism ; Amino Acid Sequence ; }, abstract = {Antiviral proteins often evolve rapidly at virus-binding interfaces to defend against new viruses. We investigated whether antiviral adaptation via missense mutations might face limits, which insertion or deletion mutations (indels) could overcome. Using high-throughput saturation missense mutagenesis, we identify one such case of a nearly insurmountable evolutionary challenge: the human anti-retroviral protein TRIM5α requires more than five missense mutations in its specificity-determining v1 loop to restrict a divergent simian immunodeficiency virus (SIV). However, through a novel saturating indel scanning methodology, we find that duplicating just one amino acid in v1 enables human TRIM5α to potently restrict SIV in a single evolutionary step. Moreover, natural primate TRIM5α v1 loops have evolved indels that confer novel antiviral specificities. Thus, indels enable antiviral proteins to overcome viral challenges otherwise inaccessible by missense mutations. Our findings reveal the potential of often-overlooked indel mutations in driving protein innovation.}, }
@article {pmid40138611, year = {2025}, author = {Aggarwal, RR and Vuky, J and VanderWeele, D and Rettig, M and Heath, EI and Quigley, D and Huang, J and Chumber, A and Cheung, A and Foye, A and Leung, S and Abbey, J and Dorr, A and Nasoff, M and Hunter, J and Wang, S and Flavell, RR and Fong, L and Liu, B and Small, EJ}, title = {Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {15}, pages = {1824-1834}, pmid = {40138611}, issn = {1527-7755}, support = {R35 CA253175/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/immunology/pathology ; Aged ; Middle Aged ; *Immunoconjugates/adverse effects/therapeutic use/administration & dosage/pharmacokinetics ; Maximum Tolerated Dose ; Aged, 80 and over ; Progression-Free Survival ; *Oligopeptides/adverse effects/administration & dosage/therapeutic use ; }, abstract = {PURPOSE: FOR46, a fully human antibody conjugated to monomethyl auristatin E, targets a tumor-selective epitope of CD46, which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). FOR46 demonstrates potent nonclinical activity in enzalutamide-resistant CRPC models.
PATIENTS AND METHODS: This was a phase I, first-in-human, dose escalation/expansion study in patients with progressive mCRPC after treatment with ≥one androgen signaling inhibitors (ClinicalTrials.gov identifier: NCT03575819). The starting dose of FOR46 was 0.1 mg/kg given intravenously every 3 weeks. The primary objective was to determine the maximally tolerated dose (MTD). Whole-blood mass cytometry (cytometry by time of flight) was used to characterize peripheral immune response and CD46 expression in CRPC tissue that underwent central pathology review.
RESULTS: Fifty-six patients were enrolled. Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). The MTD was 2.7 mg/kg using adjusted body weight. The most common grade ≥3 adverse events across all dose levels were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). One grade 3 febrile neutropenia event was observed. There were no treatment-related deaths. In the efficacy evaluable subset (patients with adenocarcinoma treated with a starting dose ≥1.2 mg/kg, n = 40), the median radiographic progression-free survival was 8.7 months (range, 0.1-33.9). Fourteen of 39 evaluable patients (36%) achieved a PSA50 response. The confirmed objective response rate was 20% (5 of 25 RECIST-evaluable patients). The median duration of response was 7.5 months. Responders had a significantly higher on-treatment frequency of circulating effector CD8[+] T cells.
CONCLUSION: FOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.}, }
@article {pmid40138497, year = {2025}, author = {Jana, S and Glabman, RA and Koehne, AL}, title = {Bridging the gap between histopathology and genomics: Spotlighting spatial omics.}, journal = {Veterinary pathology}, volume = {}, number = {}, pages = {3009858251322729}, doi = {10.1177/03009858251322729}, pmid = {40138497}, issn = {1544-2217}, abstract = {Spatial biology has emerged as a transformative field, offering insights into cellular interactions and organization within tissues. The field has evolved rapidly since the coining of the term "spatial omics." Now, the ability to spatially resolve proteins, RNA, chromatin, and lipids is becoming widespread, and the technologies are continually refined. Reagents to support the analysis of veterinary species are available and more are emerging. These new tools will allow pathologists and scientists to unravel the intricate interplay between tissue architecture and diverse cellular phenotypes. By integrating histological observations with spatially resolved genomic data, spatial biology holds immense potential for advancing diagnostic and therapeutic strategies in veterinary medicine. These tools will undoubtedly equip veterinary pathologists to better decipher complex disease processes and identify novel therapeutic targets.}, }
@article {pmid40138454, year = {2025}, author = {Hart, TM and Cui, Y and Telford, SR and Marín-López, A and Calloway, K and Dai, Y and Matias, J and DePonte, K and Jaycox, J and DeBlasio, M and Hoornstra, D and Belperron, AA and Cibichakravarthy, B and Johnson, EE and Alameh, MG and Dwivedi, G and Hovius, JWR and Bockenstedt, LK and Weissman, D and Ring, AM and Fikrig, E}, title = {Tick feeding or vaccination with tick antigens elicits immunity to the Ixodes scapularis exoproteome in guinea pigs and humans.}, journal = {Science translational medicine}, volume = {17}, number = {791}, pages = {eads9207}, pmid = {40138454}, issn = {1946-6242}, support = {P01 AI138949/AI/NIAID NIH HHS/United States ; R01 AI126033/AI/NIAID NIH HHS/United States ; S10 OD030363/OD/NIH HHS/United States ; U19 AI089992/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; *Ixodes/immunology ; Humans ; *Antigens/immunology ; *Vaccination ; *Proteome/metabolism/immunology ; Immunoglobulin G/immunology ; Mice ; Lyme Disease/immunology ; Tick Bites/immunology ; Female ; *Feeding Behavior ; }, abstract = {Ixodes scapularis is a primary vector of tick-borne pathogens in North America. Repeated exposure to these ticks can induce a humoral response to tick antigens and acquired tick resistance. However, identifying antigens contributing to this resistance is challenging because of the vast number of I. scapularis proteins secreted during feeding. To address this, we developed I. scapularis rapid extracellular antigen monitoring (IscREAM), a technique to detect antibody responses to more than 3000 tick antigens. We validated IscREAM with immunoglobulin G (IgG) from guinea pigs vaccinated with tick antigens, including a cement antigen cocktail that induced tick resistance. Furthermore, we explored the natural response to tick bites by profiling antigens recognized by IgG isolated from a tick-resistant individual, as well as from others with Lyme disease and tick-bitten guinea pigs and mice, to identify 199 recognized antigens. We observed that several antigens contained histamine-binding domains. This work enhances our understanding of the host immune response to I. scapularis and defines immunogen candidates for future antitick vaccines.}, }
@article {pmid40133165, year = {2025}, author = {Astigarraga, CC and Mpms, K and Iovino, L and Milano, F}, title = {Haploidentical transplantation: An optimal platform for graft manipulation and cellular therapies.}, journal = {Blood reviews}, volume = {72}, number = {}, pages = {101286}, doi = {10.1016/j.blre.2025.101286}, pmid = {40133165}, issn = {1532-1681}, mesh = {Humans ; *Transplantation, Haploidentical/methods/adverse effects ; Graft vs Host Disease/prevention & control/etiology ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Cell- and Tissue-Based Therapy/methods ; *Hematologic Neoplasms/therapy ; Transplantation Conditioning/methods ; }, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a curative therapeutic option for patients with high-risk hematologic malignancies. When a fully matched donor is unavailable, haploidentical hematopoietic stem cell transplantation (haplo-HCT) provides a viable alternative. Over time, haplo-HCT procedures have significantly evolved, improving outcomes in treatment related mortality (TRM), especially in graft-versus-host disease (GvHD). However, challenges such as delayed immune reconstitution and disease relapse persist. Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases.}, }
@article {pmid40132580, year = {2025}, author = {Larsen, BB and McMahon, T and Brown, JT and Wang, Z and Radford, CE and Crowe, JE and Veesler, D and Bloom, JD}, title = {Functional and antigenic landscape of the Nipah virus receptor-binding protein.}, journal = {Cell}, volume = {188}, number = {9}, pages = {2480-2494.e22}, pmid = {40132580}, issn = {1097-4172}, support = {R01 AI141707/AI/NIAID NIH HHS/United States ; }, mesh = {*Nipah Virus/immunology/genetics/metabolism ; Humans ; Antibodies, Neutralizing/immunology ; Animals ; *Receptors, Virus/metabolism/immunology ; Mutation ; Henipavirus Infections/virology/immunology ; Antibodies, Viral/immunology ; Protein Binding ; Antigens, Viral/immunology ; Virus Internalization ; }, abstract = {Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here, we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.}, }
@article {pmid40131862, year = {2025}, author = {MacLean, F and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, NB and Cruz Talavera, I and Warrier, L and Dubrulle, J and Schroeder, LK and Saito, A and Mar, C and Thomas, KK and Mack, M and Sabo, MC and Chohan, BH and Ngure, K and Mugo, NR and Lingappa, JR and Lund, JM and , }, title = {Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {10}, pages = {}, pmid = {40131862}, issn = {1558-8238}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; R01 AI131914/AI/NIAID NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI129715/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Antigens, CD/immunology ; *CD4-Positive T-Lymphocytes/immunology/pathology ; *Cervix Uteri/immunology/pathology/microbiology ; HIV Infections/immunology/pathology ; Receptors, CCR5/immunology ; *Vagina/immunology/pathology/microbiology ; *Vaginosis, Bacterial/immunology/pathology/microbiology ; }, abstract = {BACKGROUNDBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually acquired HIV, yet the immunological mechanisms underlying this association are not well understood.METHODSTo investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples.RESULTSHigh-parameter flow cytometry revealed an increased frequency of cervical CD4+ conventional T (Tconv) cells expressing CCR5 in BR+ versus BR- women. However, we found no difference in the number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV had an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv cells, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations.CONCLUSIONOur comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV, including increased HIV susceptibility.TRIAL REGISTRATIONClinicalTrials.gov NCT03701802.FUNDINGThis work was supported by National Institutes of Health grants R01AI131914, R01AI141435, and R01AI129715.}, }
@article {pmid40131369, year = {2025}, author = {Ito, S and Geramita, E and Ventura, K and Neupane, B and Bhise, S and Moore, EM and Furlan, S and Shlomchik, WD}, title = {IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation.}, journal = {JCI insight}, volume = {10}, number = {9}, pages = {}, pmid = {40131369}, issn = {2379-3708}, support = {P30 CA047904/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Graft vs Host Disease ; Graft vs Leukemia Effect/immunology ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Interferon-gamma/administration & dosage/therapeutic use/adverse effects ; *Leukemia, Myeloid, Acute/therapy ; *Leukocyte Transfusion/methods ; *Myelodysplastic Syndromes/therapy ; Transplantation, Homologous ; Pilot Projects ; }, abstract = {BACKGROUNDThe graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT.METHODSPatients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-γ for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-γ by malignant myeloblasts.RESULTSIFN-γ monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I-II graft-versus-host disease (n = 5), immune effector cell-associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. scRNA-Seq validated in vivo activation of the IFN-γ response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-γ in analyzed samples.CONCLUSIONIFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL REGISTRATIONClinicalTrials.gov NCT04628338.FUNDINGUPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers.}, }
@article {pmid40130874, year = {2025}, author = {Dadonaite, B and Burrell, AR and Logue, J and Chu, HY and Payne, DC and Haslam, DB and Staat, MA and Bloom, JD}, title = {SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals.}, journal = {Journal of virology}, volume = {99}, number = {4}, pages = {e0010925}, pmid = {40130874}, issn = {1098-5514}, support = {U01 AI144673/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01AI167966//National Institute of Allergy and Infectious Diseases/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; R01AI141707//National Institute of Allergy and Infectious Diseases/ ; UL1TR001425/NH/NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; 01 AI144673-01/NH/NIH HHS/United States ; UL1 TR001425/TR/NCATS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *SARS-CoV-2/immunology/genetics ; *Antibodies, Viral/immunology/blood ; *COVID-19/immunology/virology ; *Spike Glycoprotein, Coronavirus/immunology/genetics ; Infant ; Adult ; *Antibody Specificity/immunology ; Cross Reactions ; Mutation ; Child ; Male ; Female ; }, abstract = {The immune response to viral infection is shaped by past exposures to related virus strains, a phenomenon known as imprinting. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by an XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), the serum neutralizing activity of infants infected with only XBB* mostly targets the spike N-terminal domain. In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity toward the RBD, although the specific RBD sites targeted are different from imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.IMPORTANCEWe show that a person's exposure history to different SARS-CoV-2 strains strongly affects which regions on the viral spike that their neutralizing antibodies target. In particular, infants who have just been infected once with a recent viral strain make neutralizing antibodies that target different regions of the viral spike than adults or children who have been exposed to both older and more recent strains. This person-to-person heterogeneity means that the same viral mutation can have different impacts on the antibody immunity of different people.}, }
@article {pmid40127395, year = {2025}, author = {Lust, H and Schultz, LM and Kwon, S and Roloff, GW and Aldoss, I and Baggott, C and John, S and Rossoff, JE and McNerney, KO and Fabrizio, VA and Talano, JA and Moskop, A and Curran, KJ and Phillips, CL and Karras, N and Baumeister, SHC and Cooper, SL and Hermiston, M and Satwani, P and Qayed, M and Raikar, SS and MacMillan, M and Hall, E and Nguyen, K and Cassaday, RD and Kopmar, NE and Kota, VK and Mathews, J and Shaughnessy, P and Schwartz, MS and Ladha, A and Yaghmour, G and Kumaran, MV and Bachanova, V and Tracy, S and Othman, T and Luskin, MR and Chen, EC and Advani, AS and Jeyakumar, N and Miller, K and Zhang, A and Sutherland, KC and Shah, BD and Muffly, L and Faramand, R}, title = {Real-world outcomes for young adult patients receiving CD19 CAR T-cell therapy.}, journal = {Blood advances}, volume = {9}, number = {11}, pages = {2763-2772}, pmid = {40127395}, issn = {2473-9537}, mesh = {Humans ; *Immunotherapy, Adoptive/adverse effects/methods ; Young Adult ; *Antigens, CD19/immunology ; Adult ; Male ; Adolescent ; Female ; Treatment Outcome ; *Receptors, Chimeric Antigen/immunology ; Retrospective Studies ; Receptors, Antigen, T-Cell ; Cytokine Release Syndrome/etiology ; }, abstract = {Tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) are approved CD19 chimeric antigen receptor T-cell therapy (CAR T) products for young adults (YA) with relapsed/refractory B-cell acute lymphoblastic leukemia. A distinct analysis of YAs receiving commercial CD19 CAR T has not been reported. Using retrospective data from the Pediatric Real-World CAR T Consortium and the Real-World Outcomes of CAR T in Adult ALL collaboration, we describe the efficacy and safety of tisa-cel and brexu-cel in 70 YAs (18-26 years; tisa-cel, n = 50; brexu-cel, n = 20). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed more frequently for brexu-cel vs tisa-cel (CRS, 85% vs 56%; ICANS, 40% vs 18%). Complete response rates were similar between products at 80% for brexu-cel and 88% for tisa-cel. Relapse-free survival (RFS) at 12 months was 46% for brexu-cel and 36% for tisa-cel. Durability of remission over 12 months was 61% for brexu-cel vs 41% for tisa-cel; 12-month overall survival (OS) for brexu-cel was 84% vs 68% for tisa-cel. In multivariate analysis, low disease burden was associated with improved OS, whereas inotuzumab before CAR T was associated with inferior outcomes. This study demonstrates comparable real-world efficacy among YAs receiving CD19 CAR T irrespective of CAR T construct; however, rates of toxicity seem higher with brexu-cel.}, }
@article {pmid40124489, year = {2025}, author = {Bender Ignacio, RA and Chew, KW and Moser, C and Currier, JS and Eron, JJ and Javan, AC and Giganti, MJ and Ritz, J and Gibbs, M and Kouekam, HT and Esser, MT and Daar, ES and Choudhary, M and Deo, R and Fletcher, CV and Li, JZ and Hughes, MD and Smith, D and Wohl, DA and , }, title = {Tixagevimab/cilgavimab or placebo for COVID-19 in ACTIV-2: Safety, pharmacokinetics and neutralizing and anti-drug antibodies.}, journal = {iScience}, volume = {28}, number = {3}, pages = {111938}, pmid = {40124489}, issn = {2589-0042}, abstract = {Monoclonal antibodies have potential as rapidly developable agents for treatment and prevention of emerging viruses. The ACTIV-2 trial randomized persons with mild-moderate COVID-19 to the monoclonal antibody combination tixagevimab/cilgavimab via intramuscular injection (600 mg IM) or infusion (300 mg IV) versus placebo. We present final safety and laboratory outcomes; primary outcomes were previously reported. The analyzed IM group included 214 participants, and the IV group, 106 participants. Adverse events were not different between treatment and placebo. The half-life of both components was >90 days for IM or 75 days for IV. New anti-drug antibodies were about 3 times more likely in active vs. placebo recipients. SARS-CoV-2 neutralizing antibodies increased 157-fold at 7 days and 127-fold at 1 month (IM-treated) but were less robust in IV participants. These data can inform future development of monoclonal antibodies against SARS-CoV-2 and other viruses, even if this intervention is of low utility for contemporary SARS-CoV-2 variants.}, }
@article {pmid40122815, year = {2025}, author = {Thomson, RM and Cunningham, JA and Gatton, MM and Murphy, SC and de la Paz Ade, M and Ding, XC and Incardona, S and Legrand, E and Lucchi, N and Menard, D and Nsobya, SL and Saez, AC and Shrivastava, J and Chiodini, PL}, title = {WHO malaria nucleic acid amplification test external quality assessment scheme: results of eleven distributions over 6 years.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {94}, pmid = {40122815}, issn = {1475-2875}, support = {001/WHO_/World Health Organization/International ; }, mesh = {*Nucleic Acid Amplification Techniques/standards/methods/statistics & numerical data ; World Health Organization ; Humans ; *Malaria/diagnosis ; *Plasmodium/isolation & purification/genetics ; Quality Control ; }, abstract = {BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria before treatment. The use of nucleic-acid amplification (NAAT) for detection of Plasmodium spp. has expanded rapidly in recent years, for epidemiological research globally and clinical care in high-resource settings. Data from NAATs are frequently used to inform policy decisions, so quality control is essential to ensure results are reliable and comparable. Therefore, robust quality control, including an external quality assessment (EQA) scheme targeting malaria NAATs, is essential. The WHO Global Malaria Programme and the UK National External Quality Assessment Service (UK NEQAS) have collaborated since 2017 to implement a global malaria NAAT EQA scheme.
METHODS: Panels of specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were validated by expert referee laboratories prior to distribution. Between 37 and 51 laboratories participated in each distribution and submitted results online. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers. Change in performance over time was calculated using a generalized mixed model with a logit link function.
RESULTS: Participating laboratories were located in 42 countries. Sample format (DBS or LB) and parasite density were found to significantly affect performance, while referee labs performed better at identifying P. falciparum samples than non-referee labs. Performance of laboratories improved significantly over time, especially for lower density and P. falciparum samples.
CONCLUSIONS: Results from the first eleven distributions indicate that the EQA scheme has facilitated improved performance of laboratories over time, highlighting the value of implementing such programmes. EQA schemes are critical to safeguarding the reliability of data and diagnoses, especially in situations where NAAT methodologies and protocols are used. In future, funders should make participation in an EQA scheme a requirement for laboratories, and countries can take initiatives to embed such schemes into their own national assessment programmes.}, }
@article {pmid40119775, year = {2025}, author = {Rostad, CA and Campbell, JD and Paulsen, GC and Ghamloush, SS and Xu, W and Zheng, L and McElrath, MJ and De Rosa, SC and Girard, B and Das, R and Anderson, EJ and Creech, CB}, title = {Evaluation of Cellular Immune Responses After mRNA-1273 Vaccination in Children 6 Months to 11 Years of Age.}, journal = {The Journal of infectious diseases}, volume = {231}, number = {5}, pages = {e945-e955}, pmid = {40119775}, issn = {1537-6613}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; 75A50120C00034//Biomedical Advanced Research and Development Authority/ ; UM1AI148684/NH/NIH HHS/United States ; /HH/HHS/United States ; AI068618/NH/NIH HHS/United States ; U01 AI068618/AI/NIAID NIH HHS/United States ; UM1/NH/NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; //Administration for Strategic Preparedness and Response/ ; UM1AI068618//HIV Vaccine Trials Network/ ; UM1 AI148684/AI/NIAID NIH HHS/United States ; }, mesh = {Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *2019-nCoV Vaccine mRNA-1273/administration & dosage/immunology ; Antibodies, Neutralizing/immunology/blood ; Antibodies, Viral/blood/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; *COVID-19/prevention & control/immunology ; *Immunity, Cellular/immunology ; *SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Vaccination ; }, abstract = {BACKGROUND: Cell-mediated immunity (CMI) may help protect against emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that are less susceptible to neutralizing antibodies. We present CMI data after the mRNA-1273 primary series in a subset of participants aged 6 months to 11 years from the phase 2/3 KidCOVE trial.
METHODS: T-cell responses were assessed after 2 doses of mRNA-1273 (6 months to 5 years, 25 μg; 6-11 years, 50 μg) or placebo administered 28 days apart. Magnitude, phenotype, and percentage of ancestral SARS-CoV-2 spike (S) protein T-cell responses to pooled peptides were assessed by intracellular cytokine staining and polyfunctionality analyses.
RESULTS: A total of 68 children aged 6 months to 11 years received either the 2-dose mRNA-1273 primary series or placebo (51 and 17, respectively) at 28-day interval. mRNA-1273 induced S-protein-specific CD4+ T-cell responses exhibiting a type 1 T helper (Th1)-biased profile at day 43 and day 209 compared with placebo. S-protein-specific CD8+ T-cell responses were less frequently detected in children <5 years and undetectable in those <2 years. Compared with placebo, mRNA-1273 induced higher frequencies of S-specific polyfunctional CD4+ T cells at day 43; frequencies declined but remained detectable at day 209. Correlation between Th1 CD4+ responses and neutralizing antibodies was observed across age groups following mRNA-1273 vaccination.
CONCLUSIONS: The 2-dose mRNA-1273 primary series elicited robust and durable (≥ 6 months) Th1-biased CD4+ T-cell responses in children aged 6 months to 11 years. CD8+ T-cell responses varied by age. Clinical Trials Registration. NCT04796896.}, }
@article {pmid40119478, year = {2025}, author = {Georgakis, MK and Malik, R and Bounkari, OE and Hasbani, NR and Li, J and Huffman, JE and Shakt, G and Tack, RWP and Kimball, TN and Asare, Y and Morrison, AC and Tsao, NL and Judy, R and Mitchell, BD and Xu, H and Montasser, ME and Do, R and Kenny, EE and Loos, RJF and Terry, JG and Carr, JJ and Bis, JC and Psaty, BM and Longstreth, WT and Young, KA and Lutz, SM and Cho, MH and Broome, J and Khan, AT and Wang, FF and Heard-Costa, N and Seshadri, S and Vasan, RS and Palmer, ND and Freedman, BI and Bowden, DW and Yanek, LR and Kral, BG and Becker, LC and Peyser, PA and Bielak, LF and Ammous, F and Carson, AP and Hall, ME and Raffield, LM and Rich, SS and Post, WS and Tracy, RP and Taylor, KD and Guo, X and Mahaney, MC and Curran, JE and Blangero, J and Clarke, SL and Haessler, JW and Hu, Y and Assimes, TL and Kooperberg, C and Bernhagen, J and Anderson, CD and Damrauer, SM and Zand, R and Rotter, JI and de Vries, PS and Dichgans, M}, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {27}, pmid = {40119478}, issn = {1756-994X}, mesh = {Humans ; *Receptors, CCR2/genetics ; Male ; Female ; *Cardiovascular Diseases/genetics ; *Genetic Predisposition to Disease ; Middle Aged ; Chemokine CCL2/metabolism ; Monocytes/metabolism ; Aged ; *Genetic Variation ; Risk Factors ; }, abstract = {BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.
METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).
RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10[-5]) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10[-4]) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.
CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.}, }
@article {pmid40119158, year = {2025}, author = {Cole, FM and Laszlo, GS and Lunn-Halbert, MC and Kehret, AR and Zweidler-McKay, PA and Rodríguez-Arbolí, E and Wu, D and Nyberg, K and Li, J and Lim, SYT and Pettenger-Willey, CM and Lakshmikanthan, S and Walter, RB}, title = {Preclinical characterization of the anti-leukemia activity of the CD123 antibody-drug conjugate, pivekimab sunirine (IMGN632).}, journal = {Leukemia}, volume = {39}, number = {5}, pages = {1243-1246}, pmid = {40119158}, issn = {1476-5551}, }
@article {pmid40117529, year = {2025}, author = {Wagner, MJ and Pimenta, EM and Sweeney, NW and Loggers, ET and Roberts, JL and Brinkman, E and Chen, EY and Ricciotti, R and Haddox, CL and Berg, R and Yilma, B and Stoppler, MC and Chen, JL and Cranmer, LD}, title = {Genomic Characterization of Chondrosarcoma Reveals Potential Therapeutic Targets.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2400592}, pmid = {40117529}, issn = {2473-4284}, mesh = {Humans ; *Chondrosarcoma/genetics/pathology ; Female ; Male ; Middle Aged ; Aged ; *Bone Neoplasms/genetics ; Adult ; Microsatellite Instability ; Isocitrate Dehydrogenase/genetics ; Mutation ; B7-H1 Antigen ; Genomics ; Aged, 80 and over ; Chondrosarcoma, Mesenchymal/genetics ; Young Adult ; }, abstract = {PURPOSE: Chondrosarcomas are rare cancers of cartilage with limited systemic therapy options. To identify potential therapeutic targets, this study investigated the molecular and immune landscape of three chondrosarcoma subtypes using a large database of clinical-grade sequencing results.
METHODS: Deidentified records from patients with a histologic diagnosis of conventional, dedifferentiated, or mesenchymal chondrosarcoma sequenced by the Tempus xT DNA assay were included. Microsatellite instability (MSI) and tumor mutational burden (TMB) were determined from sequencing data. The expression of PD-L1 and mismatch repair enzymes was evaluated in cases with available immunohistochemistry (IHC) data.
RESULTS: Of the 149 patients, 103 had conventional chondrosarcoma, 31 dedifferentiated chondrosarcoma, and 15 mesenchymal chondrosarcoma. Across the cohort, 44% (n = 65) had an IDH1 or IDH2 mutation. No cases were MSI high. One conventional chondrosarcoma patient had a TMB >10 mut/Mb. Among 112 patients with available PD-L1 IHC, 10% of conventional (n = 7), 45% of dedifferentiated (n = 13), and 17% of mesenchymal cases (n = 2) were PD-L1-positive. The most common somatic alterations were in IDH1 (34%) and TP53 (28%) in conventional chondrosarcoma; TP53 (68%), TERT (65%), IDH1 (39%), IDH2 (39%), CDKN2A (35%), and CDKN2B (35%) in dedifferentiated chondrosarcoma; and HEY1-NCOA2 fusions (87%) and CDKN2A (20%) in mesenchymal chondrosarcoma. MTAP was deleted in >10% of each subtype, and potentially actionable PDGFRB mutations were identified in 13% of dedifferentiated chondrosarcomas.
CONCLUSION: These findings reinforce therapeutic efforts to target IDH signaling in chondrosarcoma, provide insight into varied subpopulation response to immune checkpoint inhibitors, and identify new potential therapeutic targets for clinical development in chondrosarcoma.}, }
@article {pmid40116910, year = {2025}, author = {Lewis, FM and Ganschow, P and Manst, D and Derry-Vick, H and Tercyak, KP and Griffith, KA and Oxford, M and Fukui, J and Gadi, VK and Phillips, F}, title = {Behavioral-Emotional Functioning of Children of Parents with Early Compared to Advanced Cancer.}, journal = {Journal of palliative medicine}, volume = {28}, number = {6}, pages = {724-731}, doi = {10.1089/jpm.2024.0326}, pmid = {40116910}, issn = {1557-7740}, mesh = {Humans ; Child ; Male ; Female ; Adolescent ; *Neoplasms/psychology/pathology ; Child, Preschool ; *Parents/psychology ; United States ; Adult ; *Child of Impaired Parents/psychology ; Middle Aged ; *Child Behavior/psychology ; }, abstract = {Background: Parental cancer represents a substantial psychological threat to children, but little is known about the relative impact of advanced compared to early-stage cancer on children's behavioral-emotional functioning. Objectives: To compare the behavioral-emotional functioning in children of parents with early compared to advanced cancer. Design: Single occasion, two-group design with historical comparison group. Setting/Participants: Participants were recruited through cancer centers, oncologists, service organizations, and self-referrals in the United States. Eligible parents had advanced or early-stage cancer, a child 5-17 years old, and spoke and read English. The Child Behavior Checklist was administered to parents to assess their children's Internalizing and Externalizing Problems. Data were obtained from 236 diagnosed parents, 176 with early and 57 with advanced cancer. Results: Internalizing and Externalizing Problems and Anxious/Depressed Mood were significantly greater for children of parents with advanced compared to early-stage cancer, even after controlling for covariates. Differences in children's functioning were not affected by parents' anxiety, depressed mood, treatment, or measures of social determinants of health. Conclusions: This is the first study to systematically compare the effects of parents' stage of cancer on children's behavioral-emotional functioning while controlling for potential confounders. Results demonstrate significantly elevated levels of behavioral-emotional problems in children affected by advanced compared to early-stage cancer that were explained by parents' stage of cancer, not other sources. Future studies need to identify mutable protective and risk factors to reduce the threat of parental cancer.}, }
@article {pmid40116755, year = {2025}, author = {Yun, J and Indorf, AL}, title = {Optimizing intermittent dosing of oral small molecule inhibitors.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251327598}, doi = {10.1177/10781552251327598}, pmid = {40116755}, issn = {1477-092X}, abstract = {IntroductionWith recent expansion of oral small molecule inhibitors, the drug development studies need to provide insight into optimal dose selection for these agents with vastly different mechanism and pharmacokinetic considerations compared to our traditional chemotherapy agents. Currently there is one published meta-analysis that examines intermittent and alternative dosing of oral small molecule inhibitors and it is unclear what guidance is available for treatment personalization beyond package insert labeling for patients undergoing toxicities from treatment.MethodsA systematic review of oral small molecule inhibitors with intermittent dosing was conducted in the National Library of Medicine PubMed database. Studies were selected based on predefined inclusion/exclusion criteria. Data was extracted to summarize findings on available guidance for intermittent or alternative dosing of oral small molecule inhibitors. Studies were categorized based on food and drug administration (FDA) approved or non-FDA approved agents, and further characterized by comparison of different dosing schemas.ResultsFifty-five trials were included in the final review and data analysis. Thirty-three trials were phase 1 trials, 26 trials for FDA approved agents and 29 non-FDA approved agents. Most trials reported on agents used in solid tumors, particularly renal cell carcinoma, with most trials examining sunitinib. Of the 55 trials, 28 compared different dosing strategies with 26 of the 28 trials examining efficacy outcomes with 27 of the 28 trials examining safety outcomes.ConclusionsThis systematic review found limited guidance for clinicians in optimizing dosing for intermittently dosed oral small molecule inhibitors.}, }
@article {pmid40116305, year = {2025}, author = {Labaf, M and Han, W and Zhang, S and Liu, M and Patten, ND and Li, M and Patalano, S and Macoska, JA and Balk, SP and Han, D and Zarringhalam, K and Cai, C}, title = {Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {5}, pages = {772-783}, pmid = {40116305}, issn = {1538-8514}, support = {R01 CA211350/CA/NCI NIH HHS/United States ; P50 CA090381/CA/NCI NIH HHS/United States ; R01 CA282906/CA/NCI NIH HHS/United States ; R01CA211350//National Cancer Institute (NCI)/ ; W81XWH-19-1-0361//U.S. Department of Defense (DOD)/ ; HT9425-24-1-0472//U.S. Department of Defense (DOD)/ ; P50CA090381//National Cancer Institute (NCI)/ ; U54 CA156734/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; U54CA156734//National Cancer Institute (NCI)/ ; }, mesh = {Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology/metabolism ; Humans ; *Testosterone/pharmacology/administration & dosage ; Animals ; Mice ; Xenograft Model Antitumor Assays ; *Retinoblastoma Protein/genetics/metabolism/deficiency ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; }, abstract = {Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.}, }
@article {pmid40115173, year = {2025}, author = {Ghobadi, A and Caimi, PF and Reese, JS and Goparaju, K and di Trani, M and Ritchey, J and Jackson, Z and Tomlinson, B and Schiavone, JM and Kleinsorge-Block, S and Zamborsky, K and Eissenberg, L and Schneider, D and Boughan, KM and Zabor, EC and Metheny, L and Gallogly, M and Kruger, W and Kadan, M and Worden A S, A and Sharma, A and Cooper, BW and Otegbeye, F and Sekaly, RP and Wald, DN and Carlo-Stella, C and DiPersio, J and Orentas, R and Dropulic, B and de Lima, M}, title = {Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trial.}, journal = {EClinicalMedicine}, volume = {81}, number = {}, pages = {103138}, pmid = {40115173}, issn = {2589-5370}, support = {T32 AI089474/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model.
METHODS: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with ≥2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3ζ costimulatory domains. Lymphodepletion included fludarabine 25 mg/m[2] for 3 days and cyclophosphamide 60 mg/kg for 1 day. Prophylactic tocilizumab was allowed. Three dose levels (0.5, 1.0 and 2.0 × 10[6] cells/kg) were tested using a 3 + 3 dose-escalation schema. The primary outcome of this study was to determine the safety as defined by the dose limiting toxicities of MB-CART-19 in patients with relapsed and refractory NHL, co-primary outcome was determining the phase 2 dose of MB-CART-19. Secondary outcomes include defining the toxicity profile and to evaluate the initial efficacy of MB-CART-19 against relapsed or refractory NHL. This study was registered in ClinicalTrials.govNCT03434769.
FINDINGS: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) had aggressive lymphoma, 7 (24%) had indolent lymphoma (follicular lymphoma and marginal zone lymphoma). The median number of previous therapies was 5 (range 2-13, interquartile range [IQR] 3-5). All enrolled patients received MB-CART-19. Median apheresis to infusion time was 13 days (range 9-20, IQR 9-13). One dose limiting toxicity (DLT) was observed in dose escalation (fatal cytokine release syndrome [CRS]), whereas one patient died in dose expansion secondary to hemophagocytic syndrome. Both deaths were considered treatment-related. Twenty (65%) patients had CRS, three (10%) grade ≥3. Ten patients (32%) experienced immune effector cell neurotoxicity syndrome (ICANS), four (13%) grade ≥3. Neutropenia (n = 28, 90%), thrombocytopenia (n = 15, 48%) and anaemia (n = 13, 42%) were the most frequent grade ≥3 adverse events. Twenty-five out of 29 (86%, 95% confidence interval [CI]: 68-96%) response-evaluable patients had disease response and 22 (76%, 95% CI: 56-90%) had complete response; the overall and complete response rates for response-evaluable aggressive lymphoma patients (n = 22) were 82% (n = 18, 95% CI: 60-95%) and 73% (n = 16, 95% CI: 50-89%). Median follow up was 24.5 (IQR 17-32) months, median progression free survival (PFS) was 26 months (95% CI: 19-not reached [NR]) and median PFS was not reached (95% CI: 25 months-NR). Two-year estimates of PFS and overall survival (OS) were 63% (95% CI: 47-83%) and 68% (95% CI: 52-88%), respectively. Median PFS was 26 months (95% CI: 7-NR) for aggressive lymphoma patients with 2-year PFS estimate of 53% (95% CI: 36-78%), while median OS had not been reached for aggressive lymphoma patients (95% CI: 19 months-NR), and 2-year OS estimate was 60% (95% CI: 43-85%).
INTERPRETATION: Point-of-care CAR T-cell manufacture was feasible and replicable across sites. MB-CART-19 has a safety profile comparable to other CAR T-cell products and high response rates. The recommended phase 2 dose is 2 × 10[6] MB-CART-19 cells/kg. Short CAR T-cell manufacturing time permits treatment of patients with rapidly progressive lymphoma, a group of patients with high risk disease for whom access to autologous immune effector cellular therapies is usually limited.
FUNDING: This clinical trial was funded through University Hospitals Seidman Cancer Center and Washington University School of Medicine Institutional Funds. Correlative analyses were funded in part by the European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (project #PNRR-MAD-2022-12376059), and the Italian Ministry of Health Ricerca Finalizzata 2019 (project #RF-2019-12370243).}, }
@article {pmid40114218, year = {2025}, author = {Takeuchi, T and Flannery, AH and Liu, LJ and Ghazi, L and Cama-Olivares, A and Fushimi, K and Chen, J and Huen, SC and Tolwani, AJ and Neyra, JA}, title = {Epidemiology of sepsis-associated acute kidney injury in the ICU with contemporary consensus definitions.}, journal = {Critical care (London, England)}, volume = {29}, number = {1}, pages = {128}, pmid = {40114218}, issn = {1466-609X}, support = {K23DK128562/DK/NIDDK NIH HHS/United States ; R01DK128208//National Institute of Diabetes and Digestive and Kidney Diseases,United States/ ; }, mesh = {Humans ; *Acute Kidney Injury/epidemiology/etiology/mortality/classification ; Male ; Female ; Retrospective Studies ; Intensive Care Units/organization & administration/statistics & numerical data ; Middle Aged ; *Sepsis/complications/epidemiology ; Aged ; Consensus ; Hospital Mortality ; Cohort Studies ; Adult ; }, abstract = {BACKGROUND: The definition of sepsis-associated acute kidney injury (SA-AKI) was updated in 2023. This study aims to describe the epidemiology of SA-AKI using updated consensus definition and to evaluate clinical outcomes.
METHODS: The study was a retrospective cohort analysis conducted at two academic medical centers. Adult patients admitted to intensive care units (ICU) between 2010 and 2022 were included and categorized as SA-AKI, sepsis alone, or AKI alone. SA-AKI was further classified by time of onset (early < 2 days from sepsis diagnosis vs. late 2-7 days following sepsis diagnosis) and presence of septic shock. Clinical outcomes included hospital mortality and major adverse kidney events (MAKE = death, kidney replacement therapy, or reduced kidney function from baseline) at discharge.
RESULTS: 187,888 adult ICU patients were included, and SA-AKI was found in nearly half of sepsis patients and about 1 in 6 ICU admissions. 1 in 4 patients with SA-AKI died during hospitalization and 37.7% experienced at least one MAKE by hospital discharge. Compared to sepsis or AKI alone, SA-AKI was associated with higher mortality (adjusted HR 1.59; 95% CI 1.51-1.66) and higher odds of MAKE (adjusted OR 3.35; 95% CI 3.19-3.51). The early clinical phenotype of SA-AKI was most common, with incident AKI decreasing daily from sepsis onset. The presence of septic shock significantly worsened outcomes.
CONCLUSIONS: Applying updated consensus definitions highlights the high prevalence of SA-AKI in the ICU and its significant associated morbidity and mortality. Outcomes differ based on clinical phenotypes, including the timing of SA-AKI onset and the presence of shock.}, }
@article {pmid40112242, year = {2025}, author = {Abida, W and Beltran, H and Raychaudhuri, R}, title = {State of the Art: Personalizing Treatment for Patients With Metastatic Castration-Resistant Prostate Cancer.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e473636}, doi = {10.1200/EDBK-25-473636}, pmid = {40112242}, issn = {1548-8756}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/pathology/therapy/genetics ; *Precision Medicine/methods ; Neoplasm Metastasis ; Biomarkers, Tumor ; }, abstract = {Until recently, the treatment of metastatic castration-resistant prostate cancer (mCRPC) relied exclusively on hormonal therapies and taxane chemotherapy. The advent of modern molecular profiling methods applied in the clinic, namely, next-generation sequencing and advanced positron emission tomography (PET) imaging, has allowed for the development of biomarker-driven therapeutics including anti-PD-L1 therapy for microsatellite instability-high or tumor mutation burden-high disease, poly(ADP-ribose) polymerase (PARP) inhibitors for patients with DNA damage repair mutations, and lutetium 177 vipivotide tetraxetan ([177]Lu-PSMA-617) for patients with prostate-specific membrane antigen (PSMA) PET-avid disease. While these targeted therapies have improved outcomes, there is an opportunity to refine biomarkers to optimize patient selection, understand resistance, and develop novel combination strategies. In addition, studies in the laboratory and in patient-derived samples have shown that a subset of mCRPC tumors lose expression of common prostate cancer markers such as prostate-specific antigen and PSMA because of lineage plasticity and the development of non-androgen receptor (AR)-driven disease. Non-AR-driven prostate cancer has been associated with aggressive behavior and poor prognosis, including in some cases histologic transformation to a poorly differentiated neuroendocrine prostate cancer (NEPC). The clinical management of NEPC typically follows the treatment paradigm for small cell lung cancer and increasingly relies on genomic and phenotypic characterization of disease, including loss of tumor suppressors and expression of cell surface markers such as DLL3. Therefore, both genomic subtyping and phenotypic subtyping are important to consider and can guide the clinical management of patients with advanced prostate cancer.}, }
@article {pmid40111318, year = {2025}, author = {Yeh, JM and Ward, ZJ and Stratton, KL and McMahon, MV and Taylor, CS and Armstrong, GT and Chow, EJ and Hudson, MM and Morton, LM and Oeffinger, KC and Diller, LR and Leisenring, WM}, title = {Accelerated Aging in Survivors of Childhood Cancer-Early Onset and Excess Risk of Chronic Conditions.}, journal = {JAMA oncology}, volume = {11}, number = {5}, pages = {535-543}, pmid = {40111318}, issn = {2374-2445}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA227576/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Neoplasms/therapy/epidemiology/radiotherapy ; Child ; Adult ; Middle Aged ; Age of Onset ; Aged ; Adolescent ; Chronic Disease/epidemiology ; Risk Factors ; Child, Preschool ; *Survivors ; Young Adult ; Risk Assessment ; *Cancer Survivors ; *Cardiovascular Diseases/epidemiology ; *Aging, Premature/epidemiology/etiology ; Time Factors ; Infant ; }, abstract = {IMPORTANCE: The lifetime risk of aging-related diseases among survivors of childhood cancer, accelerated by cancer treatment exposures, is unknown. Understanding this risk can provide a more comprehensive assessment of long-term health across the lifespan of survivors and guide adult care.
OBJECTIVE: To estimate the lifetime risks of 8 treatment-related cancers and cardiovascular conditions among childhood cancer survivors and compare them with the general population.
DESIGN, SETTING, PARTICIPANTS: Using data from the Childhood Cancer Survivor Study and national databases, this simulation modeling study projected long-term outcomes for 5-year survivors diagnosed between 1970 and 1999 based on treatment exposures and age-related risks. The general population comparator was simulated using age-, sex-, and calendar year-matched individuals who faced only age-related risks.
EXPOSURES: Treatment era (1970s, 1980s, 1990s), original cancer diagnosis, radiation treatment for primary diagnosis (any, none).
MAIN OUTCOMES AND MEASURES: Estimated lifetime risks of 8 health conditions (breast cancer, colorectal cancer, glial tumors, sarcomas, heart failure, coronary heart disease/myocardial infarction, stroke, and valvular disease). Risks were projected and compared with the general population, stratified by radiation exposure.
RESULTS: In the general population, 20% developed at least 1 health condition by age 65.0 years; in 5-year survivors this threshold was reached at age 47.3 years, representing a 17.7-year (95% uncertainty interval [UI], 14.0-21.0) acceleration in disease onset. By age 65 years, 55% of survivors were projected to develop at least 1 condition, indicating a 2.7-fold (95% UI, 2.2-3.5) higher relative risk and 34.2% (95% UI, 28.3-42.5) absolute excess risk compared with the general population. Risks were higher among those treated with radiation therapy for childhood cancer (22.0 years earlier onset [95% UI, 18.0-25.0]; 37.3% excess risk [95% UI, 31.6%-44.7%]) but still elevated for those without radiation exposure (13.5 years earlier onset [95% UI, 10.0-16.0]; 31.0% excess risk [95% UI, 23.9%-40.3%]). Reaching middle age was still associated with increased health risks. Compared with the general population, survivors who reached age 40 years had a 6.2-fold higher risk (95% UI, 4.8-9.4) of developing a new condition within 10 years.
CONCLUSIONS AND RELEVANCE: This study found that survivors of childhood cancer experience accelerated onset of aging-related diseases, regardless of prior radiation exposure. These findings underscore the importance of prioritizing cancer and cardiovascular disease prevention among survivors decades earlier than for the general population.}, }
@article {pmid40109220, year = {2025}, author = {Yeung, CC and Jones, DC and Woolston, DW and Seaton, B and Donato, EL and Lin, M and Backman, C and Oehler, V and Robinson, KL and Shimp, K and Kulikauskas, R and Long, AN and Sowerby, D and Elz, AE and Smythe, KS and Newell, EW}, title = {Spatial proteomics and transcriptomics characterization of tissue and multiple cancer types including decalcified marrow.}, journal = {Cancer biomarkers : section A of Disease markers}, volume = {42}, number = {1}, pages = {18758592241308757}, doi = {10.1177/18758592241308757}, pmid = {40109220}, issn = {1875-8592}, mesh = {Humans ; *Proteomics/methods ; *Bone Marrow/pathology/metabolism ; *Neoplasms/genetics/pathology/metabolism ; *Gene Expression Profiling/methods ; *Transcriptome ; Decalcification Technique/methods ; Tissue Array Analysis/methods ; Biomarkers, Tumor ; Immunohistochemistry ; }, abstract = {BackgroundRecent technologies enabling the study of spatial biology include multiple high-dimensional spatial imaging methods that have rapidly emerged with different capabilities evaluating tissues at different resolutions for different sample formats. Platforms like Xenium (10x Genomics) and PhenoCycler-Fusion (Akoya Biosciences) enable single-cell resolution analysis of gene and protein expression in archival FFPE tissue slides. However, a key limitation is the absence of systematic methods to ensure tissue quality, marker integrity, and data reproducibility.ObjectiveWe seek to optimize the technical methods for spatial work by addressing preanalytical challenges with various tissue and tumor types, including a decalcification protocol for processing FFPE bone marrow core specimens to preserve nucleic acids for effective spatial proteomics and transcriptomics. This study characterizes a multicancer tissue microarray (TMA) and a molecular- and protein-friendly decalcification protocol that supports downstream spatial biology investigations.MethodsWe developed a multi-cancer tissue microarray (TMA) and processed bone marrow core samples using a molecular- and protein-friendly decalcification protocol. PhenoCycler high-plex immunohistochemistry (IHC) generated spatial proteomics data, analyzed with QuPath and single-cell analysis. Xenium provided spatial transcriptomics data, analyzed via Xenium Explorer and custom pipelines.ResultsResults showed that PhenoCycler and Xenium platforms applied to TMA sections of tonsil and various tumor types achieved good marker concordance. Bone marrow decalcification with our optimized protocol preserved mRNA and protein markers, allowing Xenium analysis to resolve all major cell types while maintaining tissue morphology.ConclusionsWe have shared our preanalytical verification of tissues and demonstrate that both the PhenoCycler-Fusion high-plex spatial proteomics and Xenium spatial transcriptomics platforms work well on various tumor types, including marrow core biopsies decalcified using a molecular- and protein-friendly decalcificationprotocol. We also demonstrate our laboratory's methods for systematic quality assessment of the spatial proteomic and transcriptomic data from these platforms, such that either platform can provide orthogonal confirmation for the other.}, }
@article {pmid40109218, year = {2025}, author = {Tang, TM and Zhang, Y and Kenney, AM and Xie, C and Xiao, L and Siddiqui, J and Srivastava, S and Sanda, MG and Wei, JT and Feng, Z and Tosoian, JJ and Zheng, Y and Chinnaiyan, AM and Yu, B and , }, title = {A simplified MyProstateScore2.0 for high-grade prostate cancer.}, journal = {Cancer biomarkers : section A of Disease markers}, volume = {42}, number = {1}, pages = {18758592241308755}, pmid = {40109218}, issn = {1875-8592}, support = {U2C CA271854/CA/NCI NIH HHS/United States ; R35 CA231996/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U24 CA115102/CA/NCI NIH HHS/United States ; U01 CA113913/CA/NCI NIH HHS/United States ; P50 CA186786/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/urine/genetics/pathology/diagnosis ; Neoplasm Grading ; *Biomarkers, Tumor/urine/genetics ; }, abstract = {Background: The limited diagnostic accuracy of prostate-specific antigen screening for prostate cancer (PCa) has prompted innovative solutions, such as the state-of-the-art 18-gene urine test for clinically-significant PCa (MyProstateScore2.0 (MPS2)). Objective: We aim to develop a non-invasive biomarker test, the simplified MPS2 (sMPS2), which achieves similar state-of-the-art accuracy as MPS2 for predicting high-grade PCa but requires substantially fewer genes than the 18-gene MPS2 to improve its accessibility for routine clinical care. Methods: We grounded the development of sMPS2 in the Predictability, Computability, and Stability (PCS) framework for veridical data science. Under this framework, we stress-tested the development of sMPS2 across various data preprocessing and modeling choices and developed a stability-driven PCS ranking procedure for selecting the most predictive and robust genes for use in sMPS2. Results: The final sMPS2 model consisted of 7 genes and achieved a 0.784 AUROC (95% confidence interval, 0.742-0.825) for predicting high-grade PCa on a blinded external validation cohort. This is only 2.3% lower than the 18-gene MPS2, which is similar in magnitude to the 1-2% in uncertainty induced by different data preprocessing choices. Conclusions: The 7-gene sMPS2 provides a unique opportunity to expand the reach and adoption of non-invasive PCa screening.}, }
@article {pmid40109190, year = {2025}, author = {Curran, E and Luskin, MR and Alachkar, H and Aldoss, I and Burke, PW and Cassaday, RD and Karol, SE and Perissinotti, AJ and Rank, CU and Schmiegelow, K and Webster, J and Douer, D}, title = {Recognition, prevention, and management of adverse events associated with asparaginase / pegaspargase treatment of acute lymphoblastic leukemia in adults: consensus of an expert panel.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.286744}, pmid = {40109190}, issn = {1592-8721}, abstract = {Asparaginase (ASNase)-based chemotherapy regimens significantly improve survival outcomes in children, adolescent and young adult (AYA), and even adults with acute lymphoblastic leukemia/lymphoma (ALL); however, the incidence and severity of ASNase-associated adverse events (AEs) in adults may differ significantly from those reported in children. Strategies to mitigate, monitor for, and manage toxicities that allow adult ALL patients to receive full ASNase courses are needed. A representative 12-member panel of experts who treat AYA and adult ALL patients, incorporate ASNase into their treatment regimens, and conduct related research was assembled to consider opportunities to optimize the use of pediatric-inspired ALL regimens in these adult patients. Following 2 systematic biomedical literature searches from April 2009 through April 2024, a modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. After 2 iterative Delphi method surveys, 23 statements met the standardized definition of consensus, whereas 19 statements did not. Five statements were merged to avoid redundancy. The clinical statements were grouped into 5 distinct categories: 1) hepatotoxicity; 2) hypersensitivity reactions; 3) thromboembolic and coagulopathy complications; 4) pancreatitis and metabolic complications; and 5) dosing. The intent of these statements is to provide health care providers with information that will help them mitigate, monitor for, and manage the most common and/or unique ASNase-induced AEs in adult ALL patients, allowing these patients to receive more or all the planned ASNase doses and thereby improve outcomes.}, }
@article {pmid40108454, year = {2025}, author = {Pae, J and Schwan, N and Ottino-Loffler, B and DeWitt, WS and Garg, A and Bortolatto, J and Vora, AA and Shen, JJ and Hobbs, A and Castro, TBR and Mesin, L and Matsen, FA and Meyer-Hermann, M and Victora, GD}, title = {Transient silencing of hypermutation preserves B cell affinity during clonal bursting.}, journal = {Nature}, volume = {641}, number = {8062}, pages = {486-494}, pmid = {40108454}, issn = {1476-4687}, support = {R01 AI173086/AI/NIAID NIH HHS/United States ; R01 AI157137/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI139117/AI/NIAID NIH HHS/United States ; R01 AI119006/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Mice ; *B-Lymphocytes/immunology/cytology/metabolism ; Germinal Center/cytology/immunology ; *Somatic Hypermutation, Immunoglobulin/genetics ; *Antibody Affinity/genetics/immunology ; Female ; Cyclin-Dependent Kinase 2/metabolism ; *Clone Cells/cytology/immunology/metabolism ; Male ; Mice, Inbred C57BL ; *Gene Silencing ; Cell Proliferation ; Cell Cycle ; }, abstract = {In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM)[1-4]. Panels of mutant B cells with different binding affinities for antigens are then selected in a Darwinian manner, which leads to a progressive increase in affinity among the population[5]. As with any Darwinian process, rare gain-of-fitness mutations must be identified and common loss-of-fitness mutations avoided[6]. Progressive acquisition of mutations therefore poses a risk during large proliferative bursts[7], when GC B cells undergo several cell cycles in the absence of affinity-based selection[8-13]. Using a combination of in vivo mouse experiments and mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM during clonal-burst-type expansion, so that a large fraction of the progeny generated by these bursts does not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a mouse strain carrying a reporter of cyclin-dependent kinase 2 (CDK2) activity showed that B cells that are actively undergoing proliferative bursts lack the transient CDK2[low] 'G0-like' phase of the cell cycle in which SHM takes place. We propose a model in which inertially cycling B cells mostly delay SHM until the G0-like phase that follows their final round of division in the GC dark zone, thus maintaining affinity as they clonally expand in the absence of selection.}, }
@article {pmid40108332, year = {2025}, author = {Shah, BD and Cassaday, RD and Park, JH and Houot, R and Logan, AC and Boissel, N and Leguay, T and Bishop, MR and Topp, MS and O'Dwyer, KM and Tzachanis, D and Arellano, ML and Lin, Y and Baer, MR and Schiller, GJ and Subklewe, M and Abedi, M and Minnema, MC and Wierda, WG and DeAngelo, DJ and Stiff, P and Jeyakumar, D and Mao, D and Adhikary, S and Zhou, L and Hadjivassileva, T and Damico Khalid, R and Ghobadi, A and Oluwole, OO}, title = {Three-year analysis of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.}, journal = {Leukemia}, volume = {39}, number = {5}, pages = {1058-1068}, pmid = {40108332}, issn = {1476-5551}, mesh = {Humans ; Adult ; Male ; Female ; Middle Aged ; *Immunotherapy, Adoptive/methods ; Young Adult ; Follow-Up Studies ; Aged ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/mortality/pathology ; Survival Rate ; *Neoplasm Recurrence, Local/pathology/therapy ; Adolescent ; Antigens, CD19/immunology ; Remission Induction ; Prognosis ; Drug Resistance, Neoplasm ; }, abstract = {Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adults aged ≥18 years (≥26 years in the EU) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Brexu-cel showed an overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 73% (CR rate 60%) and median overall survival (OS) of 25.4 months in 78 patients with R/R B-ALL after 2 years in ZUMA-3. Here, we report updated outcomes after >3 years median follow-up. As of July 23, 2022, median follow-up in all patients (N = 78) was 41.6 months. Median OS (95% CI) was 25.6 months (1.2-47.0; N = 78) and was 38.9 months (25.4-not estimable) for responders (n = 58), with 9 patients in ongoing remission without subsequent therapies. Five deaths (none deemed brexu-cel-related) occurred since prior data cut. Benefits from brexu-cel were maintained regardless of age, prior therapies, and subsequent allogeneic stem cell transplantation (alloSCT). Subsequent alloSCT was not associated with survival benefit among responders versus responders without subsequent alloSCT. No secondary T-cell malignancies were reported in ZUMA-3 with long-term follow-up.}, }
@article {pmid40107155, year = {2025}, author = {Gupta, S and Climent Duran, MA and Sridhar, SS and Powles, T and Bellmunt, J and Park, SH and Gurney, H and Tsuchiya, N and Petrylak, DP and Tomita, Y and di Pietro, A and Manitz, J and Tyroller, K and Hoffman, J and Jacob, N and Grivas, P}, title = {Avelumab first-line maintenance for advanced urothelial carcinoma: long-term outcomes from the JAVELIN Bladder 100 trial in older patients.}, journal = {ESMO open}, volume = {10}, number = {4}, pages = {104506}, pmid = {40107155}, issn = {2059-7029}, mesh = {Humans ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Male ; Female ; Aged, 80 and over ; *Urinary Bladder Neoplasms/drug therapy/mortality/pathology ; *Carcinoma, Transitional Cell/drug therapy/mortality/pathology ; Treatment Outcome ; Age Factors ; Middle Aged ; *Antineoplastic Agents, Immunological/therapeutic use ; }, abstract = {BACKGROUND: In the JAVELIN Bladder 100 phase III trial, avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) versus BSC alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) without progression following platinum-based chemotherapy. Older age (≥65 years) is a known risk factor for bladder cancer with a median age at diagnosis of 73.0 years. We report exploratory analyses in subgroups based on older age (≥65 years).
MATERIALS AND METHODS: Eligible patients with la/mUC without progression after 1L platinum-based chemotherapy were randomized to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). This exploratory analysis included subgroups aged ≥65 years, ≥65-<75 years, ≥75 years, and the subset aged ≥80 years. OS (primary endpoint) and progression-free survival (PFS) from randomization were analyzed using the Kaplan-Meier method.
RESULTS: Of 700 patients, 464 (66.3%) were aged ≥65 years. Median OS with avelumab plus BSC versus BSC alone was 26.1 versus 15.5 months (hazard ratio 0.70, 95% confidence interval 0.56-0.89) in all patients aged ≥65 years and 28.7 versus 17.1, 24.0 versus 13.5, and 24.9 versus 10.0 months, respectively, in patients aged ≥65-<75, ≥75, and ≥80 years. PFS analyses favored avelumab plus BSC versus BSC alone in all subgroups. No new safety concerns were identified in patients aged ≥65 years, including those treated for ≥12 months. Quality-adjusted time without symptoms or toxicity was 4.57 months longer with avelumab plus BSC versus BSC alone (a 30.35% relative improvement). Limitations include small sample size for the ≥80-year age subgroup and the exploratory design.
CONCLUSIONS: These exploratory analyses support the efficacy and tolerability of avelumab 1L maintenance in patients aged ≥65 years with la/mUC that has not progressed following chemotherapy, suggesting that older age should not solely prevent a patient from receiving avelumab 1L maintenance.}, }
@article {pmid40106531, year = {2025}, author = {Haring, B and Aragaki, AK and Shimbo, D and Rapp, SR and Eaton, CB and LaMonte, MJ and Wactawski-Wende, J and Allison, MA and Shadyab, AH and Rossouw, JE and Whitsel, EA and Franceschini, N and Kooperberg, C and Desai, P and Simon, MS and Böhm, M and Natarajan, P and Wassertheil-Smoller, S and Manson, JE}, title = {Clonal Hematopoiesis of Indeterminate Potential and Incident Hypertension: Results From the Women's Health Initiative.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {82}, number = {4}, pages = {e70-e72}, pmid = {40106531}, issn = {1524-4563}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, }
@article {pmid40106482, year = {2025}, author = {Soneson, C and Shepherd, L and Ramos, M and Rue-Albrecht, K and Rainer, J and Pagès, H and Carey, VJ}, title = {Eleven quick tips for writing a Bioconductor package.}, journal = {PLoS computational biology}, volume = {21}, number = {3}, pages = {e1012856}, pmid = {40106482}, issn = {1553-7358}, }
@article {pmid40104982, year = {2025}, author = {Chen, YA and Kazerouni, AS and Phelps, MD and Hippe, DS and Youn, I and Lee, JM and Partridge, SC and Rahbar, H}, title = {Time to Enhancement Measured From Ultrafast Dynamic Contrast-Enhanced MRI for Improved Breast Lesion Diagnosis.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbae089}, pmid = {40104982}, issn = {2631-6129}, support = {R01CA207290, R01CA203883, and K99CA293004/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Breast MRI affords high sensitivity with intermediate specificity for cancer detection. Ultrafast dynamic contrast-enhanced (DCE) MRI assesses early contrast inflow with potential to supplement or replace conventional DCE-MRI kinetic features. We sought to determine whether radiologist's evaluation of ultrafast DCE-MRI can increase specificity of a clinical MRI protocol.
METHODS: In this IRB-approved, HIPAA-compliant study, breast MRIs from March 2019 to August 2020 with a BI-RADS category 3, 4, or 5 lesion were identified. Ultrafast DCE-MRI was acquired during the first 40 seconds after contrast injection and before conventional DCE-MRI postcontrast acquisitions in the clinical breast MRI protocol. Three radiologists masked to outcomes retrospectively determined lesion time to enhancement (TTE) on ultrafast DCE-MRI. Interreader agreement, differences between benign and malignant lesion TTE, and TTE diagnostic performance were evaluated.
RESULTS: Ninety-five lesions (20 malignant, 75 benign) were included. Interreader agreement in TTE was moderate to substantial for both ultrafast source images and subtraction maximum intensity projections (overall κ = 0.63). Time to enhancement was greater across benign lesions compared with malignancies (P <.05), and all lesions demonstrating no enhancement during the ultrafast series were benign. With a threshold TTE ≥40 seconds, ultrafast DCE-MRI yielded an average 40% specificity (95% CI, 30%-48%) and 92% sensitivity (95% CI, 81%-100%), yielding a potential reduction in 31% (95% CI, 23%-39%) of benign follow-ups based on conventional DCE-MRI.
CONCLUSION: Ultrafast imaging can be added to conventional DCE-MRI to increase diagnostic accuracy while adding minimal scan time. Future work to standardize evaluation criteria may improve interreader agreement and allow for more robust ultrafast DCE-MRI assessment.}, }
@article {pmid40103823, year = {2025}, author = {Tisoncik-Go, J and Lewis, TB and Whitmore, LS and Voss, K and Niemeyer, S and Dai, J and Kim, P and Hubbell, K and Iwayama, N and Ahrens, C and Wangari, S and Murnane, R and Edlefsen, PT and Guerriero, KA and Gale, M and Fuller, DH and O'Connor, MA}, title = {Persistent innate immune dysfunction and ZIKV replication in the gastrointestinal tract during SIV infection in pigtail macaques.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1535807}, pmid = {40103823}, issn = {1664-3224}, support = {P51 OD010425/OD/NIH HHS/United States ; P01 AI177688/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI145296/AI/NIAID NIH HHS/United States ; HHSN272201800003C/AI/NIAID NIH HHS/United States ; K01 MH123258/MH/NIMH NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Immunity, Innate ; *Virus Replication/immunology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Simian Immunodeficiency Virus/immunology/physiology ; *Zika Virus/physiology/immunology ; *Zika Virus Infection/immunology/virology ; Macaca nemestrina ; *Gastrointestinal Tract/virology/immunology ; Disease Models, Animal ; Coinfection/immunology/virology ; Leukocytes, Mononuclear/immunology/virology ; Viremia/immunology ; }, abstract = {Mosquito-borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused widespread epidemics in areas with high HIV prevalence, partly due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in areas with high HIV prevalence, little is known about the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. During acute SIV infection, peripheral ZIKV cellular targets expanded and innate immune activation increased. In vitro, peripheral blood mononuclear cells (PBMC) from SIV infected pigtail macaques were less permissive to ZIKV infection. In vivo, ZIKV viremia was delayed and ZIKV was more persistent in the gastrointestinal tissues of SIV-ZIKV co-infected animals. This persistence was associated with changes in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, reduced anti-ZIKV immunity, and sustained expression of peripheral inflammatory and innate immune genes. Collectively, these findings uniquely suggest that untreated SIV infection may promote inflammatory cellular innate responses and create a state of persistent immune activation that contributes to prolonged ZIKV viremia and persistence in the gastrointestinal tract. Furthermore, these results suggest that PLWH and other immunocompromised individuals could be at higher risk for prolonged ZIKV infection, potentially extending the window of ZIKV transmission. These insights highlight the importance of including PLWH in strategies for deploying vaccines and treatments against ZIKV.}, }
@article {pmid40103753, year = {2025}, author = {Wolock, CJ and Gilbert, PB and Simon, N and Carone, M}, title = {Assessing variable importance in survival analysis using machine learning.}, journal = {Biometrika}, volume = {112}, number = {2}, pages = {asae061}, pmid = {40103753}, issn = {0006-3444}, abstract = {Given a collection of features available for inclusion in a predictive model, it may be of interest to quantify the relative importance of a subset of features for the prediction task at hand. For example, in HIV vaccine trials, participant baseline characteristics are used to predict the probability of HIV acquisition over the intended follow-up period, and investigators may wish to understand how much certain types of predictors, such as behavioural factors, contribute to overall predictiveness. Time-to-event outcomes such as time to HIV acquisition are often subject to right censoring, and existing methods for assessing variable importance are typically not intended to be used in this setting. We describe a broad class of algorithm-agnostic variable importance measures for prediction in the context of survival data. We propose a nonparametric efficient estimation procedure that incorporates flexible learning of nuisance parameters, yields asymptotically valid inference and enjoys double robustness. We assess the performance of our proposed procedure via numerical simulations and analyse data from the HVTN 702 vaccine trial to inform enrolment strategies for future HIV vaccine trials.}, }
@article {pmid40102030, year = {2025}, author = {Batalha, MA and LeCroy, MN and Lin, J and Peters, BA and Qi, Q and Wang, Z and Wang, T and Gallo, LC and Talavera, GA and McClain, AC and Thyagarajan, B and Daviglus, ML and Hou, L and Llabre, M and Cai, J and Kaplan, RC and Isasi, CR}, title = {Life-course socioeconomic position and the gut microbiome in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2479772}, doi = {10.1080/19490976.2025.2479772}, pmid = {40102030}, issn = {1949-0984}, support = {RF1 AG077639/AG/NIA NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Bacteria/classification/genetics/isolation & purification ; Cohort Studies ; Feces/microbiology ; *Gastrointestinal Microbiome ; *Hispanic or Latino ; Socioeconomic Factors ; United States ; }, abstract = {Socioeconomic position (SEP) in childhood and beyond may influence the gut microbiome, with implications for disease risk. Studies evaluating the relationship between life-course SEP and the gut microbiome are sparse, particularly among Hispanic/Latino individuals, who have a high prevalence of low SEP. We use the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based cohort study conducted in four field centers in the United States (U.S.), to evaluate the association between life-course SEP and gut microbiome composition. Life-course SEP indicators included parental education (proxy of childhood SEP), current SEP (n = 2174), and childhood (n = 988) and current economic hardship (n = 994). Shotgun sequencing was performed on stool samples. Analysis of Compositions of Microbiomes was used to identify associations of life-course SEP indicators with gut microbiome species and functions. Parental education and current SEP were associated with the overall gut microbiome composition; however, parental education and current education explained more the gut microbiome variance than the current SEP. A lower parental education and current SEP were associated with a lower abundance of species from genus Bacteroides. In stratified analysis by nativity, we found similar findings mainly among foreign-born participants. Early-life SEP may have long-term effects on gut microbiome composition underscoring another biological mechanism linking early childhood factors to adult disease.}, }
@article {pmid40101246, year = {2025}, author = {Sorror, ML and Saber, W and Logan, B and Geller, N and Bellach, A and Kou, J and Wood, W and McCarty, JM and Knight, TG and Runaas, L and Johnston, L and Walston, J and Nakamura, R and Jarrett, L and Mishra, A and Uberti, J and Dahi, PB and Saultz, JN and McCurdy, SR and Morris, LE and Imus, PH and Hogan, WJ and Nadiminti, K and Bhatt, VR and Olin, R and Maakaron, J and Sobecks, R and Wall, SA and Mattila, D and Protz, B and Devine, SM and Horowitz, MM and Artz, AS}, title = {Novel composite health assessment risk model for older allogeneic transplant recipients: BMT-CTN 1704.}, journal = {Blood advances}, volume = {9}, number = {13}, pages = {3268-3280}, doi = {10.1182/bloodadvances.2025015793}, pmid = {40101246}, issn = {2473-9537}, mesh = {Humans ; Aged ; Female ; Male ; Middle Aged ; Transplantation, Homologous ; Risk Assessment ; *Hematopoietic Stem Cell Transplantation ; Aged, 80 and over ; Prospective Studies ; *Bone Marrow Transplantation ; Transplant Recipients ; *Hematologic Neoplasms/therapy/mortality ; }, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models' performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias-corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.}, }
@article {pmid40101143, year = {2025}, author = {Xu, J and Sussman, JH and Yang, A and Yoshimura, S and Hu, J and Chen, C and Vincent, T and Bandyopadhyay, S and Li, EY and Lim, T and Elghawy, O and Barsouk, A and Karanfilovski, D and Wald, SL and Chen, GM and Wu, D and Newman, H and Li, A and Sun, Y and Chen, CH and Bernt, K and Wood, BL and Winter, SS and Dunsmore, KP and Raetz, E and Devidas, M and Pounds, S and Loh, M and Hunger, SP and Chiang, MY and Diorio, C and Di Giacomo, D and Pölönen, P and Mullighan, CG and Yang, JJ and Tan, K and Teachey, DT}, title = {STAT1-mediated interferon signatures are associated with preclinical JAK inhibitor sensitivity in T-ALL.}, journal = {Blood}, volume = {145}, number = {23}, pages = {2793-2798}, pmid = {40101143}, issn = {1528-0020}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; F30 CA268782/CA/NCI NIH HHS/United States ; K12 CA076931/CA/NCI NIH HHS/United States ; U2C CA233285/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U54 HL165442/HL/NHLBI NIH HHS/United States ; R01 CA193776/CA/NCI NIH HHS/United States ; R01 CA264837/CA/NCI NIH HHS/United States ; T32 GM007170/GM/NIGMS NIH HHS/United States ; R03 CA256550/CA/NCI NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; F30 CA277965/CA/NCI NIH HHS/United States ; K08 CA286762/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *STAT1 Transcription Factor/genetics/metabolism ; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/metabolism/pathology ; *Janus Kinase Inhibitors/therapeutic use/pharmacology ; *Interferons/genetics/metabolism ; Male ; Drug Resistance, Neoplasm/genetics ; Female ; Child ; }, abstract = {We used single-cell genomics to characterize a patient with T-cell acute lymphoblastic leukemia treated in the Children's Oncology Group AALL0434 trial with poor clinical outcome despite favorable genomic features, identifying a STAT1-mediated interferon-related transcriptional signature and inflammatory microenvironment associated with sensitivity to small-molecule JAK inhibition.}, }
@article {pmid40100600, year = {2025}, author = {Graves, SS and Zellmer, E and Storb, R}, title = {Canine Hematopoietic Cell Transplantation for Graft-Versus-Host Disease.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2907}, number = {}, pages = {207-236}, pmid = {40100600}, issn = {1940-6029}, mesh = {*Graft vs Host Disease/etiology/therapy/pathology ; Dogs ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Animals ; Disease Models, Animal ; }, abstract = {Graft-versus-host disease (GVHD) is a risk of hematopoietic cell transplantation (HCT) in the clinical setting. The acute form of the disease is well managed, but the chronic form is more problematic. The canine HCT model, instrumental in establishing successful clinical HCT protocols, reproducibly recapitulates the clinical manifestations of GVHD. Thus, therapies for the prevention and treatment of GVHD in the canine model may be applicable to the clinic. Here, we present the methods necessary to establish both acute and chronic GVHD models in dogs.}, }
@article {pmid40100459, year = {2025}, author = {Nguyen, NH and Nguyen, MP and Mai, HK and Do, ST and Pham, VH and Vuong, DTP and Maturi, JR and Le, HVT and Cluskey, PM and Pham, VT}, title = {The correlation of clinical and histopathological features of eyelid malignancies: a 5-year retrospective study in Vietnam.}, journal = {International ophthalmology}, volume = {45}, number = {1}, pages = {107}, pmid = {40100459}, issn = {1573-2630}, mesh = {Humans ; Retrospective Studies ; Vietnam/epidemiology ; *Eyelid Neoplasms/epidemiology/pathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Carcinoma, Basal Cell/epidemiology/pathology/diagnosis ; Adult ; Aged, 80 and over ; Incidence ; *Eyelids/pathology ; Follow-Up Studies ; *Melanoma/epidemiology/pathology ; Young Adult ; Time Factors ; }, abstract = {PURPOSE: To analyze the correlation between the clinical and histopathological features of eyelid malignancies in Vietnam.
METHODS: An observational retrospective study was conducted on 190 patients who were diagnosed histopathologically after surgery with eyelid malignancies between 2017 and 2021 at Vietnam National Eye Hospital. Demographic, clinical manifestations, pathological features and outcomes were analyzed.
RESULTS: Basal cell carcinoma was the most common histopathologic type, accounting for 57.9% of cases, followed by sebaceous gland carcinoma at 27.4%. The match between clinical diagnosis and pathological diagnosis was 57.4% across all cases. The majority of basal cell carcinoma cases presented on the lower eyelid, while the majority of sebaceous gland carcinoma cases presented on the upper eyelid. Clinical features with the highest clinical correlation were ulceration (76.4%) for basal cell carcinoma and ill-defined edges (84.6%) among malignant cutaneous melanoma.
CONCLUSION: Eyelid malignancies present significant challenges in clinical diagnosis, with only moderate concordance between clinical and histopathological findings. Basal cell carcinoma is the most common eyelid malignancy in Vietnam, though its incidence is significantly lower than in Western countries. Clinical findings with the most consistent clinical correlation were high rates of ulceration in basal cell carcinoma and ill-defined edges in malignant melanoma.}, }
@article {pmid40100220, year = {2025}, author = {Duncan, FC and Triplette, M}, title = {Adherence to Follow-Up Lung Cancer Screening-A Critical Target for Intervention.}, journal = {JAMA network open}, volume = {8}, number = {3}, pages = {e250949}, doi = {10.1001/jamanetworkopen.2025.0949}, pmid = {40100220}, issn = {2574-3805}, }
@article {pmid40099861, year = {2025}, author = {Othus, M and Sharon, E and Wu, MC and Sondak, VK and Ribas, A and Patel, SP}, title = {Design considerations for randomized comparisons of neoadjuvant-adjuvant versus adjuvant-only cancer immunotherapy when tumor measurement schedules do not align (SWOG S1801).}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745251321371}, doi = {10.1177/17407745251321371}, pmid = {40099861}, issn = {1740-7753}, abstract = {BackgroundIn 2022, SWOG S1801 was the first trial to demonstrate that single-agent anti-PD-1 checkpoint inhibition used as neoadjuvant-adjuvant therapy leads to significantly improved outcomes compared to adjuvant-only therapy. Endpoints in trials comparing neoadjuvant-adjuvant to adjuvant strategies need special consideration to ensure that event measurement timing is appropriately accounted for in analyses to avoid biased comparisons artificially favoring one arm over another.MethodsThe S1801 trial is used a case study to evaluate the issues involved in selecting endpoints for trials comparing neoadjuvant-adjuvant versus adjuvant-only strategies.ResultsDefinitions and timing of measurement of events is provided. Trial scenarios when recurrence-free versus event-free survival should be used are provided.ConclusionsIn randomized trials comparing neoadjuvant-adjuvant to adjuvant-only strategies, event-free survival endpoints measured from randomization are required for unbiased comparison of the arms. The time at which events can be measured on each arm needs to be carefully considered. If measurement of events occurs at different times on the randomized arms, modified definitions of event-free survival must be used to avoid bias.}, }
@article {pmid40099838, year = {2025}, author = {Lama, JR and Bender Ignacio, RA and Duerr, A}, title = {Acute retroviral syndrome.}, journal = {Current opinion in HIV and AIDS}, volume = {20}, number = {3}, pages = {186-192}, doi = {10.1097/COH.0000000000000933}, pmid = {40099838}, issn = {1746-6318}, mesh = {Humans ; *HIV Infections/complications/drug therapy/immunology/pathology ; }, abstract = {PURPOSE OF REVIEW: To review the most important recent literature on the definition, epidemiology, clinical presentation, pathogenesis and treatment of the acute retroviral syndrome (ARS), a constellation of nonspecific symptoms and transient illness occuring in at least 50% of persons shortly after HIV acquisition. ARS is driven by initial rapid HIV viral replication and dissemination after acquisition, followed by immune activation and massive systemic inflammation. A more detailed understanding of ARS is important for the implementation of early detection efforts, treatment and public health strategies to control HIV.
RECENT FINDINGS: Recent research has provided deeper insights into ARS. Key findings include associations of ARS with heightened immune activation and elevated levels of IFNγ and multiple other cytokines, particularly IP-10, as well as with higher viral load and more severe CD4 + depletion during acute infection. These negative impacts can be mitigated by early antiretroviral therapy initiation and long-term outcomes are generally similar in treated individals with or without ARS.
SUMMARY: Current findings underscore the importance of early detection and intervention in ARS to mitigate long-term health impacts and inform the development of targeted therapeutic strategies.}, }
@article {pmid40099002, year = {2025}, author = {Gong, E and Zawacki, L and Fan, X and Hippe, DS and Menon, AA and Remington, AJ and Lachance, K and Akaike, T and Tachiki, L and Park, SY and Nghiem, P}, title = {Immunotherapy response in immunosuppressed patients with Merkel cell carcinoma: analysis of 183 patients.}, journal = {BMJ oncology}, volume = {4}, number = {1}, pages = {e000654}, pmid = {40099002}, issn = {2752-7948}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with poor outcomes in immunosuppressed patients. While immune checkpoint inhibitors (ICIs) achieve ~60% response rates in immunocompetent MCC patients, their efficacy in immunosuppressed patients remains unclear due to exclusion from trials. This study compares ICI outcomes, safety and the impact of immunosuppression subtypes between these groups.
METHODS AND ANALYSIS: This retrospective study analysed 183 advanced MCC patients on first-line ICIs from a Seattle-based data repository. Of these, 147 were immunocompetent, and 36 were immunosuppressed (chronic lymphocytic leukaemia (CLL) n=10, autoimmune disorders n=10, other haematologic malignancies n=9, solid organ transplants n=4 and HIV/AIDS n=3). Outcomes included objective response rate, disease progression, MCC-specific and overall survival probability, adjusted for age, sex and stage at ICI initiation.
RESULTS: Initial ICI response rates at 6 months were 50% in immunosuppressed and 61.5% in immunocompetent patients (HR=0.71, p=0.17). Immunosuppressed patients had higher risks of disease progression (2 years: 53.9% vs 42.1%, HR=1.65, p=0.05) and MCC-specific mortality (2 years: 38.7% vs 24.4%, HR=1.85, p=0.04). CLL patients (n=10) had a particularly low response rate (response rate: 20.0% vs 61.5%, HR=0.18, p=0.02) and high progression risk (2 years: 80.0% vs 42.1%, HR=4.09, p=0.01). Immunosuppressed patients faced higher rates of ICI toxicity (6-month risk: 51.6% vs 36.6%, HR=1.79, p=0.03).
CONCLUSIONS: ICIs provide meaningful benefits to immunosuppressed MCC patients, though their response rates are lower, and progression risk is higher compared with immunocompetent patients.}, }
@article {pmid40098997, year = {2025}, author = {Xia, T and Han, F and Wang, Y and Xie, X and Yuan, C and Lu, G and Xiao, W and Tu, B and Ren, H and Gong, W and Wang, Y}, title = {Inhibition of CD53 Reduces the Formation of ROS-Induced Neutrophil Extracellular Traps and Protects Against Inflammatory Injury in Acute Pancreatitis.}, journal = {Journal of inflammation research}, volume = {18}, number = {}, pages = {3725-3739}, pmid = {40098997}, issn = {1178-7031}, abstract = {BACKGROUND: The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation.
METHODS: Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue.
RESULTS: Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice.
CONCLUSION: The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP.}, }
@article {pmid40098681, year = {2025}, author = {Orouskhani, M and Rauniyar, S and Morella, N and Lachance, D and Minot, SS and Dey, N}, title = {Deep learning imaging analysis to identify bacterial metabolic states associated with carcinogen production.}, journal = {Discover imaging}, volume = {2}, number = {1}, pages = {2}, pmid = {40098681}, issn = {3004-9776}, abstract = {BACKGROUND: Colorectal cancer (CRC) is a globally prevalent cancer. Emerging research implicates the gut microbiome in CRC pathogenesis. Bacteria such as Clostridium scindens can produce the carcinogenic bile acid deoxycholic acid (DCA). It is unknown whether imaging methods can differentiate DCA-producing and DCA-non-producing C. scindens cells.
METHODS: Light microscopy images of anaerobically cultured C. scindens in four conditions were acquired at 100× magnification using the Tissue FAX system: C. scindens in media alone (DCA-non-producing state), C. scindens in media with cholic acid (DCA-producing state), or C. scindens in co-culture with one of two Bacteroides species (intermediate DCA production states). We evaluated three approaches: whole-image classification, per-cell classification, and image segmentation-based classification. For whole-image classification, we used a custom Convolutional Neural Network (CNN), pre-trained DenseNet, pre-trained ResNet, and ResNet enhanced by integrating the Digital Images of Bacterial Species (DIBaS) dataset. For cell detection and classification, we applied thresholding (OTSU or adaptive thresholding) followed by a ResNet model. Finally, image segmentation-based classification was performed using nnU-Net.
RESULTS: For whole-image analysis, DIBaS-enhanced ResNet models achieved the best performance in distinguishing C. scindens states in monoculture (accuracy 0.89 ± 0.006) and in co-cultures (accuracy 0.86 ± 0.004). Per-cell analysis was optimal at a C constant value of 3, with the ResNet model achieving 62-74% accuracy for C. scindens states in monoculture. Segmentation-based analysis using nnU-Net resulted in Dice coefficients of 87% for C. scindens and 74-76% for the Bacteroides species.
CONCLUSIONS: This study demonstrates feasibility of image-based deep learning models in identifying health-relevant gut bacterial metabolic states.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44352-025-00006-1.}, }
@article {pmid40098097, year = {2025}, author = {Berry, AA and Richie, TL and Church, LWP and Laurens, MB and Boyce, C and Kc, N and Joshi, S and Koudjra, AR and Butler, L and Chen, MC and Abebe, Y and Murshedkar, T and James, ER and Billingsley, PF and Sim, BKL and Hoffman, SL and Lyke, KE}, title = {Safety, tolerability and immunogenicity of a condensed, multi-dose prime regimen of PfSPZ Vaccine for the prevention of Plasmodium falciparum malaria infection.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {88}, pmid = {40098097}, issn = {1475-2875}, support = {U44 AI167783/AI/NIAID NIH HHS/United States ; U44AI167783//National Institute of Allergy and Infectious Diseases,United States/ ; }, mesh = {Humans ; *Malaria Vaccines/immunology/administration & dosage/adverse effects ; *Malaria, Falciparum/prevention & control ; Adult ; Double-Blind Method ; Female ; Male ; *Plasmodium falciparum/immunology ; Young Adult ; *Immunogenicity, Vaccine ; Adolescent ; Vaccines, Attenuated/immunology/administration & dosage/adverse effects ; Middle Aged ; Antibodies, Protozoan/blood ; Sporozoites/immunology ; }, abstract = {BACKGROUND: The World Health Organization (WHO) has called for new malaria vaccines with > 90% efficacy against Plasmodium falciparum infection to expand the anti-disease benefit provided by the RTS,S/AS01 and R21/Matrix M subunit vaccines currently administered to infants and young children in sub-Saharan Africa. Attenuated P. falciparum sporozoites (PfSPZ) are being developed as a traveller's vaccine and to fulfill WHO's call for high-level efficacy in endemic countries to support malaria elimination.
METHODS: PfSPZ Vaccine, comprised of radiation-attenuated PfSPZ, was compared with normal saline placebo in a randomized, double-blind trial targeting 60 malaria-naive US adults to assess safety, tolerability, immunogenicity, and efficacy against heterologous controlled human malaria infection three and twelve weeks after immunization. Pharmacists provided syringes to blinded clinicians using 3:1 (vaccine:placebo) blocked randomization, for administration by direct venous inoculation on days 1 and 8 (multidose prime) and day 29 (boost), a condensed regimen with superior efficacy. Primary outcomes included adverse events and antibody responses to the P. falciparum circumsporozoite protein (PfCSP).
RESULTS: 31 participants were screened, randomized and immunized twice (V1, V2) 5-7 days apart, with one withdrawal after an intercurrent adverse event. A vial issue, later traced to the vial manufacturer, halted further immunizations. Solicited local and systemic adverse events recorded for 2 and 7 days after immunizations, respectively, occurred with equal frequency and severity in the 23 vaccinees and 7 controls receiving two immunizations, as did unsolicited adverse events recorded for 28 days and laboratory abnormalities 1 and 5 weeks after V2. Four of 23 vaccinees and one of 7 controls (p = 1.00) developed grade 2 adverse events including subjective fever, headache, malaise, fatigue, rigors, arthralgia and myalgia after V2 but not V1, these symptoms generally resolving within 24 h. Twenty-two of 23 (96%) vaccinees developed IgG (median 99-fold increase over baseline) and IgM (median 1,110-fold increase) antibodies to PfCSP one week after V2. Antibody responses were not associated with reactogenicity.
CONCLUSIONS: The two-dose priming immunization regimen was safe, well tolerated and highly immunogenic. Larger studies may better define the adverse event profile of condensed regimens of PfSPZ Vaccine in malaria-naive adults.
TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05604521.}, }
@article {pmid40097658, year = {2025}, author = {Simon, S and Bugos, G and Prins, R and Rajan, A and Palani, A and Heyer, K and Stevens, A and Zeng, L and Thompson, KA and Atilla, PA and Price, JP and Kluesner, MG and Jaeger-Ruckstuhl, CA and Shabaneh, TB and Olson, JM and Su, X and Riddell, SR}, title = {Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy.}, journal = {Nature cancer}, volume = {6}, number = {4}, pages = {647-665}, pmid = {40097658}, issn = {2662-1347}, support = {P01 CA18029//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 CA114536/CA/NCI NIH HHS/United States ; SCOR 1023-20//Leukemia and Lymphoma Society (Leukemia & Lymphoma Society)/ ; SRA220501//Bristol-Myers Squibb (Bristol-Myers Squibb Company)/ ; 3405-21//Leukemia and Lymphoma Society (Leukemia & Lymphoma Society)/ ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Receptors, Chimeric Antigen/immunology/genetics ; Mice ; *Receptors, Antigen, T-Cell/immunology/genetics ; Female ; *Immunotherapy, Adoptive/methods ; T-Lymphocytes/immunology/transplantation ; Cell Line, Tumor ; *Neoplasms/therapy/immunology ; *Multiple Myeloma/immunology/therapy ; Antigens, Neoplasm/immunology ; }, abstract = {The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.}, }
@article {pmid40095530, year = {2025}, author = {Gwin, WR and Hurvitz, SA}, title = {TOP1 Priority: Advancing Biomarker-Driven Patient Selection for the Use of ADCs.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {10}, pages = {1824-1826}, doi = {10.1158/1078-0432.CCR-25-0166}, pmid = {40095530}, issn = {1557-3265}, support = {//Fred Hutchinson Cancer Center (FHCRC)/ ; }, mesh = {Humans ; *Biomarkers, Tumor/genetics ; Patient Selection ; *Immunoconjugates/therapeutic use/pharmacology ; *DNA Topoisomerases, Type I/genetics/metabolism ; Mutation ; Drug Resistance, Neoplasm/genetics ; *Topoisomerase I Inhibitors/therapeutic use/pharmacology ; *Breast Neoplasms/drug therapy/genetics ; Female ; *Neoplasms/drug therapy/genetics ; }, abstract = {A recent study reports the emergence of TOP1 mutations as a potential mechanism of resistance to topoisomerase inhibitor antibody-drug conjugates (ADC) in advanced breast cancer. This is a crucial first step in identifying biomarkers to guide ADC therapy selection and underscores the need for caution when sequencing ADCs with similar payloads. See related article by Abelman et al., p. 1966.}, }
@article {pmid40093208, year = {2025}, author = {Zhao, K and Pershad, Y and Poisner, HM and Ma, X and Quade, K and Vlasschaert, C and Mack, T and Khankari, NK and von Beck, K and Brogan, J and Kishtagari, A and Corty, RW and Li, Y and Xu, Y and Reiner, AP and Scheet, P and Auer, PL and Bick, AG}, title = {Genetic drivers and clinical consequences of mosaic chromosomal alterations in 1 million individuals.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40093208}, support = {U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 AG083736/AG/NIA NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; }, abstract = {Mosaic chromosomal alterations of the autosomes (aut-mCAs) are large structural somatic mutations which cause clonal hematopoiesis and increase cancer risk. Here, we detected aut-mCAs in 1,011,269 participants across four biobanks. Through integrative analysis of the minimum critical region and inherited genetic variation, we found that proto-oncogenes exclusively drive chromosomal gains, tumor suppressors drive losses, and copy-neutral events can be driven by either. We identified three novel inherited risk loci in CHI3L2, HLA class II, and TERT that modulate aut-mCA risk and ten novel aut-mCA-specific loci. We found specific aut-mCAs are associated with cardiovascular, cerebrovascular, or kidney disease incidence. High-risk aut-mCAs were associated with elevated plasma protein levels of therapeutically actionable targets: NPM1, PARP1, and TACI. Participants with multiple high-risk features such as high clonal fraction, more than one aut-mCA, and abnormal red cell morphology had a 50% cumulative incidence of blood count abnormalities over 2 years. Leveraging inherited variation, we causally established aut-mCAs as premalignant lesions for chronic lymphocytic leukemia. Together, our findings provide a framework integrating somatic mosaicism, germline genetics, and clinical phenotypes to identify individuals who could benefit from preventative interventions.}, }
@article {pmid40093158, year = {2025}, author = {Latorre-Crespo, E and Robertson, NA and Kosebent, EG and MacGillivray, L and Murphy, L and Uddin, M and Whitsel, E and Honigberg, M and Bick, A and Reiner, AP and Orrù, V and Marongiu, M and Cucca, F and Fiorillo, E and Deary, IJ and Harris, S and Cox, S and Marioni, R and Schumacher, L and Chandra, T and Kirschner, K}, title = {Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093158}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.}, }
@article {pmid40093114, year = {2025}, author = {Visani, GM and Pun, MN and Minervina, AA and Bradley, P and Thomas, P and Nourmohammad, A}, title = {T-cell receptor specificity landscape revealed through de novo peptide design.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093114}, issn = {2692-8205}, support = {R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {T-cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. An effective binding between T-cell receptors (TCRs) and pathogen-derived peptides presented on Major Histocompatibility Complexes (MHCs) mediate an immune response. However, predicting these interactions remains challenging due to limited functional data on T-cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC class I alleles, and to design novel immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based, physics-guided machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, the implicit physical reasoning in HERMES enables us to make accurate predictions of both TCR-pMHC binding affinities and T-cell activities across diverse viral epitopes and cancer neoantigens, achieving up to 72% correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems targeting viral and cancer peptides, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T-cells at success rates of up to 50%. Lastly, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC complexes, offering key insights into T-cell specificity in both humans and mice. Our approach provides a platform for immunogenic peptide and neoantigen design, opening new computational paths for T-cell vaccine development against viruses and cancer.}, }
@article {pmid40089329, year = {2025}, author = {Tseng, D and Lee, S}, title = {Tumor-Infiltrating Lymphocyte Therapy: A New Frontier.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3S}, pages = {S599-S609}, doi = {10.1016/j.jtct.2024.11.014}, pmid = {40089329}, issn = {2666-6367}, mesh = {Humans ; *Lymphocytes, Tumor-Infiltrating/immunology/transplantation ; *Neoplasms/therapy/immunology ; *Immunotherapy, Adoptive/methods ; Immunotherapy/methods ; }, abstract = {In recent years, the successful use of tumor-infiltrating lymphocyte (TIL) therapy to treat melanoma not only culminated in a landmark Food and Drug Administration approval, but has also fueled the emergence of a new, rapidly growing field in TIL cellular immunotherapy surrounding novel enhancements in TIL design, refined manufacturing strategies to enrich for more potent TIL populations, as well as numerous clinical trials now investigating TIL therapy in additional solid tumor types beyond melanoma. This review provides a summary of the latest advances in TIL therapy and what lies ahead for the field. The first section explores several solid cancers that demonstrate the greatest potential for future indications of TIL therapy. The second section provides insight into the promising innovations for designing the next generation of TIL with greater specificity, persistence, safety, and function.}, }
@article {pmid40088973, year = {2025}, author = {Prentice, RL and Aragaki, AK and Zheng, C and Manson, JE and Tinker, LF and Schoeller, DA and Ravelli, MN and Raftery, D and Gowda, GN and Navarro, SL and Huang, Y and Mossavar-Rahmani, Y and Wallace, RB and Johnson, KC and Lampe, JW and Neuhouser, ML}, title = {Energy intake is associated with dietary macronutrient densities: inversely with protein and monounsaturated fat and positively with polyunsaturated fat and carbohydrate among postmenopausal females.}, journal = {The American journal of clinical nutrition}, volume = {121}, number = {5}, pages = {1165-1175}, pmid = {40088973}, issn = {1938-3207}, mesh = {Aged ; Female ; Humans ; Middle Aged ; Biomarkers/blood ; *Diet ; *Dietary Carbohydrates/administration & dosage ; Dietary Fats ; *Dietary Fats, Unsaturated/administration & dosage ; *Dietary Proteins/administration & dosage ; *Energy Intake ; *Fatty Acids, Monounsaturated/administration & dosage ; *Nutrients/administration & dosage ; *Postmenopause ; United States ; }, abstract = {BACKGROUND: Associations of the macronutrient composition of the diet with total energy intake (EI) are uncertain, as are associations of macronutrient composition with self-reported energy underreporting.
OBJECTIVES: We aimed to estimate the associations of biomarker-assessed EI with both biomarker-assessed and self-reported macronutrient component densities in a Women's Health Initiative (WHI) subcohort of postmenopausal females in the United States. Secondarily, we examined energy underreporting using food records, recalls, and frequencies, for association with macronutrient densities.
METHODS: We used a previously proposed EI biomarker equation based on doubly labeled water (DLW) and updated biomarker equations for several macronutrient component densities, to estimate EI and macronutrient component densities in a WHI nutritional biomarkers subcohort (n = 436; 2007-2009). We used linear regression of EI biomarker values on biomarker and self-reported macronutrient component densities, and of EI underreporting values on biomarker densities, to examine targeted associations.
RESULTS: Using biomarker assessments, the geometric mean (95% CI) for EI corresponding to a 20% increment in carbohydrate density was 2.0% (0.1%, 3.9%) higher, and for a 20% protein density increment was 2.1% (0.5%, 3.7%) lower. The former was attributable to added sugars. Similarly, EI values for 20% increments in polyunsaturated (PUFA), and monounsaturated (MUFA) fatty acid densities were 1.4% (0.3%, 2.6%) higher and 1.5% (0.1%, 2.9%) lower, respectively. Pertinent associations were either not detected or were substantially attenuated if instead self-reported macronutrient densities were used. Also, EI underreporting was strongly related to self-reported macronutrient densities using food records, recalls, or frequencies.
CONCLUSIONS: Among postmenopausal females in the United States lower EI was associated with diets relatively high in protein or MUFA, and higher EI was associated with diets relatively high in PUFA or added sugars. These associations are of public health importance but are mostly missed using self-reported dietary density assessments. Self-reported energy underestimation is substantially associated with self-reported macronutrient densities.
CLINICAL TRIAL REGISTRY: This study is registered with clinicaltrials.gov identifier: NCT00000611.}, }
@article {pmid40088909, year = {2025}, author = {Stranix-Chibanda, L and Hamilton, EL and Ngo, J and Jiao, Y and Hanscom, B and Choudhury, RP and Agyei, Y and Piwowar-Manning, E and Marzinke, M and Delany-Moretlwe, S and Mgodi, N and Siziba, B and Naidoo, I and Gati Mirembe, B and Kamira, B and McCoig, C and Adeyeye, A and Spiegel, HML and Hosek, S and , }, title = {Safety, tolerability, and acceptability of long-acting injectable cabotegravir for HIV prevention in cisgender female adolescents (HPTN 084-01): a single-arm, open-label, phase 2b trial.}, journal = {The lancet. HIV}, volume = {12}, number = {4}, pages = {e252-e260}, pmid = {40088909}, issn = {2352-3018}, mesh = {Humans ; Female ; Adolescent ; *HIV Infections/prevention & control ; *Pyridones/administration & dosage/adverse effects/therapeutic use ; *Pre-Exposure Prophylaxis/methods ; South Africa ; Uganda ; Zimbabwe ; *Anti-HIV Agents/administration & dosage/adverse effects ; Injections, Intramuscular ; Patient Acceptance of Health Care ; Delayed-Action Preparations/administration & dosage ; Diketopiperazines ; }, abstract = {BACKGROUND: Long-acting formulations of HIV pre-exposure prophylaxis (PrEP) appear particularly well suited to adolescents. We aimed to establish the safety, tolerability, and acceptability of long-acting injectable cabotegravir as PrEP in cisgender adolescent girls.
METHODS: HPTN 084-01 is a single-arm, open-label, phase 2b trial conducted at three clinical research sites in South Africa, Uganda, and Zimbabwe. Girls were recruited via community study-outreach teams, reproductive health clinics, and peer referral. Sexually active adolescent girls (younger than 18 years) willing to use long-acting contraception, weighing at least 35 kg, and able to participate with parental or guardian consent (unless an emancipated minor) were eligible. After an oral lead-in, if no adverse events occurred, participants received a 3 mL intramuscular gluteal injection (long-acting injectable cabotegravir 600 mg) at weeks 5, 9, 17, 25, and 33. The product was discontinued for grade 3 or higher toxic effects or pregnancy. The primary outcomes were safety, tolerability, and acceptability. Safety (ie, proportions of grade 2 or higher clinical and laboratory events) was assessed at weeks 6, 10, 18, 26, and 34 in all enrolled participants. Injection tolerability (ie, proportions of premature discontinuation due to intolerability, frequency of injections, or burden of study procedures) and product acceptability (ie, proportions of scheduled injections completed and participants preferring long-acting injectable cabotegravir for future use) were assessed in all participants who received at least one injection at study end. The trial was registered with ClinicalTrials.gov (NCT04824131) and is completed.
FINDINGS: Between Nov 1, 2020, and Aug 31, 2021, 69 participants were assessed for eligibility and 55 met inclusion criteria. The mean age was 16·0 years (SD 1·1), 39 (71%) had a recent primary sexual partner, 12 (22%) reported transactional sex, and 22 (40%) had sexually transmitted infections at baseline. Two participants dropped out and did not initiate long-acting injectable cabotegravir due to adverse events unrelated to the study drug during the oral lead-in. One participant stopped long-acting injectable cabotegravir after three injections due to pregnancy. 51 (93%) participants reported at least one adverse event of grade 2 or higher, mostly unrelated, transient laboratory abnormalities. There were no long-acting injectable cabotegravir discontinuations due to intolerability. Of the 52 participants who completed step 2, all scheduled injections were completed and 32 (62%) participants reported they would consider using long-acting injectable cabotegravir for HIV prevention in the future.
INTERPRETATION: Long-acting injectable cabotegravir is a safe, tolerable, and acceptable option for the prevention of HIV in adolescent girls. Our study findings expand the HIV prevention options available to adolescent girls.
FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute on Drug Abuse, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, ViiV Healthcare, and The Bill & Melinda Gates Foundation.}, }
@article {pmid40088674, year = {2025}, author = {Kumaraswamy, A and Mannan, R and Swaim, OA and Rodansky, E and Wang, XM and Udager, A and Mehra, R and Li, H and Morrissey, C and Corey, E and Haffner, MC and Nelson, PS and Chinnaiyan, AM and Yates, JA and Alumkal, JJ}, title = {LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer.}, journal = {Neoplasia (New York, N.Y.)}, volume = {63}, number = {}, pages = {101151}, pmid = {40088674}, issn = {1476-5586}, mesh = {*Histone Demethylases/genetics/metabolism ; Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis/metabolism/pathology ; *Biomarkers, Tumor/genetics ; Animals ; Cell Line, Tumor ; Mice ; RNA, Messenger/genetics ; *Neuroendocrine Tumors/genetics/diagnosis/metabolism ; }, abstract = {BACKGROUND: Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of LSD1-LSD1+8a-has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that LSD1+8a transcripts were detected in an aggressive subtype of prostate cancer harboring a neuronal program-neuroendocrine prostate cancer (NEPC)-but not in prostate adenocarcinomas harboring a glandular program. However, the number of samples examined was limited.
METHODS: Using a large collection of prostate cancer patient cell lines and patient-derived xenografts (PDXs), we measured LSD1+8a using quantitative polymerase chain reaction (qPCR), RNA in situ hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples.
RESULTS: LSD1+8a mRNA expression was detected in every NEPC cell line and PDX examined by qPCR and RNA-ISH but in none of the prostate adenocarcinomas. We validated the RNA-ISH results in patient tumors, confirming that LSD1+8a was expressed in all NEPC tumors but in none of the adenocarcinomas. Finally, we generated a rabbit monoclonal antibody specific to LSD1+8a protein and confirmed its specificity using normal neuronal tissue samples. However, LSD1+8a protein was not detectable in NEPC tumors-likely due to the substantially lower levels of LSD1+8a mRNA in NEPC tumors vs. normal neuronal tissues.
CONCLUSIONS: Measuring LSD1+8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.}, }
@article {pmid40088469, year = {2025}, author = {Banerjee, R and Richards, A and Midha, S and Afrough, A and Anwer, F and Atanackovic, D and Atrash, S and Bachanova, V and Beitinjaneh, AM and Bhurtel, E and Castaneda Puglianini, O and Chhabra, S and Cicero, KI and Davis, JA and Dhakal, B and Dima, D and Ferreri, CJ and Forsberg, PA and Freeman, CL and Herr, MM and Jain, T and Janakiram, M and Khouri, J and Kocoglu, MH and Kumar, A and Liu, Y and Locke, F and McGuirk, JP and Mikkilineni, L and Nadeem, O and Parrondo, RD and Pasvolsky, O and Peres, LC and Purvey, S and Raza, S and Reshef, R and Richard, S and Rossi, AC and Sborov, DW and Shune, L and Wagner, CB and Zanwar, SS and Sidana, S and Patel, KK and Hansen, DK and Kumar, SK and Lin, Y and Martin, TG and Voorhees, PM and Anderson, LD and Cowan, AJ and Kaur, G}, title = {Universal driving restrictions beyond 4 weeks appear unnecessary following CAR-T therapy in multiple myeloma.}, journal = {Blood advances}, volume = {9}, number = {9}, pages = {2336-2340}, pmid = {40088469}, issn = {2473-9537}, }
@article {pmid40086733, year = {2025}, author = {Antonarelli, G and Pérez-García, JM and Gion, M and Rugo, H and Schmid, P and Bardia, A and Hurvitz, S and Harbeck, N and Tolaney, SM and Curigliano, G and Llombart-Cussac, A and Cortés, J}, title = {Redefining clinical trial strategic design to support drug approval in medical oncology.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {6}, pages = {645-650}, doi = {10.1016/j.annonc.2025.03.005}, pmid = {40086733}, issn = {1569-8041}, mesh = {Humans ; *Drug Approval/methods ; *Medical Oncology/methods ; *Research Design ; *Neoplasms/drug therapy ; *Antineoplastic Agents/therapeutic use ; *Clinical Trials as Topic/methods ; Randomized Controlled Trials as Topic/methods ; }, abstract = {Randomized clinical trials represent the gold standard for the introduction of innovative therapies in medical oncology, and they provide the highest level of evidence to ascertain the clinical activity of new drugs or novel combinations. However, the current infrastructure of clinical trials supporting innovative drug approvals is challenged by an increased body of knowledge concerning tumor biology and therapy resistance, a fast-growing armamentarium of novel anticancer compounds, an impressively upscaled data analysis capacity, as well as increasing costs related to clinical trials management. In this scenario, modern clinical trial designs need to evolve to expedite new drug approvals by tailoring patients' treatment strategies according to their medical needs. Balanced, patient-oriented clinical trial designs are eagerly warranted to increase their efficiency, to include the fast pace of technological innovations and scientific discoveries, and, ultimately, to face the challenges of the modern medical oncology field.}, }
@article {pmid40086461, year = {2025}, author = {Diallo, F and Haidara, FC and Tapia, MD and Dominguez Islas, CP and Alderson, MR and Hausdorff, WP and Martellet, L and Hosken, N and Kapse, D and Kulkarni, PS and Townsend-Payne, K and Vanni, F and Posavad, CM and Sow, SO and Kotloff, KL and Chen, WH and , }, title = {Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, W, Y, and X when co-administered with routine childhood vaccines at ages 9 months and 15 months in Mali: a single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial.}, journal = {Lancet (London, England)}, volume = {405}, number = {10484}, pages = {1069-1080}, doi = {10.1016/S0140-6736(25)00046-7}, pmid = {40086461}, issn = {1474-547X}, support = {UM1 AI148684/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Meningococcal Vaccines/immunology/administration & dosage/adverse effects ; Mali ; Infant ; Double-Blind Method ; Male ; Female ; Vaccines, Conjugate/immunology/administration & dosage/adverse effects ; *Immunogenicity, Vaccine ; *Meningococcal Infections/prevention & control ; Immunization Schedule ; Antibodies, Bacterial/blood ; Serogroup ; *Meningitis, Meningococcal/prevention & control ; Animals ; Neisseria meningitidis/immunology ; Vaccines, Combined/administration & dosage ; }, abstract = {BACKGROUND: Invasive meningococcal disease is a devastating public health problem for the African meningitis belt. We assessed the safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, Y, W, and X (NmCV-5) relative to a licensed, quadrivalent meningococcal conjugate vaccine (MenACWY-TT) when co-administered with routine childhood vaccines at ages 9 months and 15 months.
METHODS: In this single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial, children aged 9-11 months who had completed their local infant Expanded Program on Immunization (EPI) vaccines were recruited at the Centre pour le Développement des Vaccins in Bamako, Mali. Participants were randomly assigned (1:1·2) at their 9-month EPI visits to receive a meningococcal vaccine at either their 9-month or 15-month EPI vaccination visits. At each participant's designated EPI visit, they were randomly assigned a second time (2:1) to receive either NmCV-5 or MenACWY-TT. Study vaccines and designated EPI vaccines were prepared and administered by assigned unmasked study personnel. Parents or guardians, investigators, and all other trial staff were masked to meningococcal vaccine assignments. The meningococcal vaccines were co-administered with a measles and rubella vaccine (first dose) and a yellow fever vaccine at age 9 months or with a measles and rubella vaccine (second dose) at age 15 months. The primary endpoint, seroprotective response, was defined as a rabbit complement serum bactericidal antibody titre of 8 or higher, with the estimand, given as the difference in the proportions of participants for each of the five meningococcal serogroups who showed this response 28 days after vaccination, assessed in the per-protocol population. The prespecified non-inferiority margin was -10% for all five serogroups in both age groups. The non-inferiority of the NmCV-5 seroprotective response to serogroup X was evaluated in comparison with the lowest seroprotective response for MenACWY-TT among serogroups A, C, W, or Y. Safety was a secondary endpoint, assessed over 6 months in a modified intention-to-treat population that included all participants who received a randomly assigned meningococcal vaccine. This trial is registered with ClinicalTrials.gov, NCT05093829.
FINDINGS: Between March 24 and Aug 15, 2022, 1325 participants were enrolled and randomly assigned to receive a meningococcal vaccine at either age 9 months (n=602) or age 15 months (n=723). Meningococcal vaccines were administered to 600 of the 602 participants assigned to the 9-month vaccination group during that same period. Between Sept 27, 2022, and Feb 6, 2023, 600 participants received meningococcal vaccines at their 15-month visits. In both groups, 400 participants received NmCV-5 and 200 participants received MenACWY-TT. The per-protocol population assessed in the non-inferiority analysis included 564 participants vaccinated at age 9 months (373 who received NmCV-5 and 191 who received MenACWY-TT) and 549 participants vaccinated at age 15 months (367 who received NmCV-5 and 182 who received MenACWY-TT). Among the participants in the per-protocol population who received NmCV-5 at age 9 months, the difference in seroprotection prevalence for NmCV-5 relative to MenACWY-TT was 0·0% (95% CI -1·0 to 2·0) for serogroup A, -0·5% (-2·3 to 1·9) for serogroup C, -3·0% (-6·3 to 0·8) for serogroup W, and -3·0% (-5·4 to -0·4) for serogroup Y. For serogroup X, non-inferiority was assessed relative to seroprotection for serogroup W in participants who received MenACWY-TT, with a difference of 2·3% (95% CI 0·3 to 4·7). The difference in the prevalence of seroprotection among the participants who received NmCV-5 at age 15 months relative to participants who received MenACWY-TT at age 15 months was 0·8% (95% CI -0·6 to 3·7) for serogroup A, -0·8% (-3·3 to 2·5) for serogroup C, 0·3% (-1·8 to 3·5) for serogroup W, and 1·4% (-0·6 to 4·8) for serogroup Y. For serogroup X, non-inferiority was assessed in relation to seroprotection for serogroup Y in participants who received MenACWY-TT, with a difference of 1·9% (95% CI 0·0 to 4·4). NmCV-5 responses in both age groups were non-inferior to MenACWY-TT responses for all five serogroups. Six serious adverse events were recorded but none were deemed related to vaccination.
INTERPRETATION: When compared with a licensed, quadrivalent meningococcal conjugate vaccine, and given alongside other routine vaccines, a single dose of NmCV-5 was safe and elicited a non-inferior immune response in infants aged 9 months and young children aged 15 months.
FUNDING: US National Institutes of Health, UK Foreign, Commonwealth & Development Office, and Serum Institute of India.}, }
@article {pmid40086122, year = {2025}, author = {Dale, R and He, H and Chen, Y}, title = {Absorbing Markov chain model of PrEP drug adherence to estimate adherence decay rate and probability distribution in clinical trials.}, journal = {Journal of theoretical biology}, volume = {604}, number = {}, pages = {112086}, pmid = {40086122}, issn = {1095-8541}, support = {R01 AI121259/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {*Markov Chains ; Humans ; *Pre-Exposure Prophylaxis ; *HIV Infections/prevention & control/transmission ; *Medication Adherence ; Probability ; *Clinical Trials as Topic ; Anti-HIV Agents/therapeutic use ; }, abstract = {Pre-exposure prophylaxis (PrEP) is increasingly used to prevent the transmission of H.I.V. in at-risk populations. However, PrEP users may discontinue use of the medicine due to side effects, lower perceived risk, or other reasons. The usage metrics of 594 individuals was tracked over 350 days using the Wisepill electronic monitoring system. We model the PrEP drug adherence level using an absorbing Markov chain with a unique absorbing state. The transition matrix T obtained from the Wisepill data will have a trivial eigenvector (eigendistribution) associated with the first (i.e., largest) eigenvalue 1. The 2nd eigenvalue(s) then become important in determining the asymptotic behavior of the Markov chain, dictating how fast the Markov chain decays to the absorbing state. Under a fairly general assumption, we prove that the second positive eigenvalue is unique and the corresponding eigenvector will have nonnegative entries with exceptions at absorbing states. In addition, we define the asymptotic half life of the absorbing Markov chain directly from the 2nd eigenvalue. We then determine the 2nd eigenvalue of T and the asymptotic half life of the Markov chain, which turns out to be very close to the real half life of the Markov chain. Finally, we interpret the 2nd eigenvector as the relative probability distribution of X∞ with respect to the decay rate of the 2nd eigenvalue. By applying these methods to the Wisepill data, we estimate the half-life of population adherence to be 46 weeks. The bi-weekly decay rate observed in these data from 90 to 100 % adherence is 3 %. This work produces an estimate at which adherence falls over time, given no external intervention is applied. These results suggest an eigenvector-based approach to estimate adherence trends, as well as the timing of interventions to improve adherence.}, }
@article {pmid40084542, year = {2025}, author = {Cox, SN and Roychoudhury, P and Frivold, C and Acker, Z and Babu, TM and Boisvert, CL and Carone, M and Ehmen, B and Englund, JA and Feldstein, LR and Gamboa, L and Grindstaff, S and Grioni, HM and Han, PD and Hoffman, KL and Kim, HG and Kuntz, JL and Lo, NK and Lockwood, CM and McCaffrey, K and Mularski, RA and Hatchie, TL and Reich, SL and Schmidt, MA and Smith, N and Starita, LM and Varga, A and Yetz, N and Naleway, AL and Weil, AA and Chu, HY}, title = {Household Transmission and Genomic Diversity of Respiratory Syncytial Virus (RSV) in the United States, 2022-2023.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf048}, pmid = {40084542}, issn = {1537-6591}, support = {75D30121C12297/CC/CDC HHS/United States ; }, abstract = {BACKGROUND: Household transmission of respiratory viruses may drive community spread. Few recent studies have examined household respiratory syncytial virus (RSV) transmission in the United States.
METHODS: We conducted a prospective community-based cohort study from 1 June 2022 to 31 May 2023. Participants had blood samples collected and completed nasal swabs and surveys at least weekly, irrespective of symptoms. We tested serum for RSV antibody, nasal swabs by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and performed whole genome sequencing. We evaluated secondary RSV transmission and associated risk factors based on a log-linear Poisson regression model.
RESULTS: RSV was detected among 310 (10%) participants within 200 (20%) households. Most (94%) index cases were symptomatic. We identified 37 cases of potential secondary transmission within 14 days of a distinct index case (10%, 95% confidence interval [CI]: 7%, 14%); median age of index and secondary cases were 6 (interquartile range [IQR]: 3-10) and 35 (7-41) years, respectively, with 89% (24/27) of index cases aged 6 months to 12 years. Factors associated with increased risk of RSV transmission included index case viral detection ≥1 week and contact age ≤12 years. Of 120 sequenced specimens, the main lineages represented were A.d.5.2 (n = 37) and A.d.1 (n = 30). Sequenced viruses from households with ≥2 RSV infections were similar when occurring within ≤14 days (mean pairwise difference 4 [range 0-13], n = 17 households), compared to those >14 days (137 [37-236], n = 2).
CONCLUSIONS: Most RSV household transmission occurs from infants and young children to adults. Viral genome sequencing demonstrated that multiple household infections within a 14-day period are likely due to within-household transmission.}, }
@article {pmid40084371, year = {2025}, author = {Santiago-Torres, M and Westmaas, JL and Ostroff, JS and Mull, KE and Sullivan, BM and Unger, JM and Bricker, JB}, title = {Overcoming challenges of recruiting cancer patients into clinical trials: insights from a randomized trial of app-based smoking cessation interventions.}, journal = {American journal of cancer research}, volume = {15}, number = {2}, pages = {601-617}, pmid = {40084371}, issn = {2156-6976}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA253975/CA/NCI NIH HHS/United States ; }, abstract = {Behavioral clinical trials among cancer patients often fail to meet recruitment goals - especially for underrepresented groups. Comparing recruitment strategies on participant accrual and cost can inform the use of cost-effective recruitment strategies for enrollment of diverse populations of cancer patients. In this study, we compared social media, internet sites, and clinic-based recruitment on accrual, cost, and characteristics of cancer patients (i.e., sociodemographic, cancer type/stage, and smoking habits) enrolled in a randomized trial of app-based smoking cessation interventions. Fisher's exact tests for categorical variables and analysis of variance for continuous variables were used to compared data between recruitment strategies. In 35 months, 427 cancer patients from 45 US states enrolled in the trial out of 3,936 screened (rate of participation, 10.8%). Social media recruited over eight times the number of enrolled participants (n=340, 79.6%) compared with Internet sites (n=43, 10.1%) and clinics (n=42, 9.8%). Most (80.1%) participants were women, with mean age 52.3 years. About 20.4% of participants were from underrepresented racial/ethnic backgrounds, 23.0% were rural residents, and 23.7% were uninsured. Over 32 cancer types and all cancer stages were represented. Breast cancer was the most common diagnosis (n=129/427, 30.2%), followed by lung cancer (n=96/427, 23.8%). Internet recruitment generated a higher proportion of men (30.2% vs. 26.2% clinics vs. 17.4% social media, P=.005). Clinics generated a higher proportion of Hispanic participants (9.5% vs. 7.0% Internet vs. 2.6% social media, P=.04) and cancer patients aged 65 and older (28.6% vs. 11.5% social media vs. 4.7% Internet, P=.01). Social media recruited a higher proportion of participants with low income (<$20,000: 39.1% vs. 23.3% Internet vs. 19.0% clinics, P<.001), who tended to have later stage cancers (stage IV: 17.4% vs. 14.0% Internet vs. 7.1% clinics, P=.05). Cost per randomized participant ranged from $270 via social media to $454 via Internet sites to $2,240 via clinic-based recruitment. In conclusion, social media was the most efficient and cost-effective method for recruiting a quality sample of racially/ethnically, geographically, socioeconomically, and clinically diverse sample of cancer patients into a smoking cessation clinical trial. Social media has solid potential for recruiting cancer patients into behavioral clinical trials.}, }
@article {pmid40083364, year = {2025}, author = {Selby, LD and Wallner, K and Hall, E and Mayr, N and Chvetsov, A and Stacey, AW}, title = {Simultaneous conjunctival melanomas in one eye treated with both adjuvant brachytherapy and proton beam radiotherapy.}, journal = {American journal of ophthalmology case reports}, volume = {38}, number = {}, pages = {102281}, pmid = {40083364}, issn = {2451-9936}, abstract = {PURPOSE: We describe a rare case of two simultaneous primary conjunctival melanomas in the same eye that were treated sequentially with both plaque brachytherapy and proton beam radiotherapy following wide surgical excision.
OBSERVATIONS: A 66-year-old male presented with two pigmented lesions that were concerning for conjunctival melanoma. One of the lesions was on the bulbar conjunctiva near the corneal limbus, and the other in the lower fornix. The lesions were surgically removed using the "no touch" technique, and pathology confirmed invasive melanoma in two separate locations on the same eye. The two lesions were then treated separately with two different forms of adjuvant radiation therapy. The forniceal tumor was treated with proton beam radiotherapy and the limbal lesion was treated with plaque brachytherapy. 30 months after radiation therapy was completed, there were no signs of local recurrence.
CONCLUSIONS AND IMPORTANCE: The appropriate treatment for two primary malignancies in the same eye can be determined independently and, in some cases, can involve two different forms of radiation therapy.}, }
@article {pmid40082827, year = {2025}, author = {He, Y and Xiao, H and Liu, F and Dai, X and Wang, H and Yang, H and Liu, Z and Unger, JM}, title = {Healthcare utilization in the departments of obstetrics and gynecology during the first two years of the COVID-19 pandemic: time series analysis in Jining, China.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {996}, pmid = {40082827}, issn = {1471-2458}, support = {82204132//National Natural Science Foundation of China/ ; 2021J01721//Natural Science Foundation of Fujian Province/ ; XRCZX2020007//Startup Fund for High-level Talents of Fujian Medical University/ ; }, mesh = {Humans ; *COVID-19/epidemiology ; China/epidemiology ; Female ; Interrupted Time Series Analysis ; *Patient Acceptance of Health Care/statistics & numerical data ; *Obstetrics and Gynecology Department, Hospital/statistics & numerical data ; Adult ; *Obstetrics/statistics & numerical data ; *Gynecology/statistics & numerical data ; Hospitalization/statistics & numerical data ; Pandemics ; Pregnancy ; Tertiary Care Centers ; SARS-CoV-2 ; Middle Aged ; }, abstract = {INTRODUCTION: Healthcare utilization in China decreased precipitously during the initial outbreak of the COVID-19 pandemic, and women were disproportionately affected. As the COVID-19 pandemic has proven to be far more pervasive and persistent than many first surmised, a vital question is whether the utilization of non-COVID related healthcare has remained low under China's dynamic zero-COVID policy. This study aimed to estimate the initial and enduring collateral effects of the COVID-19 pandemic on the utilization of obstetrics and gynecology care at a tertiary hospital in Jining, Shandong Province, China.
METHODS: An interrupted time series analysis was conducted to estimate the impact of the COVID-19 pandemic and mobility restrictions on monthly counts of outpatient visits, inpatient admissions, and surgeries in the obstetrics and gynecology departments at a tertiary hospital in Jining, China. Outpatient visits and surgery volume were abstracted from the hospital's monthly healthcare delivery report, while inpatient admissions were obtained from de-identified individual electronic medical records of inpatients admitted between January 1, 2017 to December 31, 2021. Incidence Rate Ratios (IRRs) representing monthly service counts compared with counterfactual counts (had the pandemic not happened) and the volume (number) of patients lost due to the pandemic were estimated.
RESULTS: During the study period, there were a total of 1 181 120 outpatient visits, 89 550 inpatient admissions and 49 056 surgeries in the obstetrics department; and 847 124 outpatient visits, 42 644 inpatient admissions and 39 653 surgeries of these totals occurred in the gynecology department. Compared to the expected estimates had the pandemic not occurred, a 55.4% (95% CI: 52.6-57.9%; p < 0.001), 31.1% (95% CI: 27.2 - 34.7%; p < 0.001), and 27.6% (95% CI: 23.2- 31.8%; p < 0.001) decrease was observed in obstetric outpatient visits, inpatient admissions, and surgeries, respectively in the month of February 2020 when the lockdown was enforced; and a 87.4% (95% CI: 86.0 - 88.4%; p < 0.001), 74.6% (95% CI: 71.0 -79.2%; p < 0.001), and 75.5% (95% CI: 70.9 - 77.8%; p < 0.001) decrease was observed in gynecologic outpatient visits, inpatient admissions, and surgeries, respectively. As of December 2021, outpatient (IRR = 0.86; 95% CI: 0.80-0.94; p < 0.001), surgery (IRR = 0.88; 95% CI: 0.82-0.95; p < 0.001), and inpatient (IRR = 0.73; 95% CI: 0.68-0.79; p < 0.0001) services in the obstetrics department, and outpatient visits (IRR = 0.90; 95% CI: 0.82-0.89; p = 0.007) in the gynecology department had not fully recovered to pre-pandemic levels. Rural residents experienced a larger immediate decrease in inpatient care utilization in both obstetrics and gynecology in the month of February 2020, and the return to pre-pandemic levels in care utilization was also slower than that of urban residents.
CONCLUSIONS: The COVID-19 pandemic led to sizable disruptions in routine delivery and utilization of obstetrics and gynecology care. Disruptions were particularly substantial during the initial wave of the outbreak, and full recovery to pre-pandemic levels has not yet been achieved. The impact was more dramatic for women from rural areas, highlighting the need for policies and programs that address inequities in pandemic response and preparedness.}, }
@article {pmid40082098, year = {2025}, author = {Ramirez, M and Shah, PD and Chu, HY and Garza, L and Linde, S and Garrison, MM and Zhou, C and Bishop, S and Ibarra, G and Ko, LK}, title = {Corrigendum to "Reopening schools safely and educating youth (ROSSEY) study: Protocol for a community-based, cluster randomized controlled trial" [Contemporary Clinical Trials, 139 (2024) 107480].}, journal = {Contemporary clinical trials}, volume = {152}, number = {}, pages = {107873}, doi = {10.1016/j.cct.2025.107873}, pmid = {40082098}, issn = {1559-2030}, support = {OT2 HD107544/HD/NICHD NIH HHS/United States ; }, }
@article {pmid40080774, year = {2025}, author = {Banegas, MP and Nightingale, CL and Dressler, EV and Cooley, ME and Kamen, C and Wagner, LI and Kittel, CA and Flores, EJ and Carlos, R and Milton, A and Park, E and Parsons, SK and Wood, EG and Loh, KP and Ramsey, S and , }, title = {Screening and Referral for Health-Related Social Needs and Financial Distress: Current Processes Among National Cancer Institute Community Oncology Research Program Practices.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400902}, doi = {10.1200/OP-24-00902}, pmid = {40080774}, issn = {2688-1535}, abstract = {PURPOSE: Health-related social needs (HRSNs) are associated with adverse cancer health outcomes. We assessed the processes for screening and responding to both HRSNs and financial distress and described the methods used across National Cancer Institute Community Oncology Research Program (NCORP) practices.
METHODS: The NCORP 2022 Landscape Assessment survey focused on services to screen for and respond to HRSNs and financial distress within a national network of community oncology practices. We calculated the proportions of oncology practices that screened for and responded to HRSNs and financial distress, separately, and described the staff, tools, and methods used for each process. Multivariable logistic regression models estimated the associations between oncology practice characteristics and screening for HRSNs and financial distress.
RESULTS: The majority of community oncology practices reported screening for HRSNs (79%), and of those, most inquired about transportation (96%), family and social support (93%), housing (80%), and food security (80%). Most oncology practices reported screening for financial distress (78%). Social worker evaluation was the most common method used to screen for both HRSNs (77%) and financial distress (65%). Most oncology practices reported social work referral as the method for responding to HRSNs (89%) and financial distress (96%). Oncology practice characteristics such as having a survivorship clinic and geographic region were associated with screening for HRSNs and financial distress.
CONCLUSION: Research is needed to understand the impact of different HRSN screening and referral approaches on care delivery, clinic costs, care quality, and health outcomes of patients with cancer. These efforts are critical to generate evidence to inform best practices, clinical guidelines, and novel interventions aimed to improve cancer health equity.}, }
@article {pmid40080017, year = {2025}, author = {Gupta, A and Till, C and Vaidya, R and Hershman, DL and Unger, JM}, title = {Health Care Contact Days for Older Adults Enrolled in Cancer Clinical Trials.}, journal = {JAMA network open}, volume = {8}, number = {3}, pages = {e250778}, pmid = {40080017}, issn = {2574-3805}, mesh = {Humans ; Aged ; Male ; Female ; Aged, 80 and over ; United States ; *Neoplasms/therapy ; *Clinical Trials as Topic/statistics & numerical data ; Cohort Studies ; Medicare/statistics & numerical data ; }, abstract = {IMPORTANCE: Contact days-days with health care contact outside the home-are a measure of how much of a patient's life is consumed by health care. Clinical trials, with a more uniform patient mix and protocolized care, provide a unique opportunity to assess whether burdens differ by individuals' sociodemographic backgrounds.
OBJECTIVE: To characterize patterns of contact days for older adults with cancer participating in clinical trials.
In this cohort study, data from 6 SWOG Cancer Research Network trials across prostate, lung, and pancreatic cancers that recruited patients aged 65 years or older from 1999 to 2014 were linked with Medicare claims data. Data were analyzed from December 14, 2023, to September 26, 2024.
EXPOSURES: Demographic variables, including age, sex, self-reported race and ethnicity, and insurance status; clinical factors, such as cancer type and study-specific prognostic risk score; and social factors, such as neighborhood socioeconomic deprivation.
MAIN OUTCOMES AND MEASURES: Number of contact days, defined as number of days with contact with the health care system, percentage of health care contact days (number of contact days divided by follow-up), and sources of contact days (eg, ambulatory or inpatient) in the first 12 months after trial enrollment. Sociodemographic and clinical factors associated with contact days were examined using negative binomial regression, including an offset variable for duration of observation.
RESULTS: The study included 1429 patients (median age, 71 years [range, 65-91 years]; 1123 men [78.6%]; and 332 patients [23.5%] with rural residence). The median number of contact days was 48 (IQR, 26-71), of a median of 350 days (IQR, 178-365 days) of observation; the median percentage of contact days was 19% (IQR, 13%-29%). The most common sources of contact days were ambulatory clinician visits (median, 17 [IQR, 7-25]), tests (median, 12 [IQR, 3-24]), and treatments (median, 11 [IQR, 3-22]). A median of 70% (IQR, 50%-88%) of ambulatory contact days had only a single service performed on that day (eg, only tests). In multivariable regression, factors associated with increased contact days included age (relative risk [RR] per year, 1.02 [95% CI, 1.01-1.02]), insurance type (Medicare alone or with Medicaid or private insurance vs other: RR, 2.47 [95% CI, 2.16-2.83]), prognostic risk score (above the median vs at or below the median: RR, 1.14 [95% CI, 1.04-1.25]), and type of cancer (pancreatic vs prostate cancer: RR, 1.69 [95% CI, 1.51-1.89]; lung vs prostate cancer: RR, 1.69 [95% CI, 1.54-1.85]).
CONCLUSIONS AND RELEVANCE: In this cohort study of older adults with advanced stage cancer participating in phase 3 randomized clinical trials, patients spent nearly 1 in 5 days with health care contact. These findings highlight the need to simplify trial requirements to minimize participant burden.}, }
@article {pmid40079983, year = {2025}, author = {Gomez-Castillo, L and Cushing-Haugen, KL and Useche, M and Norouzi, A and Rizvi, Z and Ferrandino, R and Futran, N and Marchiano, E and Rodriguez, T and Harris, HR and Barber, B}, title = {High Sugar-Sweetened Beverage Intake and Oral Cavity Cancer in Smoking and Nonsmoking Women.}, journal = {JAMA otolaryngology-- head & neck surgery}, volume = {151}, number = {5}, pages = {450-457}, pmid = {40079983}, issn = {2168-619X}, mesh = {Humans ; Female ; *Sugar-Sweetened Beverages/adverse effects ; Middle Aged ; Adult ; *Mouth Neoplasms/epidemiology/etiology ; *Smoking/adverse effects/epidemiology ; Longitudinal Studies ; Risk Factors ; Incidence ; *Non-Smokers/statistics & numerical data ; United States/epidemiology ; Proportional Hazards Models ; }, abstract = {IMPORTANCE: The incidence of oral cavity cancer (OCC) is increasing among nonsmokers and young individuals without traditional risk factors worldwide. High sugar-sweetened beverage (SSB) intake is associated with various gastrointestinal cancers, but its association with OCC has not been explored.
OBJECTIVE: To evaluate the association between SSB intake and the risk of OCC among smoking and nonsmoking women participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).
This longitudinal cohort study analyzed data from women in the NHS (follow-up, 1986-2016) and NHSII (follow-up, 1991-2017) after excluding those with a history of cancer, implausible caloric intake, or missing SSB intake data. Participants were followed up until the diagnosis of OCC. Data analysis was performed from July 2023 to June 2024.
EXPOSURE: SSB intake, quantified by frequency of consumption ranging from less than 1 SSB monthly to 1 or more SSBs daily.
MAIN OUTCOME AND MEASURE: Cox proportional hazards regression models with age and questionnaire period as the time scale were used to estimate hazard ratios (HRs) and 95% CIs associated with the development of OCC for each category of SSB intake, with less than 1 SSB per month as the reference group.
RESULTS: A total of 162 602 women (mean [SD] age, 43.0 [9.9] years) were evaluated. During 30 years of follow-up, 124 invasive OCC cases were documented. In multivariable-adjusted models, participants consuming 1 or more SSB daily (5 people per 100 000 population) had a 4.87 times (95% CI, 2.47-9.60 times) higher risk of OCC compared with those consuming less than 1 SSB monthly (2 people per 100 000 population), increasing the rate of OCC to 3 more people per 100 000 population. When restricted to both nonsmokers or light smokers and nondrinkers or light drinkers, the risk of OCC was 5.46 times (95% CI, 1.75-17.07 times) higher, increasing the rate of OCC to 3 more people per 100 000 population.
CONCLUSIONS AND RELEVANCE: In this study, high SSB intake was associated with a significantly increased risk of OCC in women, regardless of smoking or drinking habits, yet with low baseline risk. Additional studies are needed in larger cohorts, including males, to validate the impact of these findings.}, }
@article {pmid40079097, year = {2025}, author = {Portuguese, AJ and Huang, JJ and Jeon, Y and Taheri, M and Albittar, A and Liang, EC and Hirayama, AV and Kimble, EL and Iovino, L and Poh, C and Gopal, AK and Shadman, M and Till, BG and Milano, F and Chapuis, AG and Otegbeye, F and Cassaday, RD and Basom, RS and Wu, QV and Maloney, DG and Gauthier, J}, title = {Real-world comparison of lisocabtagene maraleucel and axicabtagene ciloleucel in large B-cell lymphoma: an inverse probability of treatment weighting analysis with 3-year follow up.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.287010}, pmid = {40079097}, issn = {1592-8721}, abstract = {Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are FDA- and EMAapproved chimeric antigen receptor (CAR) T-cell therapies for relapsed/refractory large B-cell lymphoma (LBCL). However, comparative real-world analyses of their efficacy and toxicity with extended follow-up are lacking. We conducted a retrospective study of 160 LBCL patients treated at the Fred Hutchinson Cancer Center with commercial liso-cel or axi-cel per standard of care. Using inverse probability of treatment weighting (IPTW) to mitigate treatment allocation bias and multivariable adjustments to minimize other sources of confounding, we assessed the impact of CAR T-cell product type on outcomes. Axi-cel was associated with significantly higher rates of cytokine release syndrome (CRS; G1+: adjusted OR [aOR] 4.27, p=0.004; G2+: aOR 2.88, p=0.006), immune effector cell-associated neurotoxicity syndrome (ICANS; G1+: aOR 2.10, p=0.048), and immune effector cell-associated hematotoxicity (ICAHT; G1+: aOR 8.09, p.}, }
@article {pmid40075650, year = {2025}, author = {Bar, M and El Anbari, M and Rinchai, D and Toufiq, M and Kizhakayil, D and Manjunath, HS and Mathew, R and Cavattoni, I and Forer, S and Recla, M and Bibawi, H and Alater, A and Yahia, R and Brown, C and Miles, NL and Vo, P and Bedognetti, D and Tomei, S and Saleh, A and Cugno, C and Chaussabel, D and Deola, S}, title = {Whole-Blood Longitudinal Molecular Profiling Maps the Road of Graft Versus Host Disease (GVHD).}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075650}, issn = {2072-6694}, support = {NPRP13S-0107-200023 to Sara Deola//QNRF/ ; }, abstract = {Background: Graft versus host disease (GVHD) and the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplantation (allo-HCT) result from complex interactions between the donor immune system and the recipient environment. High-temporal longitudinal monitoring might be necessary to identify triggering events of GVHD and GVT and to intercept these events before their occurrence. But it would require an overall considerable amount of blood by venipuncture, which is unfeasible in such a fragile population. Methods: In this study, we implemented a targeted multiplex microfluidics q-PCR-based transcriptional fingerprint assay (TFA) on 50 µL of blood collected by a simple fingerstick to evaluate post-allo-HCT systemic immune perturbations associated with the development of GVHD. Fluctuations of a panel of 264 genes were measured in 31 allo-HCT patients by frequent (weekly or biweekly) analysis of 50 µL serial blood samples. Cross-sectional and longitudinal analyses correlated with detailed clinical annotations were performed. Results: Signatures of neutrophil activation and interferon (IFN) characterized the onset of acute GVHD, while an ongoing cytotoxic response was modulated in chronic mild GVHD and protein-synthesis and B-cell-related signatures characterized late acute/overlap GVHD. An unexpected erythroid signature distinguished patients with acute and mild chronic GVHD. Conclusions: Our micro-invasive approach unveiled the molecular heterogeneity of GVHD and identified hierarchically important biological processes conducive to different forms of GVHD. These findings increase our understanding of GVHD and reveal potentially targetable alterations. This approach might be implemented clinically to intercept GVHD before its occurrence and to modulate therapeutic interventions accordingly.}, }
@article {pmid40075647, year = {2025}, author = {Roeker, LE and Burke, JM and Rhodes, JM and Emechebe, N and Jawaid, D and Manzoor, BS and Jensen, CE and Ryland, L and Liu, Y and Marx, SE and Sinai, W and Roser, J and Shadman, M}, title = {Real-World Effectiveness of Frontline Treatments Among Patients with Chronic Lymphocytic Leukemia: Results from ConcertAI.}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075647}, issn = {2072-6694}, support = {N/A//AbbVie (United States)/ ; }, abstract = {Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6-10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019-March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1-36.6) for first-generation cBTKis, 13.4 (7.3-21.7) for second-generation cBTKis, 16.0 (8.4-27.8) for VenO, 21.8 (11.2-32.7) for CT/CIT, and 19.7 (10.0-33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2-25.0) and 8.6 (3.0-16.1), 9.1 (5.9-12.2), 5.6 (3.2-5.8), and 1.6 (1.6-4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years' follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies.}, }
@article {pmid40074150, year = {2025}, author = {Paulson, KG and Park, SY and Bhatia, S and Hippe, DS and Nghiem, P}, title = {Improved survival at the population level for patients with advanced Merkel cell carcinoma following availability of immunotherapy.}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {1}, pages = {89-94}, pmid = {40074150}, issn = {1097-6787}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/mortality/drug therapy/pathology/therapy/immunology ; *Skin Neoplasms/mortality/pathology/drug therapy/therapy/immunology ; Male ; Female ; SEER Program/statistics & numerical data ; Aged ; United States/epidemiology ; *Immune Checkpoint Inhibitors/therapeutic use ; Aged, 80 and over ; Middle Aged ; Survival Rate ; *Immunotherapy ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with poor survival rates. Immune checkpoint inhibitors (ICIs) were Food and Drug Administration-approved for advanced MCC in 2017, but their real-world survival impact remains unclear.
OBJECTIVE: Evaluate whether ICI introduction in the United States corresponded with improved survival.
METHODS: This cohort study analyzed Surveillance, Epidemiology, and End Results data for MCC patients diagnosed from 2010 to 2021, grouped by 3-year periods, to calculate 2-year overall and relative survival.
RESULTS: For 453 patients with metastatic MCC, 2-year relative survival improved from 23% (2010-2012) to 37% (2013-2015), 42% (2016-2018), and 54% (2019-2021) (P < .001). Median overall survival also increased from 9 to 16 months among these patients. In 4786 MCC patients overall, 2-year relative survival rose from 73% (2010-2012) to 81% (2019-2021) (P = .004), while overall survival improved from 67% to 72% (P = .012).
LIMITATIONS: Surveillance, Epidemiology, and End Results lacks case-level data to link ICI treatment directly to survival, although ICIs represent the major recent treatment advance for MCC.
CONCLUSIONS: The introduction of ICIs aligns with a >2-fold increase in survival for advanced MCC patients at the population level, translating to ∼220 fewer deaths per year in the United States.}, }
@article {pmid40073862, year = {2025}, author = {Khyzha, N and Ahmad, K and Henikoff, S}, title = {Profiling transcriptome composition and dynamics within nuclear compartments using SLAM-RT&Tag.}, journal = {Molecular cell}, volume = {85}, number = {7}, pages = {1366-1380.e4}, pmid = {40073862}, issn = {1097-4164}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; *Cell Nucleus/genetics/metabolism ; Chromatin/metabolism/genetics ; *Transcriptome ; *Gene Expression Profiling/methods ; Polycomb-Group Proteins/genetics/metabolism ; RNA Processing, Post-Transcriptional ; RNA, Messenger/genetics/metabolism ; RNA Splicing ; }, abstract = {Nuclear compartments are membrane-less regions enriched in functionally related molecules. RNA is a major component of many nuclear compartments, but the identity and dynamics of transcripts within nuclear compartments are poorly understood. Here, we applied reverse transcribe and tagment (RT&Tag) to human cell lines to identify the transcript populations of Polycomb domains and nuclear speckles. We also developed SLAM-RT&Tag, which combines RNA metabolic labeling with RT&Tag, to quantify transcript dynamics within nuclear compartments. We observed unique transcript populations with differing structures and dynamics within each compartment. Intriguingly, exceptionally long genes are transcribed adjacent to Polycomb domains and are transiently associated with chromatin. By contrast, nuclear speckles act as quality control checkpoints that transiently confine incompletely spliced polyadenylated transcripts and facilitate their post-transcriptional splicing. In summary, we demonstrate that transcripts at Polycomb domains and nuclear speckles undergo distinct RNA processing mechanisms, highlighting the pivotal role of compartmentalization in RNA maturation.}, }
@article {pmid40073837, year = {2025}, author = {Gajjar, A and Mahajan, A and Bale, T and Bowers, DC and Canan, L and Chi, S and Cluster, A and Cohen, K and Cole, B and Coven, S and Darlington, W and Dorris, K and Elster, J and Ermoian, R and Franson, A and George, E and Helgager, J and Landi, D and Lin, C and Metrock, L and Nanda, R and Palmer, J and Partap, S and Plant, A and Pruthi, S and Reynolds, R and Stearns, D and Storm, P and Wang, A and Wang, LD and Whipple, N and Zaky, W and McMillian, N and Ramakrishnan, S}, title = {Pediatric Central Nervous System Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {113-130}, doi = {10.6004/jnccn.2025.0012}, pmid = {40073837}, issn = {1540-1413}, mesh = {Humans ; Child ; *Central Nervous System Neoplasms/therapy/diagnosis ; *Medical Oncology/standards ; Adolescent ; Neoplasm Staging ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.}, }
@article {pmid40073835, year = {2025}, author = {Greenberg, PL and Stone, RM and Abaza, Y and Al-Kali, A and Anand, S and Ball, B and Bennett, JM and Borate, U and Brunner, AM and Chai-Ho, W and Curtin, P and DeZern, AE and Gaensler, K and Gahvari, Z and Garcia-Manero, G and Griffiths, EA and Haque, T and Jacoby, M and Jonas, BA and Keel, S and Khanal, R and Kishtagari, A and Madanat, Y and Maness, LJ and McCurdy, SR and McMahon, C and Odenike, O and Osman, A and Reddy, VV and Sallman, DA and Sayar, H and Shallis, R and Singh, A and Tanaka, T and Thota, S and Kovach, E and Nguyen, J and Hochstetler, C}, title = {NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {66-75}, doi = {10.6004/jnccn.2025.0013}, pmid = {40073835}, issn = {1540-1413}, mesh = {Humans ; *Myelodysplastic Syndromes/diagnosis/therapy/etiology ; Prognosis ; *Medical Oncology/standards ; }, abstract = {The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.}, }
@article {pmid40073834, year = {2025}, author = {Narkhede, M and Ujjani, CS}, title = {Immune Dysfunction and Consequences in Chronic Lymphocytic Leukemia.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {3}, pages = {}, doi = {10.6004/jnccn.2024.7090}, pmid = {40073834}, issn = {1540-1413}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/immunology/complications/therapy ; Agammaglobulinaemia Tyrosine Kinase ; }, abstract = {Infectious complications are among the leading causes of mortality in chronic lymphocytic leukemia (CLL). Over the past decade, several advances have been made in treating CLL through inhibition of Bruton tyrosine kinase and the antiapoptotic protein BCL-2. As mortality from CLL progression is expected to decline in the next several years, mortality from severe infections is anticipated to increase. Therefore, understanding the nature of immune defects in CLL and developing strategies to augment the impaired immune system are needed to keep pace with advancements in treatment. This review article summarizes the available data on immune dysfunctions, their clinical consequences, therapeutic implications, and current strategies to enhance immune function in patients with CLL.}, }
@article {pmid40073280, year = {2025}, author = {Barros, M and Leon, A and Crivera, C and Cusson, E and Kodjamanova, P and Bagnall, R and Panch, SR}, title = {Literature review of occurrence, effectiveness, safety, and hospitalization burden of blood transfusion in the management of warm autoimmune hemolytic anemia.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {30}, number = {1}, pages = {2472489}, doi = {10.1080/16078454.2025.2472489}, pmid = {40073280}, issn = {1607-8454}, mesh = {Humans ; *Anemia, Hemolytic, Autoimmune/therapy/epidemiology ; *Hospitalization ; *Erythrocyte Transfusion/adverse effects ; *Blood Transfusion ; Treatment Outcome ; Disease Management ; }, abstract = {INTRODUCTION: Cases of warm autoimmune hemolytic anemia (wAIHA) often present with life-threatening levels of hemoglobin requiring red blood cell (RBC) transfusion support.
AIM: This literature review assessed the occurrence, safety, effectiveness, and hospitalization burden of RBC transfusions in the management of patients with wAIHA.
METHODS: Electronic databases (Embase, MEDLINE) were searched from inception to December 2021 along with additional searches conducted up to March 2024.
RESULTS: Of the 1478 articles screened, 17 observational studies and reviews were included. These studies demonstrated the use of 1-50 red blood cell transfusions to reach clinically acceptable hemoglobin levels in patients with wAIHA. In general, pre-transfusion hemoglobin levels were 6 g/dL and increased by an average 1.2 g/dL following a transfusion. Approximately 50% of patients with primary or secondary wAIHA suffered relapses. No data was available to distinguish between RBC transfusions used at initial presentation versus during relapse. Five studies found no increase in hemolysis or serious adverse reactions following transfusions and two studies reported mild transfusion-related adverse effects. Limited data was available regarding the hospitalization burden of RBC transfusion. Patients with wAIHA requiring transfusions had a median hospital stay from 15 to 17 days, which is considerably higher than all causes hospitalization of 4.5 days for 2023 U.S.
CONCLUSION: In patients with wAIHA, data supports wide variability in occurrence, but relative safety and effectiveness of RBC transfusions as supportive therapy. Additional studies are needed to assess the occurrence, safety, and hospitalization burden of RBC transfusions relative to other therapies in chronic relapsing wAIHA.}, }
@article {pmid40072429, year = {2025}, author = {Heng, F and Sun, Y and Li, L and B Gilbert, P}, title = {Estimation and Hypothesis Testing of Strain-Specific Vaccine Efficacy With Missing Strain Types With Application to a COVID-19 Vaccine Trial.}, journal = {Statistics in medicine}, volume = {44}, number = {6}, pages = {e10345}, pmid = {40072429}, issn = {1097-0258}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; AI068635/NH/NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; DMS1915829//National Science Foundation/ ; R37AI054165/NH/NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/immunology ; *COVID-19/prevention & control/virology ; *SARS-CoV-2/genetics/immunology ; Computer Simulation ; *Vaccine Efficacy/statistics & numerical data ; Genotype ; Randomized Controlled Trials as Topic/statistics & numerical data ; Models, Statistical ; }, abstract = {Based on data from a randomized, controlled vaccine efficacy trial, this article develops statistical methods for assessing vaccine efficacy (VE) to prevent COVID-19 infections by a discrete set of genetic strains of SARS-CoV-2. Strain-specific VE adjusting for possibly time-varying covariates is estimated using augmented inverse probability weighting to address missing viral genotypes under a competing risks model that allows separate baseline hazards for different risk groups. Hypothesis tests are developed to assess whether the vaccine provides at least a specified level of VE against some viral genotypes and whether VE varies across genotypes. Asymptotic properties providing analytic inferences are derived and finite-sample properties of the estimators and hypothesis tests are studied through simulations. This research is motivated by the fact that previous analyses of COVID-19 vaccine efficacy did not account for missing genotypes, which can cause severe bias and efficiency loss. The theoretical properties and simulations demonstrate superior performance of the new methods. Application to the Moderna COVE trial identifies several SARS-CoV-2 genotype features with differential vaccine efficacy across genotypes, including lineage (Reference, Epsilon, Gamma, Zeta), indicators of residue match vs. mismatch to the vaccine-strain residue at Spike amino acid positions (identifying signatures of differential VE), and a weighted Hamming distance to the vaccine strain. The results show VE decreases against genotypes more distant from the vaccine strain, highlighting the need to update COVID-19 vaccine strains.}, }
@article {pmid40071691, year = {2025}, author = {Huang, Y and Kwan, ML and Heckbert, SR and Smith, NL and Othus, M and Laurent, CA and Roh, JM and Rillamas-Sun, E and Lee, VS and Kolevska, T and Cheng, RK and Irribarren, C and Nguyen-Huynh, M and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Endocrine therapy and risk of cardiovascular disease and mortality in postmenopausal breast cancer survivors.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {7}, pages = {1401-1409}, doi = {10.1093/jnci/djaf063}, pmid = {40071691}, issn = {1460-2105}, support = {R01CA214057//MPIs/ ; R01CA105274//MPIs/ ; U01CA195565//MPIs/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/mortality/pathology/epidemiology ; Postmenopause ; *Cardiovascular Diseases/epidemiology/mortality/chemically induced ; Middle Aged ; Aged ; *Aromatase Inhibitors/adverse effects/therapeutic use/administration & dosage ; *Antineoplastic Agents, Hormonal/adverse effects/therapeutic use ; *Cancer Survivors/statistics & numerical data ; *Tamoxifen/adverse effects/therapeutic use/administration & dosage ; Body Mass Index ; Risk Factors ; Follow-Up Studies ; }, abstract = {BACKGROUND: There are increasing concerns of cardiovascular safety related to endocrine therapy use in women with breast cancer (BC). We examined risk of cardiovascular disease (CVD) events and mortality associated with endocrine therapy use in postmenopausal women with early-stage BC.
METHODS: Postmenopausal women diagnosed with stage I-III hormone receptor-positive BC from 2005 to 2013 were included (n = 8495). Women were classified as aromatase inhibitor (AI) users, tamoxifen users, and non-users of endocrine therapy in the 12 months after BC diagnosis. Likelihood ratio tests examined whether the association of endocrine therapy use with CVD and mortality outcomes varied by body mass index (BMI) and history of CVD before BC diagnosis.
RESULTS: Over a median follow-up of 7.5 years, women who used AIs were less likely to develop major adverse cardiovascular events (MACE) (HR = 0.84, 95% CI = 0.73 to 0.97) and heart failure (HR = 0.81, 95% CI = 0.66 to 0.99) compared with non-users of endocrine therapy. No associations between tamoxifen use and CVD outcomes were observed. AI use was associated with lower risk all-cause, CVD-related, and non-CVD-related mortality, compared with non-use of endocrine therapy. Tamoxifen use was associated with lower risk of all-cause mortality and non-CVD-related mortality, compared with non-use of endocrine therapy, and the association was modified by BMI (P for interaction < .05).
CONCLUSION: Our findings suggest endocrine therapy use reduces all-cause mortality risk and may not increase CVD risk in postmenopausal women with early-stage hormone receptor-positive BC.}, }
@article {pmid40071498, year = {2025}, author = {Mehta, RS and Choe, H and Saultz, J and Gong, Z and Sharma, P and Al-Juhaishi, T and Petitto, GS and Lazaryan, A and Singh, A and Xue, E and Dimitrova, D and Hyder, M and McCurdy, S and Im, A and Huber, B and Aljawai, YM and Kanakry, J and Milano, F and Kanakry, CG}, title = {Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation.}, journal = {American journal of hematology}, volume = {100}, number = {6}, pages = {987-997}, doi = {10.1002/ajh.27662}, pmid = {40071498}, issn = {1096-8652}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Cytomegalovirus Infections/prevention & control/etiology/mortality ; Male ; Female ; Middle Aged ; Adult ; *Cytomegalovirus ; *Tissue Donors ; Age Factors ; Adolescent ; Graft vs Host Disease/prevention & control ; Transplantation, Homologous ; Aged ; *Donor Selection ; Cyclophosphamide/therapeutic use ; Young Adult ; }, abstract = {Cytomegalovirus (CMV) infection post-hematopoietic cell transplantation (HCT) remains a significant cause of morbidity and mortality. While letermovir prophylaxis is available for CMV-seropositive recipients, optimal donor selection for CMV-seronegative recipients remains unclear, with donor age often prioritized over CMV serostatus. We investigated the relative impact of donor age and CMV serostatus in CMV-seronegative recipients (n = 1013) with either CMV-seropositive (n = 318) or CMV-seronegative donors (n = 695), who underwent HCT with HLA-matched sibling donors with calcineurin inhibitor-based or post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis, or haploidentical donors with PTCy. Multiple conventional and machine-learning approaches were employed to account for confounding factors. Across all analyses, CMV-seropositive donor status was consistently associated with significantly inferior overall survival (OS) and disease-free survival, primarily driven by increased non-relapse mortality (NRM). Older donor age showed a statistically significant association with OS and DFS in some but not all models, and its effect size was small (about 1% increased hazard per year in Cox proportional hazard model) compared to the substantial impact of CMV-seropositive donors (about 27%-33% increased hazards for worse OS, approximately 50%-60% higher NRM in Cox proportional hazard model). However, our machine learning model revealed a more nuanced and complex non-linear effect of donor age, further demonstrating the adverse impact of donor CMV serostatus. Our findings suggest that prioritizing a CMV-seronegative donor may be associated with improved outcomes in CMV-seronegative recipients. Further research is needed to validate these findings and explore underlying mechanisms.}, }
@article {pmid40071446, year = {2025}, author = {Julceus, EF and Liese, AD and Alfalki, AM and Brown, AD and Pihoker, C and Qu, P and Malik, FS and Jones-Smith, JC and Crow, S and Loots, B and Reboussin, BA and Dolan, LM and Igudesman, D and Sauder, KA and Shapiro, ALB and Turley, CB and Mendoza, JA}, title = {The Association of Levels of Food Insecurity and Disordered Eating Behaviors Among Youth and Young Adults With Diabetes: The SEARCH for Diabetes in Youth Study.}, journal = {The International journal of eating disorders}, volume = {58}, number = {6}, pages = {1039-1047}, pmid = {40071446}, issn = {1098-108X}, support = {1UC4DK108173/DK/NIDDK NIH HHS/United States ; UC4 DK108173/DK/NIDDK NIH HHS/United States ; /CC/CDC HHS/United States ; R01 DK117461/DK/NIDDK NIH HHS/United States ; R01DK117461/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Food Insecurity ; Female ; Male ; *Feeding and Eating Disorders/epidemiology/psychology ; Cross-Sectional Studies ; Adolescent ; Young Adult ; *Diabetes Mellitus, Type 1/psychology/complications/epidemiology ; *Diabetes Mellitus, Type 2/psychology/complications/epidemiology ; Adult ; *Feeding Behavior/psychology ; *Food Supply ; }, abstract = {OBJECTIVE: To examine the relationship between levels of household food insecurity and disordered eating behaviors (DEB) among youth and young adults with youth-onset type 1 (T1D) and type 2 diabetes (T2D).
METHOD: We used cross-sectional data from the multicenter SEARCH for Diabetes in Youth Study (2015-2020). The Household Food Security Survey Module and the Diabetes Eating Problem Survey-Revised (DEPS-R) were utilized to measure household food insecurity and continuous scores for DEB. In each stratum of diabetes type, we evaluated the association of household food insecurity levels with DEB through linear regression adjusting for potential confounders.
RESULTS: Participants (n = 2669) were on average 21.5 ± 5.1 years old and had a mean diabetes duration of 11.2 ± 3.3 years; 54.2% were female, 64.0% non-Hispanic white, and respectively 12.9%, 11.1%, and 8.43% experienced marginal, low, and very low food security. The overall unadjusted mean DEPS-R score was 13.5 ± 9.5, with scores of 18.6 ± 11.8 and 21.1 ± 11.7 among T1D and T2D participants with very low food security, and scores of 11.5 ± 8.9 and 15.2 ± 8.8 among T1D and T2D participants with high food security. Compared to participants who reported high food security, adjusted DEPS-R scores among those with very low food security were 5.8 points (95% CI: 4.3, 7.4) and 6.6 points (95% CI: 3.3, 9.2) higher, respectively, in those with T1D (n = 2274) and T2D (n = 395). Less severe levels of household food insecurity showed similar associations with smaller effect sizes.
DISCUSSION: Addressing household food insecurity may decrease DEB and future adverse health outcomes for youth and young adults with diabetes.}, }
@article {pmid40070357, year = {2025}, author = {Gust, J and Cole, BL and Ronsley, R and Wilson, AL and Seidel, K and Wendler, J and Pattabhi, S and Brown, C and Rawlings-Rhea, SD and Shtanukhina, N and Browd, SR and Hauptman, JS and Lee, A and Ojemann, JG and Crotty, EE and Leary, SES and Perez, FA and Wright, JN and Albert, CM and Pinto, N and Gardner, RA and Vitanza, NA and Jensen, MC and Park, JR}, title = {Locoregional Infusion of EGFR806-CAR T Cells for Recurrent or Refractory Pediatric CNS Tumors: Results of the Completed BrainChild02 Phase 1 Clinical Trial.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaf064}, pmid = {40070357}, issn = {1523-5866}, abstract = {BACKGROUND: Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII.
METHODS: In this open-label phase 1 clinical trial, patients age 1-26 years with EGFR+ CNS tumors received weekly infusions of 1-2.5 x 107 CAR T cells into the tumor resection bed or the lateral ventricle via an implanted catheter. No lymphodepletion was used.
RESULTS: Eleven patients were enrolled. Four (3 with high-grade glioma, 1 with atypical teratoid-rhabdoid tumor) were treated and received 5-10 CAR T cell infusions without dose-limiting toxicities. The trial closed prior to reaching planned dose regimens. All treatment-related adverse events were no higher than CTCAE grade 2. The most common were headache and nausea. One patient had a grade 1 seizure, and three had new sensory changes, weakness and/or urinary changes (grade 1-2) that were possibly related to CAR T cell infusion. Three of the four treated patients had progressive disease. One patient with spinal cord diffuse midline glioma had progressive peritumoral edema that could not be conclusively attributed to either progression or pseudoprogression and was therefore defined as stable disease, followed by a complete response to subsequent chemotherapy.
CONCLUSIONS: Intracranially infused EGFR806-CAR T cells were tolerable at tested doses, with a best response of stable disease. EGFR is a potentially useful target for cellular therapy against pediatric brain tumors, particularly high-grade gliomas.}, }
@article {pmid40067465, year = {2025}, author = {Nelson, JL and Lambert, NC}, title = {The when, what, and where of naturally-acquired microchimerism.}, journal = {Seminars in immunopathology}, volume = {47}, number = {1}, pages = {20}, pmid = {40067465}, issn = {1863-2300}, support = {117737/HL/NHLBI NIH HHS/United States ; 45659//Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases/ ; R01 HL117737/HL/NHLBI NIH HHS/United States ; R01 AI045659/AI/NIAID NIH HHS/United States ; R03 AI159288/AI/NIAID NIH HHS/United States ; R21 NS118249/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Chimerism ; Pregnancy ; Female ; *Maternal-Fetal Exchange/immunology/genetics ; Animals ; HLA Antigens/immunology/genetics ; Autoimmune Diseases/immunology ; }, abstract = {Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.}, }
@article {pmid40067336, year = {2025}, author = {Shadman, M and Fakhri, B and Jain, N}, title = {Consensus in CLL: global needs matter.}, journal = {Blood advances}, volume = {9}, number = {5}, pages = {1210-1212}, pmid = {40067336}, issn = {2473-9537}, }
@article {pmid40067123, year = {2025}, author = {Wuliji, N and Jones, SMW and Gooley, T and Gerds, AT and Medeiros, BC and Shami, PJ and Galvin, J and Adekola, K and Luger, S and Baer, MR and Rizzieri, D and Wildes, TM and Wang, ES and Sekeres, MA and Mukherjee, S and Smith, J and Garrison, M and Kojouri, K and Appelbaum, J and Percival, ME and Sandmaier, BM and Lee, S and Appelbaum, FR and Rouce, R and Sorror, ML}, title = {Social determinants of health and access to allogeneic hematopoietic cell transplantation for acute myeloid leukemia.}, journal = {Blood}, volume = {145}, number = {25}, pages = {3041-3051}, doi = {10.1182/blood.2024027543}, pmid = {40067123}, issn = {1528-0020}, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Health Services Accessibility ; *Hematopoietic Stem Cell Transplantation ; *Leukemia, Myeloid, Acute/therapy/mortality ; Prospective Studies ; *Social Determinants of Health ; Transplantation, Homologous ; }, abstract = {Whether allogeneic hematopoietic cell transplant (allo-HCT) to treat acute myeloid leukemia (AML) is equitably accessible regardless of social determinants of health (SDOH) remains unknown. We examined associations of SDOH with access to allo-HCT and other outcomes. Patients presenting for treatment (n = 692) at 13 AML treatment centers were prospectively recruited to a registered clinical trial (number NCT01929408). Various patient-, AML-, and SDOH-specific variables were collected. Outcomes included mortality without allo-HCT, receipt of allo-HCT, and mortality after allo-HCT. Individual multivariable models (Fine-Gray for the first 2 outcomes, Cox regression for the third) were fit for each SDOH variable, adjusting for relevant patient- and AML-specific variables. Allo-HCT was used to treat 46% of patients. A 10% increase in the proportion with less than a high school education, in households receiving Supplemental Nutrition Assistance Program, receiving Supplemental Security Income, or in poverty led to modeled adjusted hazard ratios (aHRs) of 1.21 (0.99-1.46), 1.13 (0.97-1.31), 1.41 (1.01-1.97), and 1.16 (0.96-1.39) for death without allo-HCT. The aHRs were 0.67 (0.55-0.83), 0.88 (0.76-1.01), 0.71 (0.48-1.05), and 0.91 (0.75-1.09) for lessened receipt of allo-HCT. Among those who received allo-HCT, aHRs for mortality were 1.18 (0.87-1.60), 1.13 (0.92-1.38), 1.21 (0.81-1.82), and 1.04 (0.79-1.36). Results highlight increased mortality without allo-HCT and decreased access to allo-HCT, but lesser magnitude of increased mortality after allo-HCT, among patients from lower resourced areas due to limited education and/or increased poverty. Targeted interventions and policy changes are needed to ensure that marginalized patient populations have equitable chances for AML cure compared with others.}, }
@article {pmid40066650, year = {2025}, author = {Donzella, SM and Bryer, BN and VoPham, T and Weaver, MD and Watson, NF and Zhong, C and Patel, AV and Phipps, AI}, title = {Chronotype, sleep timing, sleep regularity, and cancer risk: A systematic review.}, journal = {Sleep}, volume = {48}, number = {6}, pages = {}, pmid = {40066650}, issn = {1550-9109}, mesh = {Humans ; *Sleep/physiology ; *Neoplasms/epidemiology/etiology ; *Circadian Rhythm/physiology ; Risk Factors ; Time Factors ; Incidence ; Chronotype ; }, abstract = {Sleep is a multidimensional modifiable lifestyle factor related to cancer risk. Prior research has primarily focused on sleep duration, despite the increasing importance of sleep timing and sleep regularity in the health research field. The objective of this systematic review was to synthesize the existing literature on the relationship of chronotype, sleep timing, and sleep regularity with cancer risk. We searched four databases (PubMed, CINAHL, PsychInfo, and Embase) in October 2024. The sleep exposures of interest included sleep timing, sleep regularity, sleep midpoint, social jetlag, chronotype, and weekend catch-up sleep, and the outcome of interest was cancer incidence (overall or site-specific). A total of 22 studies were included, of which 18 investigated chronotype, two investigated social jetlag, two investigated sleep midpoint, and one investigated weekend catch-up sleep as the sleep exposure. The majority of studies assessed sleep using self-reported questionnaires (95%) and investigated site-specific cancer incidence (91%). We found no consistent evidence linking late chronotype, later sleep midpoint, increased social jetlag, or weekend catch-up sleep to an elevated risk of cancer. This review highlights the heterogeneity in how sleep timing and sleep regularity are assessed. Future research should standardize measures on how to quantify sleep timing and sleep regularity and replication studies in diverse populations are needed. Current evidence linking sleep timing, sleep regularity, and chronotype with cancer risk remains inconclusive.}, }
@article {pmid40065283, year = {2025}, author = {Venkataraman, A and Jia, T and Ruderman, SA and Haas, CB and Nance, RM and Mixson, LS and Mayer, KH and Saag, MS and Chander, G and Moore, RD and Jacobson, J and Napravnik, S and Christopolous, K and Lee, WJ and Whitney, BM and Peter, I and Crane, HM and Delaney, JAC and Lindström, S}, title = {A genome-wide association study of methamphetamine use among people with HIV.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {46}, pmid = {40065283}, issn = {1755-8794}, support = {R01 HG010649/HG/NHGRI NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; R24AI067039/AA/NIAAA NIH HHS/United States ; R01HG010649/NH/NIH HHS/United States ; }, mesh = {Humans ; *Methamphetamine/adverse effects ; *Genome-Wide Association Study ; *HIV Infections/genetics/complications ; Polymorphism, Single Nucleotide ; Male ; Female ; Adult ; Middle Aged ; *Amphetamine-Related Disorders/genetics ; }, abstract = {BACKGROUND: Amphetamine-like stimulants are the most used psychostimulants in the world; methamphetamine use is the most prevalent in people with HIV. Prolonged methamphetamine use can cause lasting damage to the heart, gut, and brain, as well as auditory hallucinations and paranoid thinking. However, relatively little is known about methamphetamine use and its genetic contributors.
METHODS: Using genetic information from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, we conducted a multi-ancestry genome-wide association study (GWAS) of methamphetamine use among people with HIV (n = 1,196 reported ever use, n = 4,750 reported never use).
RESULTS: No single nucleotide polymorphism was statistically associated with methamphetamine use at the genome-wide level (p < 5 * 10[-8]) in our study. Further, we did not replicate previously suggested genetic variants from other studies (all p > 0.05 in our analysis).
DISCUSSION: Our study suggests that there is no single strong genetic contributor to lifetime use of methamphetamine in people with HIV enrolled in CNICS. Larger studies with more refined outcome assessment are warranted to further understand the contribution of genetics to methamphetamine use and use disorder. Investigation into social and environmental contributors to methamphetamine use are similarly necessary.}, }
@article {pmid40064621, year = {2025}, author = {Salerno, S and Yang, E and Dahlerus, C and Hirth, RA and Han, P and Xu, T and Eckard, A and Agbenyikey, W and Horton, GM and Clark, S and Messana, JM and Li, Y}, title = {Adding New Components to a Composite Quality Metric: How Good Is Good Enough?.}, journal = {Medical care}, volume = {63}, number = {4}, pages = {293-299}, doi = {10.1097/MLR.0000000000002116}, pmid = {40064621}, issn = {1537-1948}, mesh = {Humans ; *Quality Indicators, Health Care/standards/statistics & numerical data ; Reproducibility of Results ; Renal Dialysis/standards ; United States ; *Quality of Health Care ; }, abstract = {OBJECTIVES: This study illustrates how the statistical reliability of an individual measure relates to the overall reliability of a composite metric, as understanding this relationship provides additional information when evaluating measures for endorsement.
BACKGROUND: National quality measure endorsement processes typically evaluate individual metrics on criteria such as importance and scientific acceptability (eg, reliability). In practice, quality measures may be used in composite rating systems, which aid in the interpretation of overall quality differences.
METHODS: We define an individual measure's reliability by its intraclass correlation and analytically establish the relationship between a composite's reliability and the reliability of its components. We use real data to confirm this relationship under various scenarios. We are motivated by 8 quality measures, which comprise the Quality of Patient Care Star Ratings on Dialysis Facility Care Compare. These measure 4 primary outcomes (mortality, hospitalizations, readmissions, and blood transfusions), vascular access (2 measures), and facility processes (2 measures).
RESULTS: Depending on the reliability of the individual measures, their respective weights in the composite, and their pairwise correlations, there are circumstances when adding a new measure, even if it is less reliable, increases the composite's reliability. For the dialysis facility Star Ratings, we find that the combined reliability of measures grouped within certain domains of care exceeded the reliability of the individual measures within those domains.
CONCLUSIONS: New quality measures may add utility to a composite rating system under certain circumstances-a consideration that should, in part, factor into quality measure endorsement processes.}, }
@article {pmid40064297, year = {2025}, author = {Ahmed, S and Pfeiffer, RM and Volesky-Avellaneda, K and Blosser, CD and Snyder, JJ and Israni, AK and Lynch, CF and Qiao, B and Rees, JR and Zwald, F and Yu, KJ and Engels, EA}, title = {Real-world evidence regarding cancer, mortality, and graft failure risk with de novo belatacept use among kidney transplant recipients in the United States.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajt.2025.03.004}, pmid = {40064297}, issn = {1600-6143}, abstract = {Belatacept is a selective T cell costimulation blocker used in maintenance immunosuppression for kidney transplant recipients (KTRs), but evidence on cancer risk and other outcomes is limited. This retrospective cohort study used linked US transplant and cancer registry data on KTRs treated with belatacept (N = 1514) or tacrolimus (N = 7570) as initial maintenance therapy. We used multivariable Cox regression models to compare the incidence of invasive cancer, cutaneous squamous cell carcinoma, posttransplant lymphoproliferative disorder (PTLD), death, and graft failure/retransplantation (GF/RT) between belatacept and tacrolimus users. Overall, cancer incidence was 10.1 and 12.6 per 1000 person-years in belatacept and tacrolimus users, respectively. We did not find increased risk with belatacept for cancer overall (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.53-1.30), individual cancer types, or cutaneous squamous cell carcinoma. Belatacept was associated with increased risk of death (adjusted HR, 1.22; 95% CI, 1.04-1.43) but lower risk of GF/RT >4 years after transplantation (adjusted HR, 0.54; 95% CI, 0.35-0.83). PTLD risk was increased among Epstein-Barr virus-seropositive KTRs (adjusted HR, 1.96; 95% CI, 1.03-3.73). This study provides reassurance that belatacept does not increase cancer risk among KTRs, and there was a long-term protective association for GF/RT. However, we found evidence suggesting a potentially increased risk of PTLD and death with belatacept use.}, }
@article {pmid40064296, year = {2025}, author = {Blosser, CD and Marks, LJ and Dharnidharka, VR}, title = {Posttransplant lymphoproliferative disorder - it's best to face this growing challenge at the start.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {25}, number = {7}, pages = {1388-1390}, doi = {10.1016/j.ajt.2025.03.006}, pmid = {40064296}, issn = {1600-6143}, }
@article {pmid40063180, year = {2025}, author = {Pete, D and Farris, PE and Adsul, P and Bea, JW and Decker, D and Ingram, J and Semprini, J and Baker, H and Yellowhair, M and Blackwater, C and Dee, C and Briant, KJ and Parker, M and Zahnd, WE and Nash, SH}, title = {The inclusion of tribes and American Indian and Alaska Native People in State comprehensive cancer control plans.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {40063180}, issn = {1573-7225}, support = {K00CA253685/CA/NCI NIH HHS/United States ; 5P30CA069533/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; P30CA015704/NH/NIH HHS/United States ; 3P30CA086862//National Institutes of Health,United States/ ; 3P30CA086862//National Institutes of Health,United States/ ; }, abstract = {PURPOSE: State and District Comprehensive Cancer Control (CCC) plans often do not include priorities for all individuals within their state or district borders. In particular, American Indian and Alaska Native (AI/AN) people experience persistent cancer disparities, yet their inclusion in CCC plans has not been examined. Our study systematically reviewed state and district CCC plans for the inclusion of Tribal-specific cancer control strategies and priorities.
METHODS: A collaborative team of researchers from Tribal serving organizations, cancer centers, and academic institutions conducted a content analysis of state CCC plans to assess terms, concepts, context, and goals related to Tribal populations across twelve domains.
RESULTS: Seventy-three percent (n = 37) of state CCC plans addressed at least one of twelve domain criteria, while 14 states (27%) did not mention Tribal data or priorities. Specifically, the terms "Indigenous or Native" (n = 29) or "American Indian, Indian Country, Reservations, or Indian Health Service" (n = 27) were referenced most often. Three states met the highest domain criteria (New Mexico, California, Montana). Six states with federally recognized tribes within their borders did not meet any domains (Alabama, Florida, Massachusetts, Missouri, Texas, Virginia).
CONCLUSION: By highlighting state and Tribal CCC plans' best practices and incorporating Tribal priorities within state and district CCC plans and programs, we underscore the importance of addressing cancer in Tribal populations across the U.S. and offer examples of inclusive CCC plan development and implementation.}, }
@article {pmid40063046, year = {2025}, author = {Raychaudhuri, R and Lin, DW and Montgomery, RB}, title = {Prostate Cancer: A Review.}, journal = {JAMA}, volume = {333}, number = {16}, pages = {1433-1446}, doi = {10.1001/jama.2025.0228}, pmid = {40063046}, issn = {1538-3598}, mesh = {Aged ; Humans ; Male ; *Adenocarcinoma/diagnosis/epidemiology/pathology/therapy ; Androgen Antagonists/therapeutic use ; Neoplasm Grading ; Prostate-Specific Antigen/blood ; Prostatectomy ; *Prostatic Neoplasms/therapy/diagnosis/epidemiology/pathology ; Risk Factors ; Watchful Waiting ; Prostate/diagnostic imaging/pathology/surgery ; Mass Screening/methods/standards ; Early Detection of Cancer/methods/standards ; Survival Rate ; Age Factors ; Androstenes/therapeutic use ; Biopsy, Large-Core Needle ; Magnetic Resonance Imaging ; }, abstract = {IMPORTANCE: Prostate cancer is the most common nonskin cancer in men in the US, with an estimated 299 010 new cases and 35 250 deaths in 2024. Prostate cancer is the second most common cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022.
OBSERVATIONS: The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years. More than 50% of prostate cancer risk is attributable to genetic factors; older age and Black race (annual incidence rate, 173.0 cases per 100 000 Black men vs 97.1 cases per 100 000 White men) are also strong risk factors. Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening. At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Based on risk stratification that incorporates life expectancy, tumor grade (Gleason score), tumor size, and PSA level, one-third of patients with localized prostate cancer are appropriate for active surveillance with serial PSA measurements, prostate biopsies, or magnetic resonance imaging, and initiation of treatment if the Gleason score or tumor stage increases. For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options; treatment decision-making should include consideration of adverse events and comorbidities. Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors. At presentation, approximately 14% of patients have metastases to regional lymph nodes. An additional 10% of men have distant metastases that are associated with a 5-year survival rate of 37%. Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists. For patients with newly diagnosed metastatic prostate cancer, the addition of androgen receptor pathway inhibitors (eg, darolutamide, abiraterone) improves survival. Use of abiraterone improved the median overall survival from 36.5 months to 53.3 months (hazard ratio, 0.66 [95% CI, 0.56-0.78]) compared with medical castration alone. Chemotherapy (docetaxel) may be considered, especially for patients with more extensive disease.
CONCLUSIONS AND RELEVANCE: Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of patients present with cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Management includes active surveillance, prostatectomy, or radiation therapy, depending on risk of progression. Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%. First-line therapies for metastatic prostate cancer include androgen deprivation and novel androgen receptor pathway inhibitors, and chemotherapy for appropriate patients.}, }
@article {pmid40062652, year = {2025}, author = {Zhang, X and Hery, C and McLaughlin, EM and Woods, NF and Neuhouser, ML and Harris, H and Gower, EW and Wactawski-Wende, J and Shadyab, AH and Wallace, RB and Paskett, ED}, title = {The Association of Long COVID-19 Symptoms, Physical Function, and Activities of Daily Living Among Older Women.}, journal = {Journal of the American Geriatrics Society}, volume = {73}, number = {6}, pages = {1711-1721}, pmid = {40062652}, issn = {1532-5415}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; K00CA253745/CA/NCI NIH HHS/United States ; //U.S. Department of Health and Human Services/ ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; K00 CA253745/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Activities of Daily Living ; *COVID-19/epidemiology/physiopathology/complications ; Aged ; Aged, 80 and over ; SARS-CoV-2 ; *Physical Functional Performance ; United States/epidemiology ; Women's Health ; Post-Acute COVID-19 Syndrome ; }, abstract = {BACKGROUND: The impact of COVID-19 on physical function (PF) outcomes among older adults remains unclear. We examined the long-term association between COVID, PF, and Activities of Daily Living (ADLs) among women from the Women's Health Initiative (WHI).
METHODS: Participants from the WHI who completed the COVID-19 survey (2021-2022) and annual survey (2022) were included. Self-reported data on COVID-19 testing and symptoms (2021-2022) were used. PF score and ADLs were evaluated pre- and post-COVID-19 survey by the 36-Item Short Form Survey PF subscale, the Lawton Instrumental Activities of Daily Living, and the Katz Index of Independence in ADL. Multivariable linear regression and logistic regression were used and adjusted for pre-COVID functioning to examine the association between COVID status, PF, and ADLs. The interaction between pre-COVID functioning and COVID status was tested.
RESULTS: Among the 13,933 WHI participants, 71.4% were aged ≥ 80 years, and 88.6% were Non-Hispanic White. Only 8.7% tested positive for COVID-19 (n = 1210), with 35.1% having long COVID (n = 425). The most common long COVID symptoms were fatigue (18.2%), malaise (12.2%), memory problems (12.1%), and brain fog (11.2%). Women who tested COVID+ had lower PF scores (60 vs. 65, p = 0.045) and were less likely to be able to do all ADLs without help (74% vs. 79.2%, p = 0.015) compared to those who never tested COVID+. After controlling for covariates, post-COVID PF scores did not differ by COVID status (p = 0.30), although pre-COVID PF scores were significantly linked to post-COVID scores (p < 0.001). Similarly, the odds of being able to do all ADLs without any help did not differ by COVID status (p = 0.31), with pre-COVID ADLs significantly associated with post-COVID ADLs (p < 0.001).
CONCLUSIONS: In older women, after accounting for pre-COVID functional status, the association between long COVID and lower functioning became nonsignificant. Our findings highlight the importance of preserving physical functioning among older women.}, }
@article {pmid40061351, year = {2025}, author = {Siegel, SJ and DeWolf, S and Schmalz, J and Saber, W and Dong, J and Martens, MJ and Logan, B and Albanese, A and Iovino, L and Chen, E and Kaminski, J and Neuberg, D and Hebert, K and Keskula, P and Zavistaski, J and Steinberg, L and Schichter, I and Cagnin, L and Hernandez, V and Warren, M and Applegate, K and Bar, M and Chhabra, S and Choi, SW and Clark, W and Das, S and Jenq, R and Jones, RJ and Levine, JE and Murthy, H and Rashidi, A and Riches, M and Sandhu, K and Sung, AD and Larkin, K and Al Malki, MM and Gooptu, M and Elmariah, H and Alousi, A and Runaas, L and Shaffer, B and Rezvani, A and El Jurdi, N and Loren, AW and Scheffey, D and Sanders, C and Hamadani, M and Dudakov, J and Bien, S and Robins, H and Horowitz, M and Bolaños-Meade, J and Holtan, S and Bhatt, AS and Perales, MA and Kean, LS}, title = {Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40061351}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire, underpinning post-transplant clinical outcomes.}, }
@article {pmid40061317, year = {2025}, author = {Fuller, H and Agasaro, OP and Darst, BF}, title = {Pre-diagnostic circulating metabolomics and prostate cancer risk: A systematic review and meta-analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40061317}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong clinical potential to act as biomarkers. However, evidence of circulating metabolite associations has not been quantitively aggregated.
METHODS: Systematic searches were performed in PubMed and Embase (October 17[th], 2024) to identify pre-diagnostic untargeted serum metabolomic studies of PCa risk. After harmonizing metabolite names across studies, restricted maximum likelihood was used to conduct meta-analyses to quantify associations between metabolites and risk of overall PCa, low- to intermediate-risk PCa, high- to very high-risk PCa and lethal PCa, as defined by the NCCN. Statistical significance was defined as FDR-adjusted P<0.05. Enrichment analyses were conducted on significant metabolites to identify biologically relevant pathways. Correlation of effect estimates between PCa outcomes was assessed via Pearson correlation.
RESULTS: We identified 12 untargeted pre-diagnostic circulating metabolomic studies in a systematic review and meta-analyzed associations between up to 408 metabolites with four PCa outcomes. Three, eleven and nineteen metabolites were significantly associated with risk of overall, high/very high-risk and lethal PCa, respectively. Metabolites associated with high/very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. Follow-up analyses found that 13 of the significant metabolites were drug and/or dietary modifiable.
CONCLUSIONS: These findings suggest the strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.}, }
@article {pmid40060686, year = {2025}, author = {Singh, S and Islam, SMS and Liu, R and Adeniji, OS and Giron, LB and Saini, P and Danesh, A and Denton, PW and Jones, B and Xiao, H and Abdel-Mohsen, M}, title = {HIV-Induced Sialoglycans on Infected Cells Promote Immune Evasion from Myeloid Cell-Mediated Killing.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060686}, issn = {2692-8205}, support = {R01 AA029859/AA/NIAAA NIH HHS/United States ; R15 AI178516/AI/NIAID NIH HHS/United States ; R01 DK123733/DK/NIDDK NIH HHS/United States ; R01 NS117458/NS/NINDS NIH HHS/United States ; R01 AI165079/AI/NIAID NIH HHS/United States ; R01 AG062383/AG/NIA NIH HHS/United States ; P20 GM103427/GM/NIGMS NIH HHS/United States ; }, abstract = {Sialic acid-containing glycans (sialoglycans) on pathological cells interact with Siglecs, glycol-immune checkpoint receptors expressed on myeloid cells such as monocytes and neutrophils. This interaction suppresses the cytotoxic functions of these immune cells. We show that HIV infection reprograms the glycosylation machinery of infected cells to increase the expression of specific sialoglycan ligands for Siglecs-3, -7, and -9. These ligands engage Siglecs on myeloid cells, impairing their ability to target HIV-infected cells. Selective disruption of these interactions using 10-1074-Sia, an HIV-specific antibody conjugated to sialidase-an enzyme that removes sialic acids-significantly enhances monocyte- and neutrophil-mediated killing of HIV-infected cells in autologous assays. Treatment with 10-1074-Sia in humanized mice infected with HIV reduces viral load and decreases inflammation. These findings reveal a novel immune evasion mechanism exploited by HIV to evade myeloid cell immune surveillance and highlight the potential of targeting sialoglycan-Siglec interactions to improve immune clearance of HIV-infected cells.}, }
@article {pmid40060430, year = {2025}, author = {Colegrove, HL and Monnat, RJ and Feder, AF}, title = {Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060430}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; }, abstract = {Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer ≥ 0.1) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of T P 53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a T P 53 -dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.}, }
@article {pmid40060420, year = {2025}, author = {Rosero, M and Bai, J}, title = {AFD Thermosensory Neurons Mediate Tactile-Dependent Locomotion Modulation in C. elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060420}, issn = {2692-8205}, support = {R01 NS115974/NS/NINDS NIH HHS/United States ; F31 NS129545/NS/NINDS NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; R01 NS109476/NS/NINDS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; }, abstract = {Sensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation in Caenorhabditis elegans. We show that while AFD employs cGMP signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD-AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.}, }
@article {pmid40060404, year = {2025}, author = {Park, L and Tsai, YT and Lim, HK and Faulhaber, LD and Burleigh, K and Faulhaber, EM and Bose, M and Shih, AY and Hirayama, AY and Turtle, CJ and Annesley, CE and Gardner, RA and Gustafson, HH and Gust, J}, title = {Cytokine-mediated increase in endothelial-leukocyte interaction mediates brain capillary plugging during CAR T cell neurotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060404}, issn = {2692-8205}, support = {K08 NS118138/NS/NINDS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R37 CA275954/CA/NCI NIH HHS/United States ; }, abstract = {CD19-directed CAR T cells treat cancer, but also cause immune effector cell associated neurotoxicity syndrome (ICANS). Despite strong epidemiologic links between cytokine release syndrome and ICANS, it is uncertain how elevated systemic cytokines and activated immune cells cause brain dysfunction. We previously showed that leukocytes plug brain capillaries in an immunocompetent mouse model of CD19-CAR neurotoxicity. Here, we used the same model to explore how integrin activation and endothelial adhesion molecule expression contribute to capillary plugging. In vivo two-photon imaging revealed increased expression of ICAM-1 on brain capillaries, with spatially restricted VCAM-1 increases. TNF, IFN-γ, and IL-1β at concentrations equivalent to CAR T cell patient blood levels upregulated ICAM-1 and VCAM-1 in brain microendothelial cells. In mice, CAR T cells strongly upregulated VLA-4 (integrin α4β1) affinity to VCAM-1, but not affinity of LFA-1 (integrin αLβ2) to ICAM-1. Blocking integrin α4 but not integrin αL improved ICANS behavior in mice. In human CAR T cell patients, increased soluble ICAM-1 and VCAM-1 are associated with ICANS, and integrin α4 but not integrin αL is upregulated in CAR T cells after infusion. Our study highlights that cytokine-driven upregulation of endothelial-leukocyte adhesion may be sufficient to induce neurovascular dysfunction in CAR T cell patients.}, }
@article {pmid40059038, year = {2025}, author = {Cuadrado, A and Cazalla, E and Bach, A and Bathish, B and Naidu, SD and DeNicola, GM and Dinkova-Kostova, AT and Fernández-Ginés, R and Grochot-Przeczek, A and Hayes, JD and Kensler, TW and León, R and Liby, KT and López, MG and Manda, G and Shivakumar, AK and Hakomäki, H and Moerland, JA and Motohashi, H and Rojo, AI and Sykiotis, GP and Taguchi, K and Valverde, ÁM and Yamamoto, M and Levonen, AL}, title = {Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.}, journal = {Redox biology}, volume = {81}, number = {}, pages = {103569}, pmid = {40059038}, issn = {2213-2317}, mesh = {*NF-E2-Related Factor 2/metabolism/genetics/antagonists & inhibitors ; Humans ; Oxidation-Reduction ; Animals ; *Noncommunicable Diseases/drug therapy ; Oxidative Stress/drug effects ; Neoplasms/drug therapy/metabolism ; }, abstract = {Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.}, }
@article {pmid40058159, year = {2025}, author = {Gadalla, SM and Katki, HA and Lai, TP and Auer, PL and Dagnall, CL and Bupp, C and Hutchinson, AA and Anderson, JJ and Mendez, KJW and Spellman, SR and Stewart, V and Savage, SA and Lee, SJ and Levine, JE and Saber, W and Aviv, A}, title = {Donor telomeres and their magnitude of shortening post-allogeneic haematopoietic cell transplant impact survival for patients with early-stage leukaemia or myelodysplastic syndrome.}, journal = {EBioMedicine}, volume = {114}, number = {}, pages = {105641}, pmid = {40058159}, issn = {2352-3964}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Myelodysplastic Syndromes/therapy/mortality/genetics/pathology ; Female ; Male ; Middle Aged ; *Leukemia/therapy/mortality/genetics/pathology ; Transplantation, Homologous ; Adult ; *Telomere/genetics ; *Tissue Donors ; Aged ; *Telomere Shortening ; Neoplasm Staging ; Adolescent ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Donor selection is a key success factor in allogeneic haematopoietic cell transplant (HCT). We evaluated the potential impact of donor leucocyte telomere length (LTL) and LTL shortening in recipients at three-month post-HCT (LTL-3MS) on the two-year HCT outcomes.
METHODS: We identified a cohort of 384 HCT recipients for early-stage leukaemia or myelodysplastic syndrome in the Blood and Marrow Transplant Clinical Trial Network protocol#1202 with blood samples collected three-month post-HCT. Blood samples from respective donors were available at the Centre for International Blood and Marrow Transplant Research biorepository. We used Cox proportional hazards models for statistical analyses.
FINDINGS: A better two-year overall survival (OS) was associated with longer donor LTL (adjusted-hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37-0.96, for LTL ≥6.7 kb vs LTL< 6.7 kb, p = 0.03), and higher LTL-3MS (HR = 0.52, 95% CI = 0.34-0.80, for LTL-3MS ≥ 230 vs < 230 bp, p = 0.003). Longer donor LTL was associated with a lower risk of non-relapse mortality (NRM; HR = 0.48, p = 0.05), while higher LTL-3MS was associated with lower relapse risk (HR for relapse risk = 0.53, p = 0.008). The adjusted 2-year cumulative risk of all-cause mortality was reduced by about half for patients with both donor LTL ≥6.7 kb and LTL-3MS ≥ 230 bp vs patients with neither characteristic (21% vs 41%, respectively; p < 0.0001).
INTERPRETATION: Selection of donors with longer LTL may improve HCT outcomes. Limited LTL shortening in recipients post-HCT may guide relapse prediction.
FUNDING: The NCI intramural research program and NIH grant U01AG066529.}, }
@article {pmid40057520, year = {2025}, author = {Wen, X and Hu, AK and Presnell, SR and Ford, ES and Koelle, DM and Kwok, WW}, title = {Longitudinal single cell profiling of epitope specific memory CD4+ T cell responses to recombinant zoster vaccine.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2332}, pmid = {40057520}, issn = {2041-1723}, support = {HHSN272201400049C/AI/NIAID NIH HHS/United States ; }, mesh = {*CD4-Positive T-Lymphocytes/immunology ; *Herpes Zoster Vaccine/immunology ; *Immunologic Memory ; Humans ; *Memory T Cells/immunology ; Vaccines, Synthetic/immunology ; Single-Cell Analysis ; *Epitopes, T-Lymphocyte/immunology ; *Herpes Zoster/immunology/prevention & control ; Herpesvirus 3, Human/immunology ; Vaccination ; Viral Envelope Proteins/immunology ; Female ; Longitudinal Studies ; }, abstract = {Vaccination leads to rapid expansion of antigen-specific T cells within in the first few days. However, understanding of transcriptomic changes and fates of antigen-specific T cells upon vaccination remains limited. Here, we investigate the fate of memory CD4+ T cells upon reactivation to recombinant zoster vaccine for shingles at cellular and transcriptional levels. We show that glycoprotein E-specific memory CD4+ T cells respond strongly, their frequencies remain high, and they retain markers of cell activation one year following vaccination. Memory T cells with the most dominant TCR clonotype pre-vaccination remain prevalent at year one post-vaccination. These data implicate a major role for pre-existing memory T cells in perpetuating immune repertoires upon re-encountering cognate antigens. Differential gene expression indicates that cells post-vaccination are distinct from cells at baseline, suggesting committed memory T cells display transcriptional changes upon vaccination that could alter their responses against cognate immunogens.}, }
@article {pmid40057187, year = {2025}, author = {Han, YY and Gaietto, K and Chen, W and Perreira, KM and Oren, E and Pirzada, A and Garcia-Bedoya, O and Kaplan, R and Isasi, CR and Celedón, JC}, title = {Life Stressors, Resilience Resources, and Asthma Among Adults in the Hispanic Community Health Study/Study of Latinos.}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {13}, number = {6}, pages = {1375-1384.e7}, pmid = {40057187}, issn = {2213-2201}, support = {R01 HL152475/HL/NHLBI NIH HHS/United States ; R01 HL168539/HL/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Adverse Childhood Experiences ; *Asthma/epidemiology/psychology/ethnology ; Cross-Sectional Studies ; *Hispanic or Latino ; *Resilience, Psychological ; Social Support ; *Stress, Psychological/epidemiology ; Surveys and Questionnaires ; United States/epidemiology ; }, abstract = {BACKGROUND: Whether life stressors and resiliency interact on asthma risk in adults is largely unknown.
OBJECTIVE: To examine life stressors, resiliency, and asthma in Hispanic/Latino adults.
METHODS: This is a cross-sectional study of 4747 adults aged 18 to 74 years in the Sociocultural Ancillary Study of the Hispanic Community Health Study/Study of Latinos. Participants completed questionnaires on life stressors (adverse childhood experiences [ACE], traumatic stress exposure (TSE), and chronic stressors [for ≥6 months]) and resilience resources (family cohesion, perceived social support, and spiritual well-being). Logistic regression was used for the multivariable analyses of current asthma and current asthma symptoms.
RESULTS: Any ACE and any chronic stressor were associated with 54% to 69% increased odds of asthma and asthma symptoms in all individuals, with stronger associations for ACE in men and for chronic stressors in women. In a separate analysis, high family cohesion and high spiritual well-being were each associated with 35% to 36% reduced odds of asthma symptoms. There was suggestive evidence of interactions: any TSE was associated with increased odds of asthma in adults with low family cohesion (adjusted odds ratio [aOR] = 2.40, 95% confidence interval [CI] = 1.01-5.73) but not in others, and any chronic stressor was associated with increased odds of asthma symptoms in adults with low spiritual well-being (aOR = 2.24, 95% CI = 1.20-4.20) but not in others.
CONCLUSIONS: In Hispanic/Latino adults, ACE and chronic stress were associated with higher odds of asthma or asthma symptoms, whereas family cohesion and spiritual well-being were linked to lower odds of asthma or asthma symptoms. Further, resiliency may interact with life stressors on asthma.}, }
@article {pmid40056061, year = {2025}, author = {Mehta, RS and Sparapani, R and Wang, T and Spellman, S and Lee, SJ and Petersdorf, EW}, title = {Donor Age Matters for Haploidentical HCT Patients Even After Adjusting for HLA Factors: A Machine Learning Approach.}, journal = {American journal of hematology}, volume = {100}, number = {5}, pages = {937-940}, doi = {10.1002/ajh.27648}, pmid = {40056061}, issn = {1096-8652}, support = {U24CA076518/CA/NCI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; N00014-21-1-2954//Office of Naval Research/ ; N00014-23-1-2057//Office of Naval Research/ ; //National Marrow Donor Program/ ; //Medical College of Wisconsin/ ; U24CA076518/CA/NCI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; 75R60222C00011/HRSA/HRSA HHS/United States ; }, }
@article {pmid40055795, year = {2025}, author = {Skalland, TM and de Dieu Tapsoba, J and Zangeneh, SZ and Floyd, S and Ayles, H and Bock, P and Fidler, S and Eshleman, SH and Hayes, RJ and Donnell, D and , }, title = {A survey weighted analysis of HPTN 071 (PopART) primary outcome of HIV incidence.}, journal = {AIDS research and therapy}, volume = {22}, number = {1}, pages = {30}, pmid = {40055795}, issn = {1742-6405}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *HIV Infections/epidemiology/prevention & control/drug therapy/diagnosis ; Incidence ; South Africa/epidemiology ; Zambia/epidemiology ; }, abstract = {INTRODUCTION: HPTN 071 (PopART) implemented a comprehensive HIV prevention package which aimed to reduce HIV incidence within 21 communities of Zambia and South Africa: Arm A, PopART intervention of universal HIV testing and treatment; Arm B, PopART intervention of universal HIV testing with ART provided according to local guidelines; and Arm C, standard of care. Analyses so far have not accounted for the sampling design of the enrolled cohort. We performed a sample-weighted re-analysis of the primary outcome of the PopART trial to derive a population-based estimate of the intervention effect.
METHODS: Enrollment used a two-stage sampling design: household and adult participant within each household. We constructed post-stratification weights to match the age and sex distribution of the target population in these communities. Weighted Poisson regression was used to estimate community-level HIV incidence. The PopART intervention effect was estimated using log-transformed community-level incidence estimates in an ANCOVA model.
RESULTS: The analysis based on community-level incidence shows a 25% reduction in incidence for Arm B communities compared to standard of care (RR: 0.75, 95% CI: 0.56-1.02, p = 0.06) while Arm A communities show no difference in HIV incidence compared to standard of care (RR: 1.08, 95% CI: 0.81-1.46, p = 0.56).
CONCLUSIONS: Our re-analysis shows 25% reduction in HIV incidence comparing Arm B to Arm C communities. No effect was observed comparing Arm A communities to Arm C communities. These results align with the primary results of the PopART trial.
CLINICALTRIALS: gov number, NCT01900977, HPTN 071 [PopArt].}, }
@article {pmid40054143, year = {2025}, author = {Carter, JJ and Smith, RA and Scherer, EM and Skibinski, DAG and Sankaranarayanan, S and Luxembourg, A and Kollmann, T and Marty, KD and Sadarangani, M and Dobson, S and Galloway, DA}, title = {Corrigendum to "Long-Term immune memory responses to human papillomavirus (HPV) vaccination following 2 versus 3 doses of HPV vaccine" [Vaccine, Volume 50, 19 March 2025, 126,817].}, journal = {Vaccine}, volume = {54}, number = {}, pages = {126974}, doi = {10.1016/j.vaccine.2025.126974}, pmid = {40054143}, issn = {1873-2518}, }
@article {pmid40053727, year = {2025}, author = {Benjet, C and Zainal, NH and Albor, Y and Alvis-Barranco, L and Carrasco Tapia, N and Contreras-Ibáñez, CC and Cortés-Morelos, J and Cudris-Torres, L and de la Peña, FR and González, N and Gutierrez-Garcia, RA and Vargas-Contreras, E and Medina-Mora, ME and Patiño, P and Gildea, SM and Kennedy, CJ and Luedtke, A and Sampson, NA and Petukhova, MV and Zubizarreta, JR and Cuijpers, P and Kazdin, AE and Kessler, RC}, title = {The Effect of Predicted Compliance With a Web-Based Intervention for Anxiety and Depression Among Latin American University Students: Randomized Controlled Trial.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e64251}, pmid = {40053727}, issn = {2368-7959}, mesh = {Humans ; Female ; Male ; *Students/psychology/statistics & numerical data ; *Cognitive Behavioral Therapy/methods ; Universities ; Young Adult ; Colombia ; *Internet-Based Intervention ; Adult ; *Depression/therapy ; *Patient Compliance/statistics & numerical data ; *Anxiety/therapy ; Mexico ; Treatment Outcome ; }, abstract = {BACKGROUND: Web-based cognitive behavioral therapy (wb-CBT) is a scalable way to reach distressed university students. Guided wb-CBT is typically superior to self-guided wb-CBT over short follow-up periods, but evidence is less clear over longer periods.
OBJECTIVE: This study aimed to compare short-term (3 months) and longer-term (12 months) aggregate effects of guided and self-guided wb-CBT versus treatment as usual (TAU) in a randomized controlled trial of Colombian and Mexican university students and carry out an initially unplanned secondary analysis of the role of differential predicted compliance in explaining these differences.
METHODS: The 1319 participants, recruited either through email and social media outreach invitations or from waiting lists of campus mental health clinics, were undergraduates (1038/1319, 78.7% female) with clinically significant baseline anxiety (Generalized Anxiety Disorder-7 score≥10) or depression (Patient Health Questionnaire-9 score≥10). The intervention arms comprised guided wb-CBT with weekly asynchronous written human feedback, self-guided wb-CBT with the same content as the guided modality, and TAU as provided at each university. The prespecified primary outcome was joint remission (Generalized Anxiety Disorder-7 score=0-4 and Patient Health Questionnaire-9 score=0-4). The secondary outcome was joint symptom reduction (mean scores on the Patient Health Questionnaire Anxiety and Depression Scale) at 3 and 12 months after randomization.
RESULTS: As reported previously, 3-month outcomes were significantly better with guided wb-CBT than self-guided wb-CBT (P=.02) or TAU (P=.02). However, subsequent follow-up showed that 12-month joint remission (adjusted risk differences=6.0-6.5, SE 0.4-0.5, and P<.001 to P=.007; adjusted mean differences=2.70-2.69, SE 0.7-0.8, and P<.001 to P=.001) was significantly better with self-guided wb-CBT than with the other interventions. Participants randomly assigned to the guided wb-CBT arm spent twice as many minutes logged on as those in the self-guided wb-CBT arm in the first 12 weeks (mean 12.5, SD 36.9 vs 5.9, SD 27.7; χ[2]1=107.1, P<.001), whereas participants in the self-guided wb-CBT arm spent twice as many minutes logged on as those in the guided wb-CBT arm in weeks 13 to 52 (mean 0.4, SD 7.5 vs 0.2, SD 4.4; χ[2]1=10.5, P=.001). Subgroup analysis showed that this longer-term superiority of self-guided wb-CBT was confined to the 40% (528/1319) of participants with high predicted self-guided wb-CBT compliance beyond 3 months based on a counterfactual nested cross-validated machine learning model. The 12-month outcome differences were nonsignificant across arms among other participants (all P>.05).
CONCLUSIONS: The results have important practical implications for precision intervention targeting to maximize longer-term wb-CBT benefits. Future research needs to investigate strategies to increase sustained guided wb-CBT use once guidance ends.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04780542; https://www.clinicaltrials.gov/study/NCT04780542.
RR2-10.1186/s13063-022-06255-3.}, }
@article {pmid40053601, year = {2025}, author = {Binkowski, B and Klamer, Z and Gao, C and Staal, B and Repesh, A and Tran, HL and Brass, DM and Bartlett, P and Gallinger, S and Blomqvist, M and Morrow, JB and Allen, P and Shi, C and Singhi, A and Brand, R and Huang, Y and Hostetter, G and Haab, BB}, title = {Multiplexed glycan immunofluorescence identification of pancreatic cancer cell subpopulations in both tumor and blood samples.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadt0029}, pmid = {40053601}, issn = {2375-2548}, support = {U01 CA152653/CA/NCI NIH HHS/United States ; U01 CA200466/CA/NCI NIH HHS/United States ; U01 CA226158/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Polysaccharides/metabolism/blood ; *Pancreatic Neoplasms/blood/pathology/metabolism/diagnosis ; *Carcinoma, Pancreatic Ductal/blood/pathology/diagnosis/metabolism ; Biomarkers, Tumor/blood ; *Fluorescent Antibody Technique/methods ; Cell Line, Tumor ; CA-19-9 Antigen/metabolism ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays for early disease detection. We hypothesized that PDAC cell subpopulations could be identified by aberrant glycan signatures in both tumor tissue and blood samples. We used multiplexed glycan immunofluorescence to distinguish between PDAC and noncancer cell subpopulations within tumor tissue, and we developed hybrid glycan sandwich assays to determine whether the aberrant glycan signatures could be detected in blood samples. We found that PDAC cells were identified by signatures of glycans detected by four glycan-binding proteins (VVL, CA19-9, sTRA, and GM2) and that there are three types of glycan-defined PDAC tumors: sTRA type, CA19-9 type, and intermixed. In patient-matched tumor and blood samples, the PDAC tumor type could be determined by the aberrant glycans in the blood. As a result, the combined assays of aberrant glycan signatures were more sensitive and specific than any individual assay. Our results demonstrate a methodology to detect and stratify PDAC.}, }
@article {pmid40051480, year = {2024}, author = {Back, A and Myers, S and Guy, J and Perez, J and Lazar Thorn, L and McGregor, B}, title = {Evolving Guidelines for the Use of Touch During a Clinical Trial of Group Psilocybin-Assisted Therapy.}, journal = {Psychedelic medicine (New Rochelle, N.Y.)}, volume = {2}, number = {4}, pages = {187-191}, pmid = {40051480}, issn = {2831-4433}, abstract = {For a new clinical trial testing a group retreat-based format of psilocybin-assisted therapy, our research team created an initial set of practice guidelines that aimed to describe facilitator use of touch in a way that is ethical, supportive, and minimizes harm. In our first three retreats, however, we had two unexpected experiences with touch that led us to iterate our initial guidelines into a new version of guidelines. In this Technical Report, we describe our evolving guidelines specifying acceptable practices for facilitator use of touch to ensure a safe, supportive, and therapeutic participant experience. Our primary goal with these guidelines is to create a haptic experience during the psilocybin session that reinforces the participants' sense of safety and supports their own experience during the psilocybin session. Our secondary goal is to allow the facilitator team to notice and maintain therapeutic boundaries and to respond to participant experiences with empathy and openness in the context of those boundaries (Clinical Trials No: NCT05847686).}, }
@article {pmid40049206, year = {2025}, author = {Morris, ZS and Demaria, S and Monjazeb, AM and Formenti, SC and Weichselbaum, RR and Welsh, J and Enderling, H and Schoenfeld, JD and Brody, JD and McGee, HM and Mondini, M and Kent, MS and Young, KH and Galluzzi, L and Karam, SD and Theelen, WSME and Chang, JY and Huynh, MA and Daib, A and Pitroda, S and Chung, C and Serre, R and Grassberger, C and Deng, J and Sodji, QH and Nguyen, AT and Patel, RB and Krebs, S and Kalbasi, A and Kerr, C and Vanpouille-Box, C and Vick, L and Aguilera, TA and Ong, IM and Herrera, F and Menon, H and Smart, D and Ahmed, J and Gartrell, RD and Roland, CL and Fekrmandi, F and Chakraborty, B and Bent, EH and Berg, TJ and Hutson, A and Khleif, S and Sikora, AG and Fong, L}, title = {Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.}, journal = {The Lancet. Oncology}, volume = {26}, number = {3}, pages = {e152-e170}, doi = {10.1016/S1470-2045(24)00656-9}, pmid = {40049206}, issn = {1474-5488}, support = {R37 CA262557/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Combined Modality Therapy ; *Immunotherapy/methods/adverse effects ; National Cancer Institute (U.S.) ; *Neoplasms/therapy/immunology/radiotherapy ; *Radiotherapy/methods/adverse effects ; *Translational Research, Biomedical ; United States ; }, abstract = {Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and computational assessment of response, and next-generation radiotherapy-immunotherapy combinations. Panel recommendations included: developing and implementing patient selection and biomarker-guided approaches; applying mechanistic understanding to optimise delivery of radiotherapy and selection of immunotherapies; using rigorous preclinical models including companion animal studies; embracing data sharing and standardisation, advanced modelling, and multidisciplinary cross-institution collaboration; interrogating clinical data, including negative trials; and incorporating novel clinical endpoints and trial designs.}, }
@article {pmid40048931, year = {2025}, author = {Moore, M and Anderson, L and Schiffer, JT and Matrajt, L and Dimitrov, D}, title = {Durability of COVID-19 vaccine and infection induced immunity: A systematic review and meta-regression analysis.}, journal = {Vaccine}, volume = {54}, number = {}, pages = {126966}, doi = {10.1016/j.vaccine.2025.126966}, pmid = {40048931}, issn = {1873-2518}, mesh = {Humans ; *COVID-19/prevention & control/immunology ; *COVID-19 Vaccines/immunology/administration & dosage ; *SARS-CoV-2/immunology ; *Vaccine Efficacy ; Vaccination ; Immunologic Memory ; Regression Analysis ; }, abstract = {BACKGROUND: Despite the success of mRNA vaccines, COVID-19 remains a significant public health threat. Waning of immune memory and the emergence of new variants can degrade population-level protection and contribute to ongoing morbidity.
METHODS: In this systematic review and meta-regression, we searched for studies in PubMed, medRxiv and bioRxiv published January 1, 2020 - January 1, 2023 measuring vaccine effectiveness as the reduction in infection, symptomatic disease, and severe disease (resulting in hospitalization and/or death) conferred by mRNA-based vaccination and prior SARS-CoV-2 infections relative to naïve individuals. We excluded studies that did not distinguish between mRNA and non-mRNA vaccines or had less than 1000 participants. Using a multi-level model, we quantified the initial effectiveness and change over four to six months following vaccination or infection. Model covariates were COVID variant, number of vaccine doses, and the number and variant of prior infection. Our estimates were adjusted for the age of the study population.
FINDINGS: Of 828 screened, we included 123 studies in our analysis. Vaccine effectiveness against infection and disease declined both over time and with the emergence of Omicron, regardless of booster doses, though protection against severe outcomes was more durable. Booster doses reduced severe Omicron infections by 90.5 % (95 % confidence interval 87.1-93.8) and 77.6 % (70.5-84.7) at two and 26 weeks post-vaccination, respectively. Protection conferred by hybrid immunity was more durable than that from either vaccination or prior infection alone, but protection against Omicron reinfection was only 50.1 % (32.5-67.8) at 26 weeks following vaccination. Individuals with hybrid immunity had 80.6 % protection (70.0-91.2) following booster doses declining to 36.9 % (19.3-54.6) after 16 weeks.
INTERPRETATION: Our results suggest that timely deployment of pre-existing boosters can greatly mitigate seasonal COVID outbreaks even in populations with prior infection and vaccination.
FUNDING: Centers for Disease Control and Prevention (NU38OT000297-03).}, }
@article {pmid40048743, year = {2025}, author = {Nath, K and Zhang, MJ and Bye, M and Abid, MB and Benjamin, C and Betts, BC and Bhatt, NS and Arrieta-Bolaños, E and Bolon, YT and Gadalla, SM and Grunwald, MR and Krem, MM and Lee, SJ and Marsh, SGE and Martino, R and Mehta, PA and Milano, F and Prestidge, T and Saultz, JN and Shaw, BE and Spellman, SR and Choe, HK and Shaffer, BC}, title = {Transplant Outcomes Using Older Matched Sibling Donors Compared to Young Alternative Donors: A CIBMTR Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014858}, pmid = {40048743}, issn = {2473-9537}, abstract = {Whether younger donors should be prioritized over HLA-matching for allogeneic hematopoietic cell transplantation (allo-HCT) when using post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis is unclear. To address this, we compared outcomes of allo-HCT recipients aged ≥50-years using PTCy-based GvHD prophylaxis from an older (≥50-years) matched sibling donor (MSD) to those of younger alternative donors ≤35-years: HLA-matched unrelated donors (MUD), HLA-mismatched unrelated donors (MMUD), and haploidentical (haplo)-related donors reported to the Center for International Blood & Marrow Transplant Research between 2014-2021. Young MUD and older MSD receiving calcineurin inhibitor (CNI)-based allo-HCT that met study criteria were concurrently examined. The primary endpoint was overall survival (OS). Among 14,662 HCT recipients, 3,746 received PTCy- and 10,916 CNI-based GvHD prophylaxis. The median follow-up was 47 months. In patients treated with PTCy, the adjusted 5-year OS was not significantly different at 44% for MSD compared with 52% for MUD (multivariable hazard ratio [HR]: 1.20, 95%CI: 1.03-1.41, p=0.09), 45% for haplo (HR: 1.02, 0.88-1.18, p=1.00) and 46% for MMUD (HR: 1.00, 0.83-1.21, p=1.00). Compared to MSDs, receipt of younger MUD associated with improved disease-free survival (DFS) both with PTCy (HR: 1.21, 1.05-1.40, p=0.048) and CNI (HR 1.09, 1.04-1.15, p<0.01) based prophylaxis. Haplo-donor recipients associated with similar OS to MSD, but worse OS compared to MUD recipients with PTCy (HR: 1.18, 1.05-1.33, p=0.04). These data suggest that older MSDs result in similar OS compared to younger alternative donors in older-aged recipients. Younger MUDs may be preferred for older patients due to improved DFS when available.}, }
@article {pmid40048671, year = {2025}, author = {Rajdev, L and King, GG and Lieu, CH and Cohen, SA and Pant, S and Uboha, NV and Deming, D and Malla, M and Kasi, A and Klute, K and Spencer, KR and Dasari, A and Morris, VK and Botta, G and Lowy, AM and O'Hara, MH and Eads, J and King, D and Shah, MA and Hong, TS and Parikh, A and Klempner, SJ and Jabbour, SK and Chawla, A and Molena, D and George, TJ and Gibson, MK and Allegra, C and Goodman, K and Eng, C and Philip, PA}, title = {Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2400489}, pmid = {40048671}, issn = {2473-4284}, mesh = {Humans ; *Circulating Tumor DNA/blood ; *Clinical Trials as Topic ; *Gastrointestinal Neoplasms/blood/genetics/diagnosis/therapy ; United States ; National Cancer Institute (U.S.) ; Biomarkers, Tumor/blood ; }, abstract = {PURPOSE: Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials.
METHODS: The NCI GI steering committee assigned four task force members to serve as co-chairs for the working group. Co-chairs identified experts within each GI disease group to form a panel that convened to review data and provide recommendations. The group focused on ctDNA's role as a potential surrogate for assessing prognosis and guiding treatment decisions that may enhance GI cancer trials. A manuscript was drafted, circulated, revised, and voted on by the panel. The final draft was reviewed by the Cancer Therapy Evaluation Program.
RESULTS: Further data are required to support ctDNA as a primary end point for late-phase therapeutic trials, particularly in studies that could change the standard-of-care. However, the group supports ctDNA as a primary efficacy end point for phase II studies and as a noninvasive evaluation strategy for new drug development. Incorporation of ctDNA as a biomarker in trial design must consider the specific context of disease biology of the GI cancer subtypes. ctDNA should be incorporated as an exploratory end point across a variety of disease settings and indications. Several practical considerations were identified to optimize the incorporation of ctDNA in future trial design.
CONCLUSION: Prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.}, }
@article {pmid40045233, year = {2025}, author = {Yilmaz, S and Aryal, K and King, J and Bischof, JJ and Hong, AS and Wood, N and Gould Rothberg, BE and Hudson, MF and Heinert, SW and Wattana, MK and Coyne, CJ and Reyes-Gibby, C and Todd, K and Lyman, G and Klotz, A and Abar, B and Grudzen, C and Bastani, A and Baugh, CW and Henning, DJ and Bernstein, S and Rico, JF and Ryan, RJ and Yeung, SJ and Qdaisat, A and Padela, A and Madsen, TE and Liu, R and Adler, D}, title = {Understanding oncologic emergencies and related emergency department visits and hospitalizations: a systematic review.}, journal = {BMC emergency medicine}, volume = {25}, number = {1}, pages = {40}, pmid = {40045233}, issn = {1471-227X}, mesh = {Humans ; *Emergency Service, Hospital/statistics & numerical data ; *Neoplasms/therapy/complications ; *Hospitalization/statistics & numerical data ; *Emergencies ; Emergency Room Visits ; }, abstract = {BACKGROUND: Patients with cancer frequently visit the emergency department (ED) and are at high risk for hospitalization due to severe illness from cancer progression or treatment side effects. With an aging population and rising cancer incidence rates worldwide, it is crucial to understand how EDs and other acute care venues manage oncologic emergencies. Insights from other nations and health systems may inform resources necessary for optimal ED management and novel care delivery pathways. We described clinical management of oncologic emergencies and their contribution to ED visits and hospitalizations worldwide.
METHODS: We performed a systematic review of peer-reviewed original research studies published in the English language between January 1st, 2003, to December 31st, 2022, garnered from PubMed, Web of Science, and EMBASE. We included all studies investigating adult (≥ 18 years) cancer patients with emergency visits. We examined chief complaints or predictors of ED use that explicitly defined oncologic emergencies.
RESULTS: The search strategy yielded 49 articles addressing cancer-related emergency visits. Most publications reported single-site studies (n = 34/49), with approximately even distribution across clinical settings- ED (n = 22/49) and acute care hospital/ICU (n = 27/49). The number of patient observations varied widely among the published studies (range: 9 - 87,555 patients), with most studies not specifying the cancer type (n = 33/49), stage (n = 41/49), or treatment type (n = 36/49). Most studies (n = 31/49) examined patients aged ≥ 60 years. Infection was the most common oncologic emergency documented (n = 22/49), followed by pain (n = 20/49), dyspnea (n = 19/49), and gastrointestinal (GI) symptoms (n = 17/49). Interventions within the ED or hospital ranged from pharmacological management with opioids (n = 11/49), antibiotics (n = 9/49), corticosteroids (n = 5/49), and invasive procedures (e.g., palliative stenting; n = 13/49) or surgical interventions (n = 2/49).
CONCLUSION: Limited research specifically addresses oncologic emergencies despite the international prevalence of ED presentations among cancer patients. Patients with cancer presenting to the ED appear to have a variety of complaints which could result from their cancers and thus may require tailored diagnostic and intervention pathways to provide optimal acute care. Further acute geriatric oncology research may clarify the optimal management strategies to improve the outcomes for this vulnerable patient population.}, }
@article {pmid40044856, year = {2025}, author = {Tran-Kiem, C and Paredes, MI and Perofsky, AC and Frisbie, LA and Xie, H and Kong, K and Weixler, A and Greninger, AL and Roychoudhury, P and Peterson, JM and Delgado, A and Halstead, H and MacKellar, D and Dykema, P and Gamboa, L and Frazar, CD and Ryke, E and Stone, J and Reinhart, D and Starita, L and Thibodeau, A and Yun, C and Aragona, F and Black, A and Viboud, C and Bedford, T}, title = {Fine-scale patterns of SARS-CoV-2 spread from identical pathogen sequences.}, journal = {Nature}, volume = {640}, number = {8057}, pages = {176-185}, pmid = {40044856}, issn = {1476-4687}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CK000630/CK/NCEZID CDC HHS/United States ; }, mesh = {Humans ; *COVID-19/transmission/epidemiology/virology ; *SARS-CoV-2/genetics/isolation & purification/classification/pathogenicity ; *Genome, Viral/genetics ; Male ; Washington/epidemiology ; Female ; Adult ; Middle Aged ; Adolescent ; Young Adult ; Age Factors ; Child ; Aged ; Child, Preschool ; Genomics ; Infant ; }, abstract = {Pathogen genomics can provide insights into underlying infectious disease transmission patterns[1,2], but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential[3-5]. In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here we use pairs of identical sequences to characterize fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postcodes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this study improves our ability to use large pathogen genome datasets to understand the determinants of infectious disease spread.}, }
@article {pmid40043139, year = {2025}, author = {Rubio, AA and Baharani, VA and Dadonaite, B and Parada, M and Abernathy, ME and Wang, Z and Lee, YE and Eso, MR and Phung, J and Ramos, I and Chen, T and El Nesr, G and Bloom, JD and Bieniasz, PD and Nussenzweig, MC and Barnes, CO}, title = {Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern.}, journal = {Science translational medicine}, volume = {17}, number = {788}, pages = {eadq5720}, doi = {10.1126/scitranslmed.adq5720}, pmid = {40043139}, issn = {1946-6242}, mesh = {*SARS-CoV-2/immunology ; *Antibodies, Bispecific/immunology/therapeutic use/pharmacology ; Animals ; *Antibodies, Neutralizing/immunology ; Humans ; *COVID-19/immunology/virology ; Mice ; *Spike Glycoprotein, Coronavirus/immunology/chemistry/metabolism ; *Antibodies, Viral/immunology ; Antibodies, Monoclonal/immunology ; Protein Domains ; Epitopes/immunology ; Female ; Mice, Inbred BALB C ; Cryoelectron Microscopy ; }, abstract = {The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.}, }
@article {pmid40042432, year = {2025}, author = {Gao, F and Janes, H and Buchbinder, S and Donnell, D}, title = {Active-Controlled Trial Design for HIV Prevention Trials With a Counterfactual Placebo.}, journal = {Statistics in medicine}, volume = {44}, number = {6}, pages = {e70022}, doi = {10.1002/sim.70022}, pmid = {40042432}, issn = {1097-0258}, support = {R37AI029168/NH/NIH HHS/United States ; R01AI177078/NH/NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; UM1AI068617/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention & control ; *Pre-Exposure Prophylaxis/methods ; Placebos ; Anti-HIV Agents/therapeutic use ; *Research Design ; *Controlled Clinical Trials as Topic/methods ; Models, Statistical ; Sample Size ; Computer Simulation ; }, abstract = {In the quest for enhanced HIV prevention methods, the advent of antiretroviral drugs as pre-exposure prophylaxis (PrEP) has marked a significant stride forward. However, the ethical challenges in conducting placebo-controlled trials for new PrEP agents against a backdrop of highly effective existing PrEP options necessitate innovative approaches. This manuscript delves into the design and implementation of active-controlled trials that incorporate a counterfactual placebo estimate-a theoretical estimate of what HIV incidence would have been without effective prevention. We introduce a novel statistical framework for regulatory approval of new PrEP agents, predicated on the assumption of an available and consistent counterfactual placebo estimate. Our approach aims to assess the absolute efficacy (i.e., against placebo) of the new PrEP agent relative to the absolute efficacy of the active control. We propose a two-step procedure for hypothesis testing and further develop an approach that addresses potential biases inherent in non-randomized comparisons to counterfactual placebos. By exploring different scenarios with moderately and highly effective active controls and counterfactual placebo estimates from various sources, we demonstrate how our design can significantly reduce sample sizes compared to traditional non-inferiority trials and offer a robust framework for evaluating new PrEP agents. This work contributes to the methodological repertoire for HIV prevention trials and underscores the importance of adaptability in the face of ethical and practical challenges.}, }
@article {pmid40041932, year = {2025}, author = {Yuan, JM and Kensler, TW and Dacic, S and Hartman, DJ and Wang, R and Balogh, PA and Sufka, P and Turner, MA and Fuhrer, K and Seigh, L and Pham, YT and Adams-Haduch, J and Valacchi, G and Singh, SV and Herman, JG and Wilson, DO}, title = {Randomized Phase II Clinical Trial of Sulforaphane in Former Smokers at High Risk for Lung Cancer.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {18}, number = {6}, pages = {335-345}, doi = {10.1158/1940-6207.CAPR-24-0386}, pmid = {40041932}, issn = {1940-6215}, support = {R01CA213123//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; }, mesh = {Humans ; *Isothiocyanates/administration & dosage/therapeutic use ; Sulfoxides ; Male ; Female ; *Lung Neoplasms/prevention & control/pathology/etiology ; Middle Aged ; Aged ; *Anticarcinogenic Agents/therapeutic use/administration & dosage ; Ki-67 Antigen/metabolism ; Apoptosis/drug effects ; Smokers ; Double-Blind Method ; Bronchi/pathology/drug effects ; *Smoking/adverse effects ; Caspase 3/metabolism ; }, abstract = {Experimental studies have shown that dietary isothiocyanates reduced cellular proliferative marker Ki-67 and increased apoptotic markers caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in animals, but human data are lacking. The present study was to assess whether sulforaphane would stop/reverse the progression of bronchial histopathology, reduce the Ki-67 index, and/or increase caspase-3 and TUNEL indices in humans. A randomized clinical trial (NCT03232138) was conducted in former smokers. Forty-three subjects were randomly assigned to the placebo or the treatment with a potential daily dose of 95 μmol sulforaphane for 12 months. The endpoints were the changes in histopathology scores and Ki-67, caspase-3, and TUNEL indices in post- versus pretreatment bronchial biopsies. Thirty-seven participants (17 in the sulforaphane and 20 in the placebo group) completed the study. Supplementation of sulforaphane did not show significant impact on bronchial histopathology but significantly reduced the Ki-67 index with a 20% decrease in the sulforaphane group and a 65% increase in the placebo (P = 0.014). The difference was even greater in high-density (3+) positive Ki-67, with a 44% decrease in the sulforaphane group compared with a 71% increase in the placebo (P = 0.004). Higher bioavailability of sulforaphane was correlated with greater reduction of the Ki-67 index (P for trend = 0.019). Sulforaphane treatment had no impact on the caspase-3 or TUNEL index in bronchial biopsies. No severe adverse event was observed in the study participants. The findings of oral sulforaphane that significantly reduced the Ki-67 index in bronchial tissue support further development as a potential chemopreventive agent against lung cancer development. Prevention Relevance: High intake of cruciferous vegetables and their sulforaphane is associated with lower incidence of lung cancer in humans and animal models. This clinical trial has demonstrated that oral supplementation of sulforaphane for 12 months significantly reduced the Ki-67 index, a potential surrogate endpoint of biomarkers for lung cancer risk.}, }
@article {pmid40040586, year = {2025}, author = {Owens, L and Fung, A and Shuhendler, J and Glick, J and Ryser, MD and Gulati, R and Etzioni, R}, title = {Trends in young-onset cancer incidence: a modeling perspective.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {7}, pages = {1350-1359}, pmid = {40040586}, issn = {1460-2105}, support = {//Rosalie and Harold Rea Brown Endowed Chair/ ; R35CA274442/CA/NCI NIH HHS/United States ; R50CA221836/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Incidence ; Age of Onset ; *Neoplasms/epidemiology/diagnosis ; Female ; Male ; Adult ; Middle Aged ; United States/epidemiology ; Aged ; Young Adult ; Birth Cohort ; Age Factors ; }, abstract = {BACKGROUND: Recent increases in the diagnosis of certain cancers among younger individuals are generating intense concern. Many studies attribute the increase in the so-called "young-onset" cancer to an etiologic cause but questions have also arisen about the role of earlier diagnosis.
METHODS: We simulated incidence trends from a natural history model that includes healthy, preclinical, and clinical disease states, where the transition from the healthy to the preclinical state represents disease onset and the transition from the preclinical to the clinical state represents diagnosis. We superimposed birth-cohort effects on the rate of disease onset and period effects on the rate of disease diagnosis to identify those that match patterns of relative incidence by age group and 5-year calendar interval from 2000 to 2019 for 6 "young-onset" cancers (colon, rectum, female breast, stomach, pancreas, and kidney).
RESULTS: Two types of effects are broadly consistent with the observed increasing incidence trends in younger individuals: (1) a birth-cohort effect on disease onset that begins around 1970 and becomes more pronounced in later birth years or (2) a period effect consistent with progressive reduction over time in the duration of preclinical disease. An earlier, protective birth-cohort effect is consistent with recent declining trends in incidence in older individuals for colon, rectal, and stomach cancers.
CONCLUSIONS: A disease model provides clues about the possible drivers of cancer incidence trends, suggests constraints on the patterns of exposures that might be implicated etiologically, and indicates that the role of diagnostic changes warrants consideration alongside potential etiologic explanations.}, }
@article {pmid40038837, year = {2025}, author = {Yousefiasl, M and Soltanattar, A and Ezzatollahi Tanha, A and Azami, P and Alaei, M and Alamdari, AA and Esmailsorkh, F and Habibzadeh, A and Khanmohammadi, S}, title = {Association of triglyceride-glucose index with bone mineral density and fracture: a systematic review.}, journal = {Diabetology & metabolic syndrome}, volume = {17}, number = {1}, pages = {77}, pmid = {40038837}, issn = {1758-5996}, abstract = {BACKGROUND AND AIM: Studies have found inconsistent results regarding triglyceride-glucose (TyG) index and bone health. This systematic review aims to synthesize the existing evidence on the association between the (TyG) index, bone mineral density (BMD), and bone fractures.
METHOD: A comprehensive search of PubMed, Scopus, Web of Science, and Embase databases was performed for studies published up to December 26, 2024. Inclusion criteria encompassed human studies examining the TyG index in relation to BMD or fractures. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Data synthesis included both qualitative and descriptive statistical analyses.
RESULTS: From 201 studies identified, 12 met the inclusion criteria comprising 817,242 participants. Most studies reported a significant association between TyG index and bone fractures. The studies reported inconsistent findings regarding the association between the TyG index and BMD. While some studies found no correlation between the TyG index and BMD in individuals aged ≥ 50 years, studies on the general population aged ≥ 18 years demonstrated a significant correlation between the TyG index and BMD. Variations in the age of study populations, the presence of diabetes, BMI, and adjustment factors likely contributed to these discrepancies. Further research is needed to clarify the role of the TyG index in bone health and its potential utility as a surrogate marker.
CONCLUSION: The TyG index is associated with bone fractures and can serve as a surrogate marker for osteoporosis in the general populations rather than exclusively for the elderly.}, }
@article {pmid40038122, year = {2025}, author = {Javid, SH and Kilgore, MR and Austin, EJ and Parker, EU and Alvarez, R and Flanagan, MR and Brewer, EG and Gibbons, C and Holt, SK and Lee, JM and Donlan, AW and DeStefano, LM and Gore, JL}, title = {The development and comparative effectiveness of a patient-centered pathology report for breast cancer care: a randomized clinical trial.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {3}, pages = {248}, pmid = {40038122}, issn = {1433-7339}, mesh = {Humans ; Female ; *Breast Neoplasms/pathology/psychology/therapy ; Middle Aged ; *Patient-Centered Care ; Self Efficacy ; Decision Making ; Adult ; *Health Knowledge, Attitudes, Practice ; Aged ; Communication ; }, abstract = {PURPOSE: Pathology reports contain complex medical terminology that may be confusing or overwhelming for patients newly diagnosed with breast cancer. We evaluated the effectiveness of patient-centered pathology reports (PCPRs), which translate pathology results into patient-friendly language.
METHODS: Sixty-six participants newly diagnosed with breast cancer were randomized to receive either a PCPR and standard pathology report (intervention arm) or a standard pathology report alone (control arm). Patients were surveyed at initial pathology disclosure and 1 month later to assess breast cancer knowledge and ratings of decisional confidence, conflict, and self-efficacy for treatment decision-making. Knowledge was assessed for four pathology domains independently.
RESULTS: Accuracy of breast cancer knowledge across all domains trended higher for the intervention group compared with the control group (66% vs. 50%, p = 0.11); cancer type and surgical margin status knowledge domains exceeded 75% accuracy for the intervention group. No significant differences between groups were observed for patient-reported ratings of communication, decisional conflict, and decision self-efficacy.
CONCLUSIONS: PCPRs in lay language appeared to improve patients' knowledge of their breast cancer diagnosis, were acceptable to patients and providers, and have the potential to be broadly applied in an effort to improve patient knowledge and improve the patient experience surrounding a breast cancer diagnosis.}, }
@article {pmid40037704, year = {2025}, author = {Wang, MF and Li, MY and Yang, YC and Chuang, YC and Tsai, CY and Binder, MN and Ma, L and Lin, SW and Li, HW and Smith, GR and Chi, P}, title = {Mug20-Rec25-Rec27 binds DNA and enhances meiotic DNA break formation via phase-separated condensates.}, journal = {Nucleic acids research}, volume = {53}, number = {5}, pages = {}, pmid = {40037704}, issn = {1362-4962}, support = {MOST 111-2311-B-002-006-MY3//Ministry of Science and Technology/ ; //National Science and Technology Council/ ; NIH R35 GM118120/NH/NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; //Cellular Imaging Shared Resource/ ; }, mesh = {*Meiosis/genetics ; *Schizosaccharomyces pombe Proteins/metabolism/genetics ; *DNA Breaks, Double-Stranded ; *Schizosaccharomyces/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Binding ; *DNA, Fungal/metabolism/genetics ; *Nuclear Proteins/metabolism/genetics ; Homologous Recombination ; Biomolecular Condensates/metabolism ; }, abstract = {During meiosis, programmed DNA double-strand breaks (DSBs) are formed at hotspots to initiate homologous recombination, which is vital for reassorting genetic material. In fission yeast, the linear element (LinE) proteins Mug20, Rec25, and Rec27 interdependently bind chromosomal hotspots with high specificity and are necessary for high-level DSB formation. However, their mechanistic role in regulating the meiotic DSB machinery remains unknown. Here, using purified Mug20-Rec25-Rec27 (MRR) complex and functional intracellular analyses, we reveal that the MRR-DNA nucleoprotein complex assembles phase-separated condensates that compact the DNA. Notably, MRR complex formation is a prerequisite for DNA binding and condensate assembly, with Rec27 playing a pivotal role in directly binding DNA. Consistent with this finding, failure to form MRR-DNA condensates results in defective intracellular meiotic DSB formation and recombination. Our results provide mechanistic insights into how LinEs enhance meiotic DSB formation and provide a paradigm for studies in other species.}, }
@article {pmid40036963, year = {2025}, author = {Coronado, GD and Rutter, CM}, title = {Response to McElroy and Everett.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {6}, pages = {1281-1282}, pmid = {40036963}, issn = {1460-2105}, support = {R01 CA265020/CA/NCI NIH HHS/United States ; NCI R01 CA265020-01/CA/NCI NIH HHS/United States ; }, }
@article {pmid40036318, year = {2025}, author = {Alagoz, O and Caswell-Jin, JL and de Koning, HJ and Huang, H and Huang, X and Lee, SJ and Li, Y and Plevritis, SK and Sarkar, S and Schechter, CB and Stout, NK and Trentham-Dietz, A and van Ravesteyn, N and Lowry, KP and , }, title = {Mathematical Modeling to Address Questions in Breast Cancer Screening: An Overview of the Breast Cancer Models of the Cancer Intervention and Surveillance Modeling Network.}, journal = {Journal of breast imaging}, volume = {7}, number = {2}, pages = {141-154}, pmid = {40036318}, issn = {2631-6129}, support = {P30 CA014520/CA/NCI NIH HHS/United States ; U01 CA253911/CA/NCI NIH HHS/United States ; 21-078-01-CPSH//American Cancer Society/ ; U01CA253911, P30CA014520/NH/NIH HHS/United States ; }, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging/mortality ; Female ; *Early Detection of Cancer ; *Models, Theoretical ; United States ; Mammography ; }, abstract = {The National Cancer Institute-funded Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer mathematical models have been increasingly utilized by policymakers to address breast cancer screening policy decisions and influence clinical practice. These well-established and validated models have a successful track record of use in collaborations spanning over 2 decades. While mathematical modeling is a valuable approach to translate short-term screening performance data into long-term breast cancer outcomes, it is inherently complex and requires numerous inputs to approximate the impacts of breast cancer screening. This review article describes the 6 independently developed CISNET breast cancer models, with a particular focus on how they represent breast cancer screening and estimate the contribution of screening to breast cancer mortality reduction and improvements in life expectancy. We also describe differences in structures and assumptions across the models and how variation in model results can highlight areas of uncertainty. Finally, we offer insight into how the results generated by the models can be used to aid decision-making regarding breast cancer screening policy.}, }
@article {pmid40036070, year = {2025}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Kwok, WW and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, Å}, title = {Two DRB3 residues predictively associate with the progression to type 1 diabetes among DR3 carriers.}, journal = {JCI insight}, volume = {10}, number = {7}, pages = {}, pmid = {40036070}, issn = {2379-3708}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/genetics/immunology ; Disease Progression ; Female ; Male ; *HLA-DRB3 Chains/genetics/chemistry ; Genetic Predisposition to Disease ; Adult ; Alleles ; Haplotypes ; Heterozygote ; Adolescent ; HLA-DRB1 Chains/genetics ; Child ; }, abstract = {HLA-DR genes are associated with the progression from stage 1 and stage 2 to onset of stage 3 type 1 diabetes (T1D), after accounting HLA-DQ genes with which they are in high linkage disequilibrium. Based on an integrated cohort of participants from 2 completed clinical trials, this investigation finds that, sharing a haplotype with the DRB1*03:01 (DR3) allele, DRB3*01:01:02 and *02:02:01 have respectively negative and positive associations with the progression. Furthermore, we uncovered 2 residues (β11, β26, participating in pockets 6 and 4, respectively) on the DRB3 molecule responsible for the progression among DR3 carriers; motif RY and LF respectively delay and promote the progression (hazard ratio [HR] = 0.73 and 2.38, P = 0.039 and 0.017, respectively). Two anchoring pockets 6 and 4 probably bind differential autoantigenic epitopes. We further investigated the progression association with the motifs RY and LF among carriers of DR3 and found that carriers of the motif LF have significantly faster progression than carriers of RY (HR = 1.48, P = 0.019 in unadjusted analysis; HR = 1.39, P = 0.047 in adjusted analysis), results of which provide an impetus to examine the possible role of specific DRB3-binding peptides in the progression to T1D.}, }
@article {pmid40035770, year = {2025}, author = {Haberman, M and Kamyshinsky, R and Reznik, N and Yeshaya, N and Khmelnitsky, L and Plender, EG and Eichler, EE and Fass, D}, title = {MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2419717122}, pmid = {40035770}, issn = {1091-6490}, support = {R01 HG010169/HG/NHGRI NIH HHS/United States ; 101097867//EC | ERC | HORIZON EUROPE European Research Council (ERC)/ ; 2660/20//Israel Science Foundation (ISF)/ ; }, mesh = {*Mucin 5AC/chemistry/metabolism/genetics ; Humans ; Mucin-5B/chemistry/metabolism ; Mucin-2/chemistry/metabolism ; Mucins/chemistry ; Models, Molecular ; Amino Acid Sequence ; Intestinal Mucosa/metabolism ; }, abstract = {Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.}, }
@article {pmid40034763, year = {2025}, author = {Orchard, P and Blackwell, TW and Kachuri, L and Castaldi, PJ and Cho, MH and Christenson, SA and Durda, P and Gabriel, S and Hersh, CP and Huntsman, S and Hwang, S and Joehanes, R and Johnson, M and Li, X and Lin, H and Liu, CT and Liu, Y and Mak, ACY and Manichaikul, AW and Paik, D and Saferali, A and Smith, JD and Taylor, KD and Tracy, RP and Wang, J and Wang, M and Weinstock, JS and Weiss, J and Wheeler, HE and Zhou, Y and Zoellner, S and Wu, JC and Mestroni, L and Graw, S and Taylor, MRG and Ortega, VE and Johnson, CW and Gan, W and Abecasis, G and Nickerson, DA and Gupta, N and Ardlie, K and Woodruff, PG and Zheng, Y and Bowler, RP and Meyers, DA and Reiner, A and Kooperberg, C and Ziv, E and Ramachandran, VS and Larson, MG and Cupples, LA and Burchard, EG and Silverman, EK and Rich, SS and Heard-Costa, N and Tang, H and Rotter, JI and Smith, AV and Levy, D and , and , and Aguet, F and Scott, L and Raffield, LM and Parker, SCJ}, title = {Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40034763}, support = {R01 ES015794/ES/NIEHS NIH HHS/United States ; HHSN268201600032C/ES/NIEHS NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; HHSN268200900016C/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268200900018C/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268200900019C/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; U24 HL141762/HL/NHLBI NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; R01 HL133135/HL/NHLBI NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; K01 HL157613/HL/NHLBI NIH HHS/United States ; R00 CA246076/CA/NCI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 HL166992/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; HHSN268200900015C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; U01 HL137880/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01 HL171213/HL/NHLBI NIH HHS/United States ; R01 HL117004/HL/NHLBI NIH HHS/United States ; HHSN268200900017C/HL/NHLBI NIH HHS/United States ; HHSN268200900020C/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; HHSN268200900013C/HL/NHLBI NIH HHS/United States ; R01 HL124233/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; 75N92023D00011/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268200900014C/HL/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R01 HL144718/HL/NHLBI NIH HHS/United States ; P01 HL114501/HL/NHLBI NIH HHS/United States ; }, abstract = {Most genetic variants associated with complex traits and diseases occur in non-coding genomic regions and are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterize 14,324 ancestrally diverse RNA-sequencing samples from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and integrate whole genome sequencing data to perform cis and trans expression and splicing quantitative trait locus (cis-/trans-e/sQTL) analyses in six tissues and cell types, most notably whole blood (N=6,454) and lung (N=1,291). We show this dataset enables greater detection of secondary cis-e/sQTL signals than was achieved in previous studies, and that secondary cis-eQTL and primary trans-eQTL signal discovery is not saturated even though eGene discovery is. Most TOPMed trans-eQTL signals colocalize with cis-e/sQTL signals, suggesting many trans signals are mediated by cis signals. We fine-map European UK BioBank GWAS signals from 164 traits and colocalize the resulting 34,107 fine-mapped GWAS signals with TOPMed e/sQTL signals, finding that of 10,611 GWAS signals with a colocalization, 7,096 GWAS signals colocalize with at least one secondary e/sQTL signal. These results demonstrate that larger e/sQTL analyses will continue to uncover secondary e/sQTL signals, and that these new signals will benefit GWAS interpretation.}, }
@article {pmid40034245, year = {2025}, author = {Apolo, A and Baumann, BC and Al-Ahmadie, H and Ballas, L and Bangs, R and Brothers, K and Greenberg, SC and Delacroix, S and Dignam, JJ and Efstathiou, JA and Feldman, AS and Foster, JC and Hahn, NM and Hall, E and Hansel, DE and Hoffman-Censits, J and Kamat, AM and Kamran, SC and Khani, F and Lerner, SP and Lipman, R and Mann, B and McConkey, D and McKiernan, J and Rose, TL and Smith, AB and Tangen, C and Amiri, AT and Weinstock, C and West, PJ and Milowsky, MI and Black, PC}, title = {Summary from the NCI clinical trials planning meeting on next generation of clinical trials in non-muscle invasive bladder cancer.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {11}, number = {1}, pages = {23523735251319185}, pmid = {40034245}, issn = {2352-3735}, abstract = {The National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on 'Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)' led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network.}, }
@article {pmid40032074, year = {2025}, author = {Kinoshita, H and Walti, CS and Webber, K and Pezzella, G and Jensen-Wachspress, M and Lang, H and Shuey, K and Boonyaratanakornkit, J and Pergam, SA and Chu, HY and Bollard, CM and Keller, MD and Hill, JA}, title = {T Cell Immune Response to Influenza Vaccination When Administered Prior to and Following Autologous Chimeric Antigen Receptor-Modified T Cell Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {5}, pages = {327-338}, pmid = {40032074}, issn = {2666-6367}, support = {U01 CA247548/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Influenza Vaccines/immunology ; Female ; Male ; Middle Aged ; Adult ; *T-Lymphocytes/immunology ; *Vaccination/methods ; *Receptors, Chimeric Antigen/immunology/metabolism ; Aged ; *Immunotherapy, Adoptive/methods ; *Influenza, Human/prevention & control/immunology ; }, abstract = {Chimeric antigen receptor-modified T (CAR-T) cell therapies are gaining wider use in relapsed and refractory malignancies. However, data on vaccination in this population is lacking. We evaluated T cell responses in an established cohort of CAR-T recipients and healthy controls before and after 2019 to 2020 influenza vaccination. Peripheral blood mononuclear cells were isolated from healthy controls and patients who received the 2019 to 2020 influenza vaccine pre- or post-CD19, CD20, or B cell maturation antigen CAR-T. T cells were expanded in vitro for 10 days with peptide libraries for hemagglutinin (HA) and nucleoprotein from the 2019 to 2020 vaccine influenza A strains and analyzed by flow cytometry following interferon-γ/tumor necrosis factor-α (IFNγ/TNFα) intracellular staining. Antibody response was evaluated by a hemagglutination inhibition assay. Twenty-nine participants, including eight immunocompetent adults, seven pre-CAR-T, and 14 post-CAR-T patients, were evaluated. IFNγ[+]/TNFα[+] T cell responses after influenza vaccination in healthy controls varied with an increased response to HA-Kansas after vaccination in 7/8 individuals. In the pre-CAR-T cohort, there was a rise in CD4+ T cell response to HA-Brisbane in 6/7 patients after vaccination that remained detectable in 3/4 evaluable patients 90 days post-CAR-T. Five of six patients who lacked an antibody response nonetheless demonstrated a T cell response to HA-Brisbane. There was no association between time since CAR-T administration, baseline immunoglobulin G, or absolute lymphocyte count and change in CD4+ T cell IFNγ[+]/TNFα[+] response pre- to postvaccine for the post-CART cohort. These data demonstrate that cell-mediated immunity to the influenza vaccine can be elicited in patients vaccinated pre-CAR-T and sustained post-CAR-T, filling an important gap from lack of humoral responses.}, }
@article {pmid40030014, year = {2025}, author = {Torgbor, C and Sohn, H and Dizon, BLP and Mutic, EC and George, R and Kwak, K and Akkaya, M and Ulker, EB and Traver, M and Brzostowski, J and Galloway, DA and Thompson, CD and Çuburu, N and Schiller, JT and Pierce, SK}, title = {In the activation of HPV-specific human B cells HPV-VLP vaccines mimic membrane-associated antigens.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2414514122}, pmid = {40030014}, issn = {1091-6490}, mesh = {*B-Lymphocytes/immunology/metabolism ; *Papillomavirus Vaccines/immunology ; *Artificial Virus-Like Particles/immunology ; HLA-D Antigens/immunology/metabolism ; Virus Internalization ; Ion Channels/antagonists & inhibitors/genetics/metabolism ; *Lysosomal-Associated Membrane Protein 1/metabolism ; Humans ; RNA, Small Interfering/genetics ; Antigen Presentation/immunology ; *Lymphocyte Activation ; Papillomavirus Infections/immunology/prevention & control/virology ; Papillomaviridae/immunology ; Gene Knockdown Techniques ; Cell Line, Tumor ; }, abstract = {B cell responses to membrane-presented antigens appear to be strongly favored over soluble antigens in vivo suggesting that vaccines that mimic membrane-presented antigens may be highly efficacious. We recently demonstrated that human B cell responses to membrane-associated but not to soluble antigens in vitro depended on the expression and activity of the plasma membrane mechanosensitive ion channel, Piezo1. Here, we provide evidence that the efficacy of the current human papillomavirus virus-like particle (HPV VLP) vaccines may be due in part to their inherent ability to mimic Piezo1-dependent membrane presentation of antigens to B cells. We compared HPV-specific human B cell responses to HPV VLPs versus soluble HPV pentameric capsomeres and showed that although both induced calcium responses, only HPV VLP-induced responses were blocked by Piezo1 inhibitors. The kinetics of internalization of HPV-VLP and capsomeres into HPV-specific B cells were similar and neither required Piezo1 function as shown by small interfering RNA (siRNA)-mediated knockdown of Piezo. However, trafficking of HPV-VLPs into intracellular major histocompatibility complex (MHC) class II, lysosomal associated membrane protein 1 (LAMP1)[+] antigen-processing compartments was Piezo1-dependent, whereas trafficking of capsomeres was not. In addition, a time course of intracellular trafficking suggested that colocalization of HPV-VLP with MHC classII was more stable over time as compared to capsomeres. Taken together these findings suggest that the ability of HPV-VLP vaccines to mimic Piezo1-dependent membrane antigen presentation may be exploited in the design of highly effective human vaccines.}, }
@article {pmid40030000, year = {2025}, author = {Gopal, AK and Armand, P and Neelapu, SS and Bartlett, NL and Spurgeon, SE and Kuruvilla, J and Savage, KJ and Leonard, JP and Gelb, AB and Ahmed, N and Dong, S and Bathena, SP and Suryawanshi, R and Wu, JQ and Wang, S and Gladstone, DE}, title = {Nivolumab plus relatlimab for patients with relapsed or progressed B-cell malignancies in RELATIVITY-022.}, journal = {Blood advances}, volume = {9}, number = {13}, pages = {3383-3394}, doi = {10.1182/bloodadvances.2024015086}, pmid = {40030000}, issn = {2473-9537}, mesh = {Humans ; *Nivolumab/administration & dosage/therapeutic use/adverse effects ; Female ; Male ; Middle Aged ; Aged ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Antibodies, Monoclonal, Humanized/administration & dosage/therapeutic use/adverse effects ; Lymphocyte Activation Gene 3 Protein ; Aged, 80 and over ; *Lymphoma, B-Cell/drug therapy/mortality ; Young Adult ; }, abstract = {Despite high response rates, anti-programmed death 1 (anti-PD-1) monotherapy eventually fails in most patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) and is ineffective in most other B-cell malignancies. The lymphocyte activation gene 3 (LAG-3) cell-surface receptor represents another immune checkpoint that can be targeted to induce remissions in these diseases; dual inhibition of PD-1 and LAG-3 is approved in advanced melanoma. We performed a multicenter phase 1/2a open-label study of the anti-LAG-3 antibody relatlimab (RELATIVITY-022) administered as monotherapy or in combination with nivolumab in patients with R/R B-cell malignancies. We treated 106 patients and no dose-limiting toxicities were observed during escalation. The recommended phase 2 dose was relatlimab 240 mg as monotherapy or nivolumab 240 mg plus relatlimab 160 mg, administered every 2 weeks. No unexpected safety signals were observed compared with anti-PD-1 monotherapy. In the HL expansion cohorts, objective response rate (ORR) was 62% and complete response rate (CRR) was 19% in anti-PD-1/anti-programmed death ligand 1 (anti-PD-[L]1)-naive patients (n = 21), with a median progression-free survival (PFS) of 19 months; ORR was 15% and CRR 0%, with median PFS of 6 months in anti-PD-(L)1-progressed patients (n = 20). In diffuse large B-cell lymphoma, ORR was 7% with no CRs (n = 15), and median PFS was 2 months. Nivolumab plus relatlimab appeared to be safe and tolerable. Responses in patients with anti-PD-(L)1-naive HL was encouraging, although the contribution of relatlimab to overall efficacy of the combination needs to be further evaluated. This trial was registered at www.ClinicalTrials.gov as #NCT02061761.}, }
@article {pmid40029972, year = {2025}, author = {Sommers, J and Dizon, DS and Lewis, MA and Stone, E and Andreoli, R and Henderson, V}, title = {Assessing Health Information Seeking Behaviors Among Targeted Social Media Users Using an Infotainment Video About a Cancer Clinical Trial: Population-Based Descriptive Study.}, journal = {JMIR cancer}, volume = {11}, number = {}, pages = {e56098}, pmid = {40029972}, issn = {2369-1999}, support = {K01 CA248852/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U54 CA132381/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Social Media/statistics & numerical data ; *Information Seeking Behavior ; Female ; Male ; *Clinical Trials as Topic ; *Neoplasms/therapy/psychology ; Middle Aged ; Adult ; Video Recording ; Information Dissemination/methods ; Health Knowledge, Attitudes, Practice ; }, abstract = {BACKGROUND: The lack of information and awareness about clinical trials, as well as misconceptions about them, are major barriers to cancer clinical trial participation. Digital and social media are dominant sources of health information and offer optimal opportunities to improve public medical awareness and education by providing accurate and trustworthy health information from reliable sources. Infotainment, material intended to both entertain and inform, is an effective strategy for engaging and educating audiences that can be easily disseminated using social media and may be a novel way to improve awareness of and recruitment in clinical trials.
OBJECTIVE: The purpose of this study was to evaluate whether an infotainment video promoting a clinical trial, disseminated using social media, could drive health information seeking behaviors.
METHODS: As part of a video series, we created an infotainment video focused on the promotion of a specific cancer clinical trial. We instituted a dissemination and marketing process on Facebook to measure video engagement and health information seeking behaviors among targeted audiences who expressed interest in breast cancer research and organizations. To evaluate video engagement, we measured reach, retention, outbound clicks, and outbound click-through rate. Frequencies and descriptive statistics were used to summarize each measure.
RESULTS: The video substantially increased health information seeking behavior by increasing viewership from 1 visitor one month prior to launch to 414 outbound clicks from the video to the clinical trial web page during the 21-day social media campaign period.
CONCLUSIONS: Our study shows that digital and social media tools can be tailored for specific target audiences, are scalable, and can be disseminated at low cost, making it an accessible educational, recruitment, and retention strategy focused on improving the awareness of clinical trials.}, }
@article {pmid40029708, year = {2025}, author = {Johnson, ACM and Zager, RA}, title = {Veverimer, a Nonabsorbed Gastrointestinal Tract HCl Binder, Decreases Renal Ammoniagenesis and Mitigates Nephrotoxic Serum Nephritis.}, journal = {Kidney360}, volume = {6}, number = {5}, pages = {696-706}, pmid = {40029708}, issn = {2641-7650}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; RO1 38432/NH/NIH HHS/United States ; }, abstract = {KEY POINTS: Veverimer, a nonabsorbed gastrointestinal tract HCl binder, increases bicarbonate generation, causes bicarbonaturia, and thus decreases renal ammoniagenesis. Decreases in ammoniagenesis can suppress kidney disease–induced alternative complement pathway activation. As a result of the above changes, decreases in renal injury, as induced by nephrotoxic serum injection, can occur.
BACKGROUND: Increased tubular ammoniagenesis is an adaptive response to progressive kidney disease, facilitating net acid excretion. However, excess ammonia production can also exacerbate kidney disease progression, in part, by activating the alternative complement cascade. Oral Na bicarbonate therapy can decrease the systemic H[+] burden, limiting ammonia production. However, poor compliance limits bicarbonate's efficacy. Veverimer is an oral, Na[+]-free, nonabsorbed polymer that binds H[+] within the gastrointestinal (GI) tract. This stimulates GI carbonic anhydrase-mediated bicarbonate production and systemic bicarbonate uptake. Hence, the goals of this study were to test whether GI HCl binding decreases renal tubular ammoniagenesis, to assess whether complement activation decreases, and to determine whether these changes can mitigate nephrotoxic serum (NTS) nephritis, in which complement activation may play a role.
METHODS: A normal diet± veverimer (4.5% w/w) was fed to normal mice for approximately 1 week. Veverimer's effect on plasma bicarbonate; blood/urinary pH; urinary ammonia excretion; and tubular H[+] transporter, NHE3, density was assessed. Additional mice were fed the normal or veverimer diet after NTS injection. Urine protein, albumin, ammonia, C5b-9 excretion, and plasma C3a levels were measured 1 week and/or 2 weeks after NTS injection. Renal histologic changes (hematoxylin and eosin stain; C5b-9, CD45 immunohistochemistry), and selected injury mediators/biomarkers (NGAL, IL-6, MCP-1, TGFβ1, and endothelin-1 mRNAs) were also assessed.
RESULTS: Veverimer increased plasma bicarbonate/urinary pH, reduced urinary ammonia, and decreased NHE3 in normal mice. Veverimer also reduced NTS-induced proteinuria/albuminuria, urinary ammonia, and C5b-9 excretion (by approximately 60%, 75%, and 50%, respectively). Significant reductions in NTS-induced glomerular/tubulointerstitial injury, inflammatory/profibrotic gene expression, renal C5b-9 deposition, and suppressed plasma C3a levels were observed. Oral bicarbonate also conferred protection, implicating bicarbonate's role in veverimer's beneficial effect.
CONCLUSIONS: Veverimer-mediated bicarbonate generation can suppress renal ammoniagenesis and complement activation. These findings suggest a potential benefit of veverimer/bicarbonate therapy in selected complement-mediated kidney diseases.}, }
@article {pmid40029702, year = {2025}, author = {Lee, CI and Elmore, JG}, title = {FDA Breast Density Reporting Requirements and Evidence-Based Medical Practice.}, journal = {JAMA}, volume = {333}, number = {18}, pages = {1632-1633}, doi = {10.1001/jama.2025.0001}, pmid = {40029702}, issn = {1538-3598}, }
@article {pmid40028765, year = {2025}, author = {Henikoff, S and Levens, DL}, title = {The plusses and minuses of DNA torsion.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40028765}, issn = {2050-084X}, mesh = {*RNA Polymerase II/metabolism ; *DNA/chemistry/metabolism ; *Nucleic Acid Conformation ; }, abstract = {A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.}, }
@article {pmid40028346, year = {2025}, author = {Weinfurtner, K and Tischfield, D and McClung, G and Crainic, J and Gordan, J and Jiao, J and Furth, EE and Li, W and Supan, ET and Nadolski, GJ and Hunt, SJ and Kaplan, DE and Gade, TPF}, title = {Human GM-CSF/IL-3 enhance tumor immune infiltration in humanized HCC patient-derived xenografts.}, journal = {JHEP reports : innovation in hepatology}, volume = {7}, number = {3}, pages = {101264}, pmid = {40028346}, issn = {2589-5559}, support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND & AIMS: Response to immunotherapy in hepatocellular carcinoma (HCC) is suboptimal with no biomarkers to guide patient selection. "Humanized" mice represent promising models to address this deficiency but are limited by variable chimerism and underdeveloped myeloid compartments. We hypothesized that expression of human GM-CSF and IL-3 increases tumor immune cell infiltration, especially myeloid-derived cells, in humanized HCC patient-derived xenografts.
MATERIAL AND METHODS: NOG (NOD/Shi-scid/IL-2Rγ[null]) and NOG-EXL (huGM-CSF/huIL-3 NOG) mice conditioned with busulfan underwent i.v. injection of human CD34+ cells. HCC patient-derived xenograft tumors were then implanted subcutaneously or orthotopically. Following serial blood sampling, mice were euthanized at defined tumor sizes. Tumor, blood, liver, and spleen were analyzed by flow cytometry and immunohistochemistry.
RESULTS: Humanized NOG-EXL mice demonstrated earlier and higher levels of human chimerism compared to humanized NOG mice (82.1% vs. 43.8%, p <0.0001) with a greater proportion of human monocytes (3.2% vs. 1.1%, p = 0.001) and neutrophils (0.8% vs. 0.3%, p = 0.02) in circulation. HCC tumors in humanized NOG-EXL mice exhibited greater human immune cell infiltration (57.6% vs. 30.2%, p = 0.04) with higher proportions of regulatory T cells (14.6% vs. 6.8%, p = 0.04), CD4+ PD-1 expression (84.7% vs. 32.0%, p <0.01), macrophages (1.2% vs. 0.6%, p = 0.02), and neutrophils (0.5% vs. 0.1%, p <0.0001). No differences were observed in tumor engraftment or growth latency in subcutaneous tumors, but orthotopic tumors required implantation at 2 rather than 4 weeks post-humanization for successful engraftment. Finally, utilizing adult bone marrow instead of fetal livers enabled partial HLA-matching to HCC tumors but required more CD34+ cells.
CONCLUSIONS: Human GM-CSF and IL-3 expression in humanized mice resulted in features more closely approximating the immune microenvironment of human disease, providing a promising model for investigating critical questions in immunotherapy for HCC.
IMPACT AND IMPLICATIONS: This study introduces a unique mouse model at a critical point in the evolution of treatment paradigms for patients with hepatocellular carcinoma (HCC). Immunotherapies have become the first-line treatment for advanced HCC; however, response rates remain low with no clear predictors of response to guide patient selection. In this context, animal models that recapitulate human disease are greatly needed. Leveraging xenograft tumors derived from patients with unresectable HCCs and a commercially available immunodeficient mouse strain that expresses human GM-CSF and IL-3, we demonstrate a novel but accessible approach for modeling the HCC tumor microenvironment.}, }
@article {pmid40027810, year = {2025}, author = {Newsom, OJ and Sullivan, LB}, title = {Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027810}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; }, abstract = {Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.}, }
@article {pmid40027790, year = {2025}, author = {Li, S and Song, K and Sun, H and Tao, Y and Huang, A and Bhatia, V and Hanratty, B and Patel, RA and Long, HW and Morrissey, C and Haffner, MC and Nelson, PS and Graeber, TG and Lee, JK}, title = {Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027790}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; DP2 CA271301/CA/NCI NIH HHS/United States ; R01 CA222877/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, abstract = {Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.}, }
@article {pmid40027747, year = {2025}, author = {Hart, ML and Davidsen, K and Danquah, S and Zheng, E and Sokolov, D and Sullivan, LB}, title = {Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027747}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; U54 CA132381/CA/NCI NIH HHS/United States ; }, abstract = {Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.}, }
@article {pmid40027237, year = {2025}, author = {Le, C and Tatunay, K and Liu, W and Lu, H and Rodis, NA and Nam, T and Laurino, MY and Dubard-Gault, ME}, title = {Lessons learned in migrating from one commercial genetics clinical decision-making tool to another: Assessment of data integrity and utilization.}, journal = {Genetics in medicine open}, volume = {3}, number = {}, pages = {101913}, pmid = {40027237}, issn = {2949-7744}, abstract = {PURPOSE: Rapid advancements in information technology have greatly influenced clinicians' engagement with patient data for health maintenance. The electronic health record often contains multiple ways to record risk factors and to identify patients at an elevated genetic risk for cancer. However, these variables exist in multiple forms and disparate locations in each commercial electronic health record solution resulting in significant variations in how family history or genetic data is codified. Furthermore, there is pressure to migrate from one commercial solution to another at times, prompting the need for a process ensuring data integrity during such a transition.
METHODS: Between July and December 2023, the genetics team migrated a family history database from one commercial software solution to another. After the data migration of 13,000 patient records, we reviewed 500 randomly selected charts in both support tools to measure the rate of concordance of information transferred.
RESULTS: A total of 461 patient charts were reviewed. Of these, 425 (92.2%) were noted to be concordant. Of the 36 charts that were discordant, 9 had incorrect genetic testing results entered, 19 had missing information, 5 charts contained data recorded on paper before 2017 (legacy data), and 3 had additional information transferred.
CONCLUSION: There was high data integrity after migration from one commercial software solution to another. Although these results can ease clinicians' concerns after such support tool transitions, our effort also highlights areas for improvement in how family and patient genetic data are recorded and utilized for clinical care and research within an institution.}, }
@article {pmid40026777, year = {2025}, author = {Hartlage, W and Castillo, AY and Kassamali Escobar, Z and Bajenov, M and Martinez-Paz, N and Lynch, JB and Bryson-Cahn, C and Chan, JD}, title = {Stewarding the inappropriate diagnosis and treatment of urinary tract infection: leveraging the urinalysis to understand true antibiotic overuse.}, journal = {Antimicrobial stewardship & healthcare epidemiology : ASHE}, volume = {5}, number = {1}, pages = {e49}, pmid = {40026777}, issn = {2732-494X}, abstract = {We evaluated 249 asymptomatic patients receiving antibiotics for urinary infection: 222 had asymptomatic pyuria and/or nitrituria (ASPN) and 133 had asymptomatic bacteriuria (ASB, growth ≥10[5] colony forming units/ml). ASPN identified 40% more cases of unnecessary antibiotics compared to ASB and may be a more comprehensive measure of unnecessary antibiotic use.}, }
@article {pmid40025499, year = {2025}, author = {Fang, H and Tronco, AR and Bonora, G and Nguyen, T and Thakur, J and Berletch, JB and Filippova, GN and Henikoff, S and Shendure, J and Noble, WS and Duan, Z and Disteche, CM and Deng, X}, title = {CTCF-mediated insulation and chromatin environment modulate Car5b escape from X inactivation.}, journal = {BMC biology}, volume = {23}, number = {1}, pages = {68}, pmid = {40025499}, issn = {1741-7007}, support = {U54DK107979/GF/NIH HHS/United States ; UM1HG011586/GF/NIH HHS/United States ; UM1 HG011586/HG/NHGRI NIH HHS/United States ; GM131745/GF/NIH HHS/United States ; R35 GM131745/GM/NIGMS NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; GM1273727/GF/NIH HHS/United States ; R01 GM127327/GM/NIGMS NIH HHS/United States ; }, mesh = {CCCTC-Binding Factor ; Animals ; Mice ; *Chromatin/metabolism/genetics ; Female ; *X Chromosome Inactivation/genetics ; *Repressor Proteins/metabolism/genetics ; Binding Sites ; Chromosomal Proteins, Non-Histone/metabolism ; Male ; Protein Binding ; Epigenesis, Genetic ; Cohesins ; Cell Cycle Proteins/metabolism ; }, abstract = {BACKGROUND: Genes that escape X-chromosome inactivation (XCI) in female somatic cells vary in number and levels of escape among mammalian species and tissues, potentially contributing to species- and tissue-specific sex differences. CTCF, a master chromatin conformation regulator, is enriched at escape regions and may play an important role in regulating escape, but the molecular mechanisms remain elusive.
RESULTS: CTCF binding profiles and epigenetic features were systematically examined at escape genes (escapees) using mouse allelic systems with skewed XCI to distinguish the inactive X (Xi) and active X (Xa) chromosomes. We found that six constitutive and two facultative escapees are located inside 30-800 kb domains marked by convergent arrays of CTCF binding sites, consistent with the formation of chromatin loops. Facultative escapees show clear differences in CTCF binding depending on their XCI status in specific cell types/tissues. In addition, sets of strong and in some cases divergent CTCF binding sites located at the boundary between an escapee and its adjacent neighbors subject to XCI would also help insulate domains. Indeed, deletion but not inversion of a CTCF binding site at the boundary between the facultative escapee Car5b and its silent neighbor Siah1b results in a dramatic reduction of Car5b escape. This is associated with reduced CTCF and cohesin binding, which indicates loss of looping and insulation and is supported by 3C combined with Hi-C analysis. In addition, enrichment in the repressive mark H3K27me3 invades the Car5b domain in deleted cells, consistent with loss of expression from the Xi. In contrast, cells with an inversion of the CTCF binding site retain CTCF and cohesin binding, as well as looping, in line with persistence of escape. Interestingly, the levels of escape increase in cells with deletion of either Dxz4, which disrupts the Xi-specific compact 3D structure, or Firre, which results in lower H3K27me3 enrichment on the Xi, indicating that the structural and epigenetic features of the Xi constrain escape from XCI in wild type conditions.
CONCLUSIONS: Taken together, our findings support the idea that escape from XCI in female somatic cells is modulated by both the topological insulation of domains via CTCF binding and the surrounding heterochromatin environment.}, }
@article {pmid40025364, year = {2025}, author = {Javid, SH and Kazerouni, AS and Hippe, DS and Hirano, M and Schnuck-Olapo, J and Biswas, D and Bryant, ML and Li, I and Xiao, J and Kim, AG and Guo, A and Dontchos, B and Kilgore, M and Kim, J and Partridge, SC and Rahbar, H}, title = {Correction: Preoperative MRI to Predict Upstaging of DCIS to Invasive Cancer at Surgery.}, journal = {Annals of surgical oncology}, volume = {32}, number = {5}, pages = {3350}, doi = {10.1245/s10434-025-17029-x}, pmid = {40025364}, issn = {1534-4681}, }
@article {pmid40023656, year = {2025}, author = {Sullivan, KM and Sanders, JE}, title = {The Cure of Thalassemia and the Angst of a Junior Attending.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3}, pages = {113-117}, doi = {10.1016/j.jtct.2025.02.006}, pmid = {40023656}, issn = {2666-6367}, }
@article {pmid40022306, year = {2025}, author = {Zhou, P and Yeshoua, BJ and Konuthula, N and Pan, CJ and Ferrandino, RM and Holte, SE and Rizvi, Z and Marchiano, EM and Futran, ND and Barber, BR}, title = {Association of Oral Health Determinants With Oral Squamous Cell Carcinoma in Never-Smoking Adults.}, journal = {Head & neck}, volume = {47}, number = {7}, pages = {2025-2032}, pmid = {40022306}, issn = {1097-0347}, support = {T32 DC000018/DC/NIDCD NIH HHS/United States ; //RFPU-NW research award/ ; }, mesh = {Humans ; Male ; Female ; Case-Control Studies ; Middle Aged ; *Mouth Neoplasms/epidemiology/etiology ; *Carcinoma, Squamous Cell/epidemiology ; *Oral Health ; Risk Factors ; Adult ; United States/epidemiology ; Aged ; Logistic Models ; Incidence ; Periodontal Diseases/epidemiology ; Databases, Factual ; Risk Assessment ; Non-Smokers/statistics & numerical data ; }, abstract = {BACKGROUND: The incidence of oral cavity squamous cell carcinoma (OCSCC) is increasing among non-smokers. This study investigates the association between local and systemic oral health determinants and OCSCC in never-smoking adults.
METHODS: A case-control study using the National Institutes of Health All of Us database was conducted. Lifetime exposures to periodontal disease, acquired absence of teeth, hyperlipidemia, hyperglycemia, HIV, oral-related autoimmune diseases, depression, and eating disorders were analyzed. Multivariate logistic regression estimated odds ratios (ORs) and 95% confidence intervals to identify independent OCSCC risk factors.
RESULTS: Several risk factors were independently associated with OCSCC: periodontal disease (OR 4.99), hyperlipidemia (OR 1.53), HIV infection (OR 2.96), oral-related autoimmune diseases (OR 2.40), depression (OR 1.51), and eating disorders (OR 8.46). Acquired absence of teeth and hyperglycemia did not show statistical significance.
CONCLUSIONS: This study highlights the complex pathophysiology of OCSCC in never-smoking adults and underscores the need for comprehensive risk assessment and prevention strategies.}, }
@article {pmid40022201, year = {2025}, author = {Jennings-Shaffer, C and Rich, DH and Macaulay, M and Karcher, MD and Ganapathy, T and Kiami, S and Kooperberg, A and Zhang, C and Suchard, MA and Matsen, FA}, title = {Finding high posterior density phylogenies by systematically extending a directed acyclic graph.}, journal = {Algorithms for molecular biology : AMB}, volume = {20}, number = {1}, pages = {2}, pmid = {40022201}, issn = {1748-7188}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10OD028685/RI/ORIP NIH HHS/United States ; AI162611/NH/NIH HHS/United States ; }, abstract = {Bayesian phylogenetics typically estimates a posterior distribution, or aspects thereof, using Markov chain Monte Carlo methods. These methods integrate over tree space by applying local rearrangements to move a tree through its space as a random walk. Previous work explored the possibility of replacing this random walk with a systematic search, but was quickly overwhelmed by the large number of probable trees in the posterior distribution. In this paper we develop methods to sidestep this problem using a recently introduced structure called the subsplit directed acyclic graph (sDAG). This structure can represent many trees at once, and local rearrangements of trees translate to methods of enlarging the sDAG. Here we propose two methods of introducing, ranking, and selecting local rearrangements on sDAGs to produce a collection of trees with high posterior density. One of these methods successfully recovers the set of high posterior density trees across a range of data sets. However, we find that a simpler strategy of aggregating trees into an sDAG in fact is computationally faster and returns a higher fraction of probable trees.}, }
@article {pmid40019842, year = {2025}, author = {Kronenberger, DW and Zimmers, TA and Ralston, RK and Runco, DV}, title = {Circulating Growth Differentiation Factor 15 (GDF15) in Paediatric Disease: A Systematic Review.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {2}, pages = {e13712}, pmid = {40019842}, issn = {2190-6009}, mesh = {Humans ; *Growth Differentiation Factor 15/blood ; Child ; Biomarkers/blood ; Female ; Adolescent ; Child, Preschool ; }, abstract = {BACKGROUND: Growth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF-β superfamily, has a well-established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.
METHODS: This review follows the PRISMA-ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.
RESULTS: Sixty-two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089 pg/mL (interquartile range 3805-13 306) and mitochondrial diseases 4640 pg/mL (1896-14 064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8 ± 221.0 pg/mL, with a range of 90-1134 pg/mL for study averages.
CONCLUSIONS: Circulating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.}, }
@article {pmid40019453, year = {2025}, author = {Di, M and Maurer, MJ and Flowers, CR}, title = {End points and Outcomes in Follicular Lymphoma: What should we measure, how, and why?.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024026978}, pmid = {40019453}, issn = {1528-0020}, abstract = {Overall survival (OS) and quality of life (QoL) are clinically relevant outcomes/endpoints during examination of therapies. However, with median OS approaching 20 years for patients with follicular lymphoma (FL), it is often not feasible to use OS as a primary endpoint in clinical studies. While validated tools for assessing QoL in patient with lymphoma exist, QoL data are rarely the sole basis for drug approvals in FL. Therefore, other survival endpoints, surrogates, and intermediate clinical endpoints have all been used to measure outcomes in FL trials. In this review, we discuss the strengths and limitations of these commonly used traditional endpoints in FL trials and examine the current gaps, including delayed availability of results and suboptimal sensitivity in distinguishing difference in therapeutic effects. To help address the gaps identified, well-validated surrogates, such as complete remission 30 months after starting frontline immunochemotherapy (CR30), may be used as the primary or co-primary endpoint in confirmatory randomized trials. Emerging intermediate endpoints like minimal residual disease, may be useful in early phase trials and in guiding accelerated approvals after appropriate validation. As patient preference plays a crucial role in treatment decisions in FL, it is critical to include QoL as an important secondary trial endpoint and to measure non-medical burdens, including time and financial toxicities. Endpoints that are clinically relevant, timely, and patient-centered may identify new drugs that help patients with FL live longer and better lives.}, }
@article {pmid40016020, year = {2025}, author = {Indorf, A and Kwok, M and Jao, M and Chen, A and Baek, GT and Banerjee, R and Cicero, KI and Cowan, AJ and Portuguese, AJ and Yoon, L and Segal, EM}, title = {Enhancing Multiple Myeloma Care: Implementation of Pharmacist-Led Prescribing of Immunomodulatory Drugs in an Academic Medical Setting.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {25}, number = {6}, pages = {e424-e434}, doi = {10.1016/j.clml.2025.01.013}, pmid = {40016020}, issn = {2152-2669}, mesh = {Humans ; *Multiple Myeloma/drug therapy ; *Pharmacists ; Male ; Female ; Middle Aged ; Aged ; *Immunomodulating Agents/therapeutic use ; Academic Medical Centers ; Quality Improvement ; Drug Prescriptions ; }, abstract = {BACKGROUND: The oncology healthcare landscape has transformed and has demonstrated the need for efficient care delivery models due to improved survival resulting in larger patient panels. Pharmacists can prescribe oral anticancer agents (OAA), laboratory orders, and supportive care treatments as licensed independent practitioners (LIP) under their pharmacist license. Using immunomodulators (IMiDs) for patients with multiple myeloma (MM) has complexities with regulatory requirements for prescribing. At our institution, the care team was spending about 240 hours per month satisfying regulatory activities. We aim to characterize the effectiveness of pharmacist LIPs for patients with MM receiving IMiD treatment.
METHODS: A multidisciplinary quality improvement team implemented a model for OAA management with pharmacist LIPs. Patients were evaluated for IMiD adherence. Medication possession ratios (MPR) were collected using fill history for patients with 6 months of fill history pre and postpharmacist LIPs involvement, and paired McNemar's Test assessed differences in adherence. A care team survey gauged satisfaction.
RESULTS: The pharmacist patient panel comprised 246 patients. There were similar adherence rates, with an MPR of 96% preintervention and 96.55% postintervention. All survey participants recommended the pharmacist prescriber for IMiDs and reported positive reviews of pharmacist involvement.
CONCLUSION: Management of OAAs by pharmacist LIPs is viable clinical model. The care team reduced their administrative burden while empowering pharmacists to practice at the top of their license. This framework serves as a guide for institutions to adapt and optimize OAA management in an increasingly complex therapeutic landscape.}, }
@article {pmid40015292, year = {2025}, author = {Haidar, G and Thomas, S and Loubet, P and Baker, RI and Benfield, T and Boonyaratanakornkit, J and Kiertiburanakul, S and Kim, AHJ and Longbrake, EE and Molina, JM and Paredes, R and Tucker, D and Uriel, A and Weinmann-Menke, J and Aksyuk, AA and Clegg, LE and Currie, A and Yang, H and Flyrin, K and Gibbs, M and Shroff, M and Perez, JL and Chang, LJ and Cohen, TS and , }, title = {Efficacy and safety of sipavibart for prevention of COVID-19 in individuals who are immunocompromised (SUPERNOVA): a randomised, controlled, double-blind, phase 3 trial.}, journal = {The Lancet. Infectious diseases}, volume = {25}, number = {7}, pages = {813-826}, doi = {10.1016/S1473-3099(24)00804-1}, pmid = {40015292}, issn = {1474-4457}, mesh = {Humans ; Double-Blind Method ; Female ; Male ; *COVID-19/prevention & control/immunology/virology ; Middle Aged ; *Immunocompromised Host ; *SARS-CoV-2/immunology/drug effects ; Adult ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage/adverse effects ; Aged ; Antibodies, Neutralizing/therapeutic use ; *COVID-19 Drug Treatment ; Adolescent ; Treatment Outcome ; Young Adult ; *Antiviral Agents/therapeutic use ; }, abstract = {BACKGROUND: Sipavibart is an anti-spike monoclonal antibody that neutralises SARS-CoV-2 with exceptions, including Phe456Leu-containing variants (eg, KP.2* and KP.3*). This trial assessed sipavibart efficacy and safety for prevention of symptomatic COVID-19 in participants who are immunocompromised.
METHODS: In this ongoing, double-blind, international, phase 3 trial, we enrolled participants who were immunocompromised and aged 12 years or older at 197 hospitals, university health centres, and clinical trial units in 18 countries. Participants were randomly allocated 1:1 to a sipavibart group (intramuscular sipavibart 300 mg on days 1 and 181) or a comparator group (tixagevimab 300 mg-cilgavimab 300 mg on day 1 and placebo on day 181 or placebo on days 1 and 181), stratified by previous COVID-19 vaccination and infection status and use of tixagevimab-cilgavimab. The primary efficacy outcomes were symptomatic COVID-19 caused by any variant or symptomatic COVID-19 caused by non-Phe456Leu-containing variants within 181 days of dosing, assessed in the SARS-CoV-2-negative set, comprising all participants without a positive RT-PCR test for SARS-CoV-2 at baseline and who received at least one trial intervention dose. Safety outcomes for adverse events were assessed 90 days following the first dose and for serious adverse events throughout the study in the safety analysis set (ie, all participants who received at least one injection of sipavibart or comparator). This study is registered with ClinicalTrials.gov, NCT05648110.
FINDINGS: Participants were screened from March 31 to Oct 27, 2023; 3349 participants (56·8% female) were randomly assigned: 1674 to the sipavibart group (five no first dose; 1669 sipavibart) and 1675 to the comparator group (nine no first dose; 1105 tixagevimab-cilgavimab and 561 placebo). Within 181 days of dosing, 122 (7·4%) of 1649 participants in the sipavibart group and 178 (10·9%) of 1631 participants in the comparator group had symptomatic COVID-19 due to any variant (relative risk reduction [RRR] 34·9% [97·5% CI 15·0 to 50·1]; p=0·0006), 54 (3·3%) participants in the sipavibart group and 90 (5·5%) participants in the comparator group had symptomatic COVID-19 due to non-Phe456Leu-containing variants (RRR 42·9% [95% CI 19·9 to 59·3]; p=0·0012), and 47 (2·9%) participants in the sipavibart group and 64 (3·9%) participants in the comparator group had symptomatic COVID-19 due to Phe456Leu-containing variants (30·4% [-1·8 to 52·5]). Adverse events occurred in 833 (49·9%) of 1671 participants in the sipavibart group and 857 (51·5%) of 1663 participants in the comparator group within 3 months of the first dose. One COVID-19-related death occurred in the comparator group. Serious adverse events considered related to trial intervention occurred in two (0·1%) of 1671 participants in the sipavibart group and seven (0·4%) of 1663 participants in the comparator group (none fatal). No serious cardiovascular or thrombotic events were considered to be related to sipavibart.
INTERPRETATION: The primary analysis showed efficacy and safety of sipavibart in preventing symptomatic COVID-19 in participants who are immunocompromised when susceptible (ie, non-Phe456Leu-containing) variants dominated, although no efficacy was shown against resistant (ie, Phe456Leu-containing) variants that dominate as of November, 2024.
FUNDING: AstraZeneca.}, }
@article {pmid40014858, year = {2025}, author = {Nudy, M and Aragaki, AK and Jiang, X and Manson, JE and Shadyab, AH and Jung, SY and Martin, LW and Wild, RA and Womack, C and Mouton, CP and Rossouw, JE and Schnatz, PF}, title = {Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the Women's Health Initiative Hormone Therapy Clinical Trials.}, journal = {Obstetrics and gynecology}, volume = {145}, number = {4}, pages = {357-367}, pmid = {40014858}, issn = {1873-233X}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; KL2 TR002015/TR/NCATS NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; Biomarkers/blood ; *Estrogens, Conjugated (USP)/administration & dosage/therapeutic use ; Middle Aged ; *Estrogen Replacement Therapy/methods ; *Medroxyprogesterone Acetate/administration & dosage/therapeutic use ; *Cardiovascular Diseases/blood ; Women's Health ; Cholesterol, LDL/blood ; Insulin Resistance ; Cholesterol, HDL/blood ; Blood Glucose ; Insulin/blood ; Triglycerides/blood ; Aged ; Lipoprotein(a)/blood ; }, abstract = {OBJECTIVE: To assess the long-term changes in cardiovascular biomarkers during the WHI (Women's Health Initiative) hormone therapy (HT) clinical trials of conjugated equine estrogens (CEE) alone and CEE plus medroxyprogesterone acetate (MPA).
METHODS: HT trial participants from the CEE alone (n=1,188, 0.625 mg/d CEE or placebo) and the CEE+MPA (n=1,508, 0.625 mg/d CEE plus continuous 2.5 mg/d MPA or placebo) trials provided blood samples at baseline and after 1, 3, and 6 years. Low-density lipoprotein cholesterol (LDL-C; primary endpoint), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, lipoprotein(a), glucose, insulin, and homeostatic model assessment for insulin resistance were measured. Repeated-measures regression models estimated the geometric means of each log-transformed biomarker by restricted maximum likelihood. A constant treatment effect across visits was used to estimate the overall effect, expressed as a ratio of geometric means, and was complemented with geometric means (95% CIs) by randomization group and corresponding ratios of geometric means (95% CI; HT vs placebo) at each visit.
RESULTS: During the intervention phase of the CEE-alone trial, randomization to CEE reduced LDL-C by 11% over 6 years (ratio of geometric means 0.89, 95% CI, 0.88-0.91, P <.001). The overall reduction in LDL-C was similar for CEE+MPA relative to placebo (ratio of geometric means 0.88, 95% CI, 0.86-0.89, P <.001). Relative to placebo, HDL-C and triglycerides were 13.0% and 7.0% higher with CEE and CEE+MPA, respectively. The homeostatic model assessment for insulin resistance decreased by 14.0% and 8.0% for CEE-alone and CEE+MPA trial participants, respectively. Relative to placebo, lipoprotein(a) decreased by 15.0% and 20.0% for participants randomized to CEE alone and CEE+MPA, respectively.
CONCLUSION: Lipoprotein(a), LDL-C, and homeostatic model assessment for insulin resistance were lower and HDL-C levels were higher for HT compared with placebo. Triglycerides increased in both the CEE and CEE+MPA trials, however. Future research should assess whether other progestogens attenuate the effect of estrogen on HDL-C. These results may be used to counsel younger menopausal women with bothersome symptoms who are deciding whether to initiate oral HT within the context of published effects of oral HT on rates of cardiovascular events.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT00000611.}, }
@article {pmid40014402, year = {2025}, author = {Arias-Badia, M and Chen, P and Lwin, YM and Srinath, A and Lyu, A and Fan, Z and Kwek, SS and Luong, DN and Setayesh, A and Sakamoto, M and Clark, M and Lea, A and Wolters, RM and Goodearl, A and Harding, FA and Gorman, JV and Ritacco, W and Fong, L}, title = {Sequential JAK inhibition enhances antitumor immunity after combined anti-PD-1 and anti-CTLA4.}, journal = {JCI insight}, volume = {10}, number = {7}, pages = {}, pmid = {40014402}, issn = {2379-3708}, support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Immune Checkpoint Inhibitors/pharmacology ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; Interferon-gamma/metabolism/immunology ; *CTLA-4 Antigen/antagonists & inhibitors/immunology ; *Janus Kinase Inhibitors/pharmacology ; Female ; Cell Line, Tumor ; Humans ; T-Lymphocytes/immunology/drug effects ; *Janus Kinase 1/antagonists & inhibitors ; Mice, Inbred C57BL ; *Neoplasms/immunology/drug therapy ; Imidazoles/pharmacology ; Signal Transduction/drug effects ; Aminopyridines ; Pyrroles ; }, abstract = {While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.}, }
@article {pmid40014323, year = {2025}, author = {Hirayama, AV and Bleakley, M}, title = {Competition for CD19 binding may accelerate CAR efficacy.}, journal = {Blood}, volume = {145}, number = {9}, pages = {902-903}, pmid = {40014323}, issn = {1528-0020}, }
@article {pmid40013681, year = {2025}, author = {Childers, CP and Petty, AM and Selzer, DJ and Senkowski, CK}, title = {Obesity and Work in Abdominal Surgery.}, journal = {Journal of the American College of Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1097/XCS.0000000000001367}, pmid = {40013681}, issn = {1879-1190}, abstract = {BACKGROUND: Recent analyses have shown that Modifier 22 does not reimburse surgeons for the increased work required to care for the most complex patients. New strategies are needed to identify patients that require additional work to create a financial system that ensures equitable access. Obesity has been identified as a growing and potentially reliable patient risk factor that could be used to identify cases that require additional work.
STUDY DESIGN: Using 2022 ACS NSQIP data, this study evaluated 10 common general surgery operations (appendectomy, cholecystectomy, colon/rectal operations, hernia repairs). The primary predictor was BMI category (Normal: 18.5-25, overweight: 25-29.9, class I obesity: 30-34.9, class II obesity: 35-39.9, class III obesity 40-49.9, extreme obesity >=50). Primary outcomes were operative time and composite measures of complications.
RESULTS: The final sample included 158,692 operations. Across the entire cohort, 22.2% were normal weight and 76.3% were overweight or obese. Overall, operative time was increased by 5.6% (95% CI 4.8-6.3%) for overweight, by 10.6% (CI 9.8-11.5%) for class I obesity, by 14.7% (CI 13.6-15.8%) for class II obesity, by 18.9% (CI 17.6-20.2%) for class III obesity, and by 26.8% (CI 14.1-29.6%) for extreme obesity compared to those with normal BMI. Obesity was associated with higher odds of any complication or serious complication, driven by wound complications, pulmonary emboli, and renal insufficiency.
CONCLUSION: Obesity is a growing challenge in abdominal surgery and is associated with increase operative time and risk of complications. The consistency of the magnitude of effect makes it an ideal target for a modifier or add-on code that could identify cases requiring additional work.}, }
@article {pmid40013392, year = {2025}, author = {Haney, M and Ashraf, A and Lake, KE and Strecker, L and Myers, KC and Towe, C and Walkup, L and Woods, J and Edwards, SL and Cooper, R and Lehmann, LE and Cisneros, GS and Freedman, JL and Baker, KS and Doherty, E and MacMillan, ML and Goldfarb, SB and Davies, SM and Koo, J and Groups, T}, title = {Community respiratory viruses are generally well-tolerated in hematopoietic stem cell transplant recipients: a brief report from the TRANSPIRE study.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.287107}, pmid = {40013392}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid40009771, year = {2025}, author = {Collin, LJ and Cushing-Haugen, KL and Terry, KL and Goode, EL and Wu, AH and Harris, HR and Sasamoto, N and Cramer, DW and Modugno, F and Elishaev, E and Fu, Z and Moysich, KB and Fasching, PA and Pearce, CL and Menon, U and Gentry-Maharaj, A and Gayther, SA and Wentzensen, N and Goodman, MT and George, J and Talhouk, A and Anglesio, MS and Ramus, SJ and Bowtell, DDL and Tworoger, SS and Schildkraut, JM and Webb, PM and Doherty, JA}, title = {Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {5}, pages = {762-773}, pmid = {40009771}, issn = {1538-7755}, support = {R21 CA267050/CA/NCI NIH HHS/United States ; R01 CA172404/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; K99 CA277580/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; ZIA CP010126/ImNIH/Intramural NIH HHS/United States ; K99CA277580//National Cancer Institute (NCI)/ ; R01 CA248288/CA/NCI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; CA259058//National Cancer Institute (NCI)/ ; R01 CA259058/CA/NCI NIH HHS/United States ; M01 RR000056/RR/NCRR NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; 1092856//National Health and Medical Research Council (NHMRC)/ ; R01 CA076016/CA/NCI NIH HHS/United States ; R01 CA168758/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/genetics/epidemiology/pathology ; *Cystadenocarcinoma, Serous/genetics/epidemiology/pathology ; Middle Aged ; Case-Control Studies ; Risk Factors ; Aged ; Neoplasm Grading ; Adult ; }, abstract = {BACKGROUND: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes.
METHODS: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models.
RESULTS: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only.
CONCLUSIONS: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes.
IMPACT: The different patterns of associations may provide key information about the etiology of the four subtypes.}, }
@article {pmid40007996, year = {2025}, author = {Crotty, EE and Sato, AA and Abdelbaki, MS}, title = {Integrating MAPK pathway inhibition into standard-of-care therapy for pediatric low-grade glioma.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1520316}, pmid = {40007996}, issn = {2234-943X}, abstract = {Pediatric low-grade gliomas (pLGG) are a group of tumors largely driven by alterations in a single genetic pathway, known as the RAS-RAF-mitogen-activated protein kinase (MAPK) pathway. Recent biologic insights and therapeutic targeting of MAPK-alterations have dramatically shifted the treatment approach in pLGG. While chemotherapy remains front-line therapy for unresectable pLGG in most scenarios (with the notable exception of BRAF [V600E]-altered tumors), many patients recur following cytotoxic agents and require further treatment. Inhibitors of the MAPK pathway, primarily MEK and RAF kinase inhibitors, have emerged as effective and tolerable second-line or later therapy for pLGG. As familiarity with these targeted agents increases, their indications for use continue to expand and Phase 3 clinical trials investigating their utility in the front-line setting are ongoing. We have adopted mitigation strategies for their associated toxicities; skin toxicity, in particular, is now managed by prevention strategies and early dermatologic intervention. This review highlights current approaches for the clinical implementation of MEK and RAF kinase inhibitors for pLGG, focusing on the practical aspects of drug administration, toxicity management, response monitoring, and distribution to patients experiencing geographic or financial barriers to care. Additionally, we review important considerations for the off-label use of these agents while contemporaneous clinical trials assessing front-line efficacy are ongoing. We discuss the potential for more expansive or histology-agnostic tumor targeting using MEK inhibitors, harnessing their biologic relevance for other RAS-altered conditions.}, }
@article {pmid40006680, year = {2025}, author = {Shen, X and Korber, B and Spreng, RL and Sawant, SS and deCamp, A and McMillan, AS and Mathura, R and Zolla-Pazner, S and Pinter, A and Parks, R and Bowman, C and Sutherland, L and Scearce, R and Yates, NL and Montefiori, DC and Haynes, BF and Tomaras, GD}, title = {A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses.}, journal = {Vaccines}, volume = {13}, number = {2}, pages = {}, pmid = {40006680}, issn = {2076-393X}, support = {UM1 AI100645/AI/NIAID NIH HHS/United States ; AI100645//Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery/ ; P30AI064518//Duke Center for AIDS Research/ ; P30 AI064518/AI/NIAID NIH HHS/United States ; UM1 AI144371/AI/NIAID NIH HHS/United States ; AI067854//Center for HIV/AIDS Vaccine Immunology/ ; U01 AI067854/AI/NIAID NIH HHS/United States ; HHSN27201100016C/AI/NIAID NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region's highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity.
METHODS: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&2 (V1V2) scaffold proteins and linear V2 peptides.
RESULTS: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at [169]K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site ([179]LDV/I[181]) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions.
CONCLUSIONS: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.}, }
@article {pmid40006664, year = {2025}, author = {Gwin, WR and Salazar, LG and Dai, JY and Higgins, D and Coveler, AL and Childs, JS and Blancas, R and Dang, Y and Reichow, J and Slota, M and Lu, H and Disis, ML}, title = {A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer.}, journal = {Vaccines}, volume = {13}, number = {2}, pages = {}, pmid = {40006664}, issn = {2076-393X}, support = {R21 CA114958/CA/NCI NIH HHS/United States ; }, abstract = {Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1-5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved ≥25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p < 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study.}, }
@article {pmid40004846, year = {2025}, author = {Costa, BA and Dima, D and Mark, T and Sadek, NL and Ijioma, S and Ray, D and Goel, U and Dranitsaris, G and Sheng, T and Moshier, E and Mouhieddine, TH and Khouri, J and Rossi, A}, title = {Impact of Prior Selinexor Exposure on Outcomes of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: An Exploratory Analysis.}, journal = {Journal of clinical medicine}, volume = {14}, number = {4}, pages = {}, pmid = {40004846}, issn = {2077-0383}, support = {NA//Karyopharm Therapeutics/ ; }, abstract = {Background/Objectives: Chimeric antigen receptor T-cell therapy (CAR-T) has become a key treatment option for relapsed/refractory multiple myeloma (RRMM), but factors impairing T-cell fitness may diminish efficacy. Our exploratory analysis aimed to evaluate the impact of prior treatment with a selinexor-containing regimen on CAR-T outcomes for RRMM patients. Methods: Data for this retrospective cohort study were sourced from electronic medical records at two US academic centers. Kaplan-Meier estimates assessed duration of response (DOR), progression-free survival (PFS), and overall survival (OS), reported as medians with interquartile ranges (IQRs). Cox proportional hazards regression analyzed factors potentially associated with PFS and OS, reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Among 45 patients exposed to selinexor before undergoing BCMA-directed CAR-T, median therapy line numbers for selinexor use and CAR-T were 7 and 9, respectively, with 24.4% receiving selinexor as part of bridging. At median follow-up of 68 months, median PFS and OS post CAR-T were 8.0 (IQR 3.1-39.5) and 35.9 (IQR 14.2-NR) months, respectively. Overall response rate to CAR-T was 89%, with a median DOR of 8.1 months (IQR 2.9-39.0). In our multivariable model, patients who received a selinexor-based regimen in the line of therapy preceding CAR-T showed a trend toward reduced risk of death (HR = 0.08; 95% CI 0.02-0.46) and/or disease progression (HR = 0.40; 95% CI 0.14-1.09). Conclusions: Prior selinexor exposure does not appear to compromise CAR-T outcomes in heavily pretreated RRMM, suggesting potential T-cell sparing. Our findings warrant larger, prospective studies to determine whether preemptive selinexor treatment can optimize CAR-T efficacy.}, }
@article {pmid40000903, year = {2025}, author = {Itkin, T and Houghton, S and Schreiner, R and Lin, Y and Badwe, CR and Voisin, V and Murison, A and Seyedhassantehrani, N and Kaufmann, KB and Garcia-Prat, L and Booth, GT and Geng, F and Liu, Y and Gomez-Salinero, JM and Shieh, JH and Redmond, D and Xiang, JZ and Josefowicz, SZ and Trapnell, C and Pietras, EM and Spencer, JA and Levine, R and Xiao, W and Zangi, L and Hadland, B and Dick, JE and Xie, SZ and Rafii, S}, title = {Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.}, journal = {Nature immunology}, volume = {26}, number = {3}, pages = {378-390}, pmid = {40000903}, issn = {1529-2916}, mesh = {Animals ; *Hematopoiesis/genetics ; *Hematopoietic Stem Cells/physiology/metabolism ; Humans ; Mice ; *Proto-Oncogene Protein c-fli-1/metabolism/genetics ; *Stem Cell Niche/genetics ; Signal Transduction ; Receptor, Notch1/metabolism/genetics ; *Transcriptional Activation ; *Regeneration/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; }, abstract = {Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.}, }
@article {pmid39999848, year = {2025}, author = {Ugalde-Morales, E and Wilf, R and Pluta, J and Ploner, A and Fan, M and Damra, M and Aben, KK and Anson-Cartwright, L and Chen, C and Cortessis, VK and Daneshmand, S and Ferlin, A and Gamulin, M and Gietema, JA and Gonzalez-Niera, A and Grotmol, T and Hamilton, RJ and Harland, M and Haugen, TB and Hauser, R and Hildebrandt, MAT and Karlsson, R and Kiemeney, LA and Kim, J and Lessel, D and Lothe, RA and Loveday, C and Chanock, SJ and McGlynn, KA and Meijer, C and Nead, KT and Nsengimana, J and Popovic, M and Rafnar, T and Richiardi, L and Rocca, MS and Schwartz, SM and Skotheim, RI and Stefansson, K and Stewart, DR and Turnbull, C and Vaughn, DJ and Winge, SB and Zheng, T and Monteiro, AN and Almstrup, K and Kanetsky, PA and Nathanson, KL and Wiklund, F and , }, title = {Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study.}, journal = {American journal of human genetics}, volume = {112}, number = {3}, pages = {630-643}, pmid = {39999848}, issn = {1537-6605}, support = {U01 CA164947/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Testicular Neoplasms/genetics ; Male ; *Neoplasms, Germ Cell and Embryonal/genetics ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; *Transcriptome/genetics ; Polymorphism, Single Nucleotide/genetics ; Gene Expression Regulation, Neoplastic ; Gene Expression Profiling ; }, abstract = {Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.}, }
@article {pmid39996762, year = {2025}, author = {Gang, M and Othus, M and Walter, RB}, title = {Significance of Measurable Residual Disease in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996762}, issn = {2073-4409}, support = {T32-HL007093//NIH/NHLBI/ ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/pathology ; *Neoplasm, Residual/diagnosis ; *Hematopoietic Stem Cell Transplantation/methods ; Transplantation, Homologous ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) remains an important curative-intent treatment for many patients with acute myeloid leukemia (AML), but AML recurrence after allografting is common. Many factors associated with relapse after allogeneic HCT have been identified over the years. Central among these is measurable ("minimal") residual disease (MRD) as detected by multiparameter flow cytometry, quantitative polymerase chain reaction, and/or next-generation sequencing. Demonstration of a strong, independent prognostic role of pre- and early post-HCT MRD has raised hopes MRD could also serve as a predictive biomarker to inform treatment decision-making, with emerging data indicating the potential value to guide candidacy assessment for allografting as a post-remission treatment strategy, the selection of conditioning intensity, use of small molecule inhibitors as post-HCT maintenance therapy, and preemptive infusion of donor lymphocytes. Monitoring for leukemia recurrence after HCT and surrogacy for treatment response are other considerations for the clinical use of MRD data. In this review, we will outline the current landscape of MRD as a biomarker for patients with AML undergoing HCT and discuss areas of uncertainty and ongoing research.}, }
@article {pmid39996711, year = {2025}, author = {Morishita, T and Martin, PJ and Inamoto, Y}, title = {Treatment Response in Individual Organs Affected by Chronic Graft-Versus-Host Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996711}, issn = {2073-4409}, support = {22K08517//Japan Society for the Promotion of Science/ ; }, mesh = {*Graft vs Host Disease/drug therapy/therapy/pathology ; Humans ; Chronic Disease ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Treatment Outcome ; }, abstract = {Chronic graft-versus-host disease (GVHD) occurs in 30-70% of patients after allogeneic hematopoietic cell transplantation (HCT) and increases the risks of morbidity and mortality. Systemic corticosteroids are the standard initial treatment, but one-third of patients require subsequent treatment with other systemic agents. Treatment decisions are often based on physicians' experience. The expected treatment response rates in specific organs affected by chronic GVHD may inform such decisions. In this review, we identify 20 studies reporting treatment response rates in individual organs according to objective criteria, summarize the results, discuss the caveats in data interpretation, identify the unmet needs, and suggest future directions in the field. For cutaneous sclerosis, we observed large discrepancies in organ response rates according to the current NIH criteria and patient-reported improvement, highlighting the need for better measurement tools. High response rates for lung involvement with certain novel drugs deserve further investigation.}, }
@article {pmid39994463, year = {2025}, author = {Banerjee, R and Fritz, AR and Akhtar, OS and Freeman, CL and Cowan, AJ and Shah, N and Landau, HJ and Kumar, SK and Vogl, DT and Efebera, YA and McCarthy, PL and Vesole, DH and Mendizabal, A and Krishnan, AY and Somlo, G and Stadtmauer, EA and Pasquini, MC}, title = {Urine-free response criteria predict progression-free survival in multiple myeloma: a post hoc analysis of BMT CTN 0702.}, journal = {Leukemia}, volume = {39}, number = {4}, pages = {1001-1004}, pmid = {39994463}, issn = {1476-5551}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid39992626, year = {2025}, author = {Krishnamoorthy, GP and Glover, AR and Untch, BR and Sigcha-Coello, N and Xu, B and Vukel, D and Liu, Y and Tiedje, V and Pineda, JMB and Berman, K and Tamarapu, PP and Acuña-Ruiz, A and Saqcena, M and de Stanchina, E and Boucai, L and Ghossein, RA and Knauf, JA and Abdel-Wahab, O and Bradley, RK and Fagin, JA}, title = {RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {5}, pages = {}, pmid = {39992626}, issn = {1540-9538}, support = {R01 CA50706-31/NH/NIH HHS/United States ; R01 CA255211/CA/NCI NIH HHS/United States ; RG183080//National Health and Medical Research Council/ ; //Marie-Josée and Henry R. Kravis Center for Molecular Oncology/ ; R01 CA050706/CA/NCI NIH HHS/United States ; P30 CA008748-58/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA249663/CA/NCI NIH HHS/United States ; //Cycle for Survival/ ; //Royal Australasian College of Surgeons Foundation/ ; }, mesh = {Animals ; Humans ; *Extracellular Matrix/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; Hyaluronan Receptors/genetics/metabolism ; rac1 GTP-Binding Protein/metabolism ; Neoplasm Metastasis/genetics ; *Cytoskeleton/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; Tenascin/genetics/metabolism ; Cell Line, Tumor ; Vinculin/genetics/metabolism ; Exons/genetics ; *RNA Splicing/genetics ; Thyroid Neoplasms/genetics/pathology/metabolism ; Gene Expression Regulation, Neoplastic ; Cell Movement/genetics ; Alternative Splicing ; }, abstract = {RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.}, }
@article {pmid39991196, year = {2025}, author = {Jefferson, JA and Chen, K and Hingorani, S and Malik, AB and Tykodi, SS and Keller, KH and Huang, Y and Smith, KD and Reed, RC and Weins, A and Akilesh, S}, title = {Genetic and Iatrogenic Defects in Peripheral Tolerance Associated with Anti-Nephrin Antibody-Associated Minimal Change Disease.}, journal = {Glomerular diseases}, volume = {5}, number = {1}, pages = {74-83}, pmid = {39991196}, issn = {2673-3633}, abstract = {INTRODUCTION: Minimal change disease (MCD) is a common cause of nephrotic syndrome in children and adults. Immune dysregulation is a contributor, but the relative roles of individual components of the immune system in MCD pathogenesis remain unclear.
CASE PRESENTATION: Here, we present 2 patients with defects in immune tolerance mechanisms that developed MCD associated with anti-nephrin antibodies. The first patient had a pathogenic deletion in FOXP3, leading to reduced regulatory T cells. Serum could not be obtained from this patient during the active phase of MCD to directly establish the presence of anti-nephrin antibodies. However, this patient demonstrated IgG dusting over podocyte cell bodies by immunofluorescence microscopy, as well as colocalization of IgG with nephrin in confocal microscopy. The second patient developed MCD in the context of immune checkpoint inhibitor treatment for metastatic carcinoma. Anti-nephrin antibodies were detected in this patient during active disease. The patient's kidney biopsy also showed evidence of binding of anti-nephrin antibodies within the glomeruli.
CONCLUSION: These cases demonstrate that genetic and iatrogenic mechanisms of breakdown in peripheral tolerance can lead to MCD.}, }
@article {pmid39990799, year = {2025}, author = {Chen, KY and Toro-Moreno, M and Subramaniam, AR}, title = {GitHub is an effective platform for collaborative and reproducible laboratory research.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39990799}, issn = {2331-8422}, support = {R01 AT012826/AT/NCCIH NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; }, abstract = {Laboratory research is a complex, collaborative process that involves several stages, including hypothesis formulation, experimental design, data generation and analysis, and manuscript writing. Although reproducibility and data sharing are increasingly prioritized at the publication stage, integrating these principles at earlier stages of laboratory research has been hampered by the lack of broadly applicable solutions. Here, we propose that the workflow used in modern software development offers a robust framework for enhancing reproducibility and collaboration in laboratory research. In particular, we show that GitHub, a platform widely used for collaborative software projects, can be effectively adapted to organize and document all aspects of a research project's lifecycle in a molecular biology laboratory. We outline a three-step approach for incorporating the GitHub ecosystem into laboratory research workflows: 1. designing and organizing experiments using issues and project boards, 2. documenting experiments and data analyses with a version control system, and 3. ensuring reproducible software environments for data analyses and writing tasks with containerized packages. The versatility, scalability, and affordability of this approach make it suitable for various scenarios, ranging from small research groups to large, cross-institutional collaborations. Adopting this framework from a project's outset can increase the efficiency and fidelity of knowledge transfer within and across research laboratories. An example GitHub repository based on this approach is available at https://github.com/rasilab/github_demo and a template repository that can be copied is available at https://github.com/rasilab/github_template.}, }
@article {pmid39990376, year = {2025}, author = {Wang, Y and Gornalusse, GG and Siegel, DA and Barbehenn, A and Hoh, R and Martin, J and Hecht, F and Pilcher, C and Semenova, L and Murdoch, DM and Margolis, DM and Levy, CN and Jerome, KR and Rudin, CD and Hladik, F and Deeks, SG and Lee, SA and Browne, EP}, title = {NF-κB dependent gene expression and plasma IL-1β, TNFα and GCSF drive transcriptomic diversity and CD4:CD8 ratio in people with HIV on ART.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39990376}, issn = {2692-8205}, support = {R01 DA054994/DA/NIDA NIH HHS/United States ; K23 GM112526/GM/NIGMS NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; R01 AI184122/AI/NIAID NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; INV-008500/GATES/Gates Foundation/United States ; UM1 AI164567/AI/NIAID NIH HHS/United States ; UM1 AI126623/AI/NIAID NIH HHS/United States ; }, abstract = {Despite antiretroviral therapy (ART), people with HIV (PWH) on ART experience higher rates of morbidity and mortality vs. age-matched HIV negative controls, which may be driven by chronic inflammation due to persistent virus. We performed bulk RNA sequencing (RNA-seq) on peripheral CD4+ T cells, as well as quantified plasma immune marker levels from 154 PWH on ART to identify host immune signatures associated with immune recovery (CD4:CD8) and HIV persistence (cell-associated HIV DNA and RNA). Using a novel dimension reduction tool - Pairwise Controlled Manifold Approximation (PaCMAP), we defined three distinct participant transcriptomic clusters. We found that these three clusters were largely defined by differential expression of genes regulated by the transcription factor NF-κB. While clustering was not associated with HIV reservoir size, we observed an association with CD4:CD8 ratio, a marker of immune recovery and prognostic factor for mortality in PWH on ART. Furthermore, distinct patterns of plasma IL-1β, TNF-α and GCSF were also strongly associated with the clusters, suggesting that these immune markers play a key role in CD4+ T cell transcriptomic diversity and immune recovery in PWH on ART. These findings reveal novel subgroups of PWH on ART with distinct immunological characteristics, and define a transcriptional signature associated with clinically significant immune parameters for PWH. A deeper understanding of these subgroups could advance clinical strategies to treat HIV-associated immune dysfunction.}, }
@article {pmid39990346, year = {2025}, author = {Prodanov, T and Plender, EG and Seebohm, G and Meuth, SG and Eichler, EE and Marschall, T}, title = {Locityper: targeted genotyping of complex polymorphic genes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39990346}, issn = {2692-8205}, support = {R01 HG002385/HG/NHGRI NIH HHS/United States ; }, abstract = {The human genome contains numerous structurally-variable polymorphic loci, including several hundred disease-associated genes, almost inaccessible for accurate variant calling. Here we present Locityper, a tool capable of genotyping such challenging genes using short and long-read whole genome sequencing. For each target, Locityper recruits and aligns reads to locus haplotypes, for instance extracted from a pangenome, and finds the likeliest haplotype pair by optimizing read alignment, insert size and read depth profiles. Locityper accurately genotypes up to 194 of 256 challenging medically relevant loci (95% haplotypes at QV33), an 8.8-fold gain compared to 22 genes achieved with standard variant calling pipelines. Furthermore, Locityper provides access to hyperpolymorphic HLA genes and other gene families, including KIR, MUC and FCGR. With its low running time of 1h10m per sample at 8 threads, Locityper is scalable to biobank-sized cohorts, enabling association studies for previously intractable disease-relevant genes.}, }
@article {pmid39990276, year = {2025}, author = {Goel, U and Zanwar, S and Cowan, AJ and Banerjee, R and Khouri, J and Dima, D}, title = {Ciltacabtagene Autoleucel for the Treatment of Relapsed/Refractory Multiple Myeloma: Efficacy, Safety, and Place in Therapy.}, journal = {Cancer management and research}, volume = {17}, number = {}, pages = {357-372}, pmid = {39990276}, issn = {1179-1322}, abstract = {Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two chimeric antigen receptor T cell (CAR T) therapies approved for use in patients with relapsed/refractory multiple myeloma (MM). Initially approved for late line MM (>4 prior lines), these were recently approved for use in MM with 1-2 prior lines of therapy in April 2024. As their use outside of the pivotal clinical trials continues to expand, it is important to critically evaluate the safety and efficacy of these therapies. Further, it is important to identify patients that would be most likely to benefit from the use of CAR T in earlier lines of therapy. Cilta-cel was initially studied in the phase-I LEGEND-2 study, followed by CARTITUDE-1 and CARTITUDE-4 trials, demonstrating remarkable efficacy. A recent large real-world study also demonstrated similar efficacy, in a mostly pivotal trial ineligible patient population. Based on these impressive results, cilta-cel is currently being studied in trials for newly diagnosed as well as smoldering multiple myeloma. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are known toxicities of cilta-cel (and other CAR Ts), however movement and cognitive disorders (delayed neurotoxicity) and second primary malignancies are an evolving concern. In this article we discuss safety and efficacy data from existing cilta-cel studies. We propose that all patients with MM who have received ≥4 prior lines of therapy should be considered for CAR T. Earlier line use of CAR T should be restricted to patients with a high-risk disease phenotype (eg, functional high-risk disease). This disease phenotype has historically shown poor outcomes with standard triplet regimens and would be most likely to benefit from earlier use of CAR T: considering the availability of other safe and highly effective therapies, and potential high-risk toxicities of CAR T.}, }
@article {pmid39990199, year = {2025}, author = {Meehan, KA and Waters, AR and Wangen, M and Odebunmi, OO and Ferrari, RM and Marciniak, MW and Brenner, AT and Wheeler, SB and Shah, PD}, title = {Not just about pills: Findings from a national survey of pharmacists to understand their views on addressing social determinants of health.}, journal = {Preventive medicine reports}, volume = {51}, number = {}, pages = {102991}, pmid = {39990199}, issn = {2211-3355}, abstract = {OBJECTIVE: We evaluated community pharmacists' perspectives on addressing social determinants of health for their patients in the United States.
METHODS: From 9/2022-1/2023, we conducted a national, online survey of 578 pharmacists to evaluate their perspectives on social barriers affecting their patients, their pharmacy staff's ability to address these social barriers, and resources available or needed to address barriers.
RESULTS: Healthcare access and quality was perceived as the most addressable social barrier (59 %), while education (24 %) and neighborhood/built environment were perceived as the least addressable (14 %). Staff capacity to address social needs was significantly associated with increases in the pharmacy's ability to address social determinants of health across all five domains. Pharmacists were more likely to report adequate staff capacity if they practiced in independent community pharmacies.
CONCLUSIONS: Pharmacists commonly address social determinants of health of their patients, but most lack adequate staff capacity to address patient social barriers. Pharmacies with capacity can only address a portion of the social needs of their patient population. Greater access to resources and staffing support are needed to improve pharmacy's role in addressing patient unmet social needs.}, }
@article {pmid39989965, year = {2025}, author = {Nicholas, JC and Katz, DH and Tahir, UA and Debban, CL and Aguet, F and Blackwell, T and Bowler, RP and Broadaway, KA and Chen, J and Clish, CB and Coresh, J and Cornell, E and Cruz, DE and Deo, R and Doyle, MF and Durda, P and Ekunwe, L and Floyd, JS and Gill, D and Guo, X and Hoogeveen, RC and Johnson, C and Lange, LA and Li, Y and Manning, A and Meigs, JB and Mi, MY and Mychaleckyj, JC and Olson, NC and Pratte, KA and Psaty, BM and Reiner, AP and Ruan, P and Sevilla-Gonzalez, M and Shah, AM and Sun, Q and Tracy, RP and Wen, J and Wood, AC and Wilson, JG and Young, KL and Yu, B and Rooney, MR and Manichaikul, A and Dubin, R and Mohlke, KL and Rich, SS and Rotter, JI and Ganz, P and Gerszten, RE and Taylor, KD and Raffield, LM}, title = {Cross-Ancestry Comparison of Aptamer and Antibody Proteomics Measures.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39989965}, issn = {2693-5015}, support = {U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL071259/HL/NHLBI NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; R01 HL071250/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; OT3 HL142481/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; R01 HL071205/HL/NHLBI NIH HHS/United States ; R01 HL071258/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; OT3 HL142478/HL/NHLBI NIH HHS/United States ; UL1 RR033176/RR/NCRR NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; T32 GM135128/GM/NIGMS NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL071251/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 DK072193/DK/NIDDK NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; OT3 HL147154/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL071051/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; U01 AG082042/AG/NIA NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; OT3 HL142480/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL133870/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; OT3 HL142479/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; R01 HL151855/HL/NHLBI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; }, abstract = {Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants (pQTL) and phenotypes. Here, we examined 2,157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1,930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2,157 proteins followed a bimodal distribution (median r=0.30). Protein measures from each platform were associated with genetic variants (pQTLs), and one-third of the pQTL signals were driven by protein-altering variants (PAVs). We highlight 80 proteins that correlate differently across ancestry groups likely due to differing PAV frequencies by ancestry. Furthermore, adjustment for PAVs with opposite directions of effect by platform improved inter-platform protein measure correlation and resulted in more concordant genetic and phenotypic associations. Hence, PAVs need to be accounted for across ancestries to facilitate platform-concordant and accurate protein measurement.}, }
@article {pmid39989958, year = {2025}, author = {von Delft, F and Ni, X and Richardson, R and Godoy, A and Ferla, M and Kikawa, C and Scheen, J and Hannon, W and Capkin, E and Lahav, N and Balcomb, B and Marples, P and Fairhead, M and Wang, S and Williams, E and Tomlinson, C and Aschenbrenner, J and Lithgo, R and Winokan, M and Giroud, C and Chandran, A and Walsh, M and Thompson, W and Bloom, J and Barr, H and Kirkegaard, K and Koekemoer, L and Fearon, D and Evans, M}, title = {Crystallographic fragment screening and deep mutational scanning of Zika virus NS2B-NS3 protease enable development of resistance-resilient inhibitors.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39989958}, issn = {2693-5015}, support = {U19 AI171399/AI/NIAID NIH HHS/United States ; }, abstract = {The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 47 fragments with diverse scaffolds were identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we performed deep mutational scanning of NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points that maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.}, }
@article {pmid39989044, year = {2025}, author = {Unger, JM and Mazza, GL and Elsaid, MI and Duan, F and Dressler, EV and Snavely, AC and Enserro, DM and Pugh, SL}, title = {When to adjust for multiplicity in cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {3-9}, pmid = {39989044}, issn = {1745-6614}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1CA189974/NH/NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; U10 CA180794/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; UG1CA189828//NRG Oncology/ ; 5UG1CA189955-11//Children's Oncology Group/ ; UG1 CA189867/CA/NCI NIH HHS/United States ; P30 CA016058-47S1//ACRIN/ ; UG1CA189974//SWOG/ ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189823//SWOG Cancer Research Network/ ; U10CA180822//Wake Fores NCORP Research Base/ ; P30 CA016058/CA/NCI NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1CA189867//NCI Community Oncology Research Program/ ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189824//URCC NCORP Research Base/ ; U10 CA180820/CA/NCI NIH HHS/United States ; UG1CA189961//Alliance NCORP Research Base/ ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/therapy ; *Clinical Trials as Topic/methods/statistics & numerical data ; *Research Design ; United States ; Data Interpretation, Statistical ; False Positive Reactions ; }, abstract = {Interpreting cancer clinical trial results often depends on addressing issues of multiplicity. When testing multiple hypotheses, unreliable findings can occur by chance due to the inflation of the type I error rate, the probability of mistakenly rejecting the null hypothesis when the null hypothesis is true. In this setting, researchers may often set the type I error rate (or the alpha level) low to limit false positive findings and the interpretation of a causal relationship where none exists. Conversely, overly conservative type I error control may result in declaring findings, that do not meet multiplicity-adjusted alpha levels, as false when they are actually true, reducing opportunities for new discovery. This presentation focuses on multiplicity adjustment in the context of clinical trials conducted within the NCI's Community Oncology Research Program (NCORP). Because federally sponsored trials often require long-term participation from patients and represent a substantial investment by taxpayers, striking the right balance between optimizing what is learned from these trials, while avoiding false positive results, should be a priority.}, }
@article {pmid39989043, year = {2025}, author = {Mazza, GL and Culakova, E and Enserro, DM and Dignam, JJ and Unger, JM}, title = {Design and analysis considerations for investigating patient subgroups of interest within cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {22-29}, pmid = {39989043}, issn = {1745-6614}, support = {UG1CA189823/NH/NIH HHS/United States ; 5UG1CA189955-11//Children's Oncology Group/ ; //NCI Community Oncology Research Program/ ; UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; UG1CA189974//SWOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; U10 CA180822/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; UG1CA189867//NRG Oncology/ ; }, mesh = {Humans ; *Neoplasms/therapy ; *Clinical Trials as Topic/methods/standards ; *Research Design ; United States ; Precision Medicine/methods ; }, abstract = {Examining treatment effects in subgroups of patients defined by demographic, genetic, or clinical characteristics is increasingly of interest given the pursuit of personalized medicine and the importance of representation and equity in treatment decisions. The magnitude or even the direction of the treatment effect may vary across subgroups, and these differential treatment effects could have clinical implications. Subgroup analyses require caution in their interpretation, however, because of the high probability of a false-positive or false-negative conclusion. We outline study design and analysis considerations for responsibly investigating and reporting differential treatment effects across subgroups in oncology trials, with examples from the National Cancer Institute's National Clinical Trials Network and Community Oncology Research Program. Recommendations include ensuring appropriate representation of patients from subgroups of interest, recognizing power and multiplicity limitations, and treating exploratory subgroup analyses as hypothesis generating rather than practice changing.}, }
@article {pmid39989038, year = {2025}, author = {Bandos, H and Torres-Saavedra, PA and Culakova, E and Gunn, HJ and Lee, MK and Duan, F and Cecchini, RS and Unger, JM and Dueck, AC and Steingrimsson, JA}, title = {Best practices and pragmatic approaches for patient-reported outcomes and quality of life measures in cancer clinical trials.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {14-21}, pmid = {39989038}, issn = {1745-6614}, support = {//Community Oncology Research Program/ ; UG1 CA189974/CA/NCI NIH HHS/United States ; UG1CA189974//SWOG/ ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; 5UG1CA189955-11//Children's Oncology Group/ ; UG1 CA189867/CA/NCI NIH HHS/United States ; //ECOG/ ; U10CA180822/BC/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; UG1CA189824//Wake Forest University/ ; UG1CA189867//NRG Oncology/ ; /NH/NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Quality of Life ; *Patient Reported Outcome Measures ; *Neoplasms/therapy/psychology ; *Clinical Trials as Topic/methods/standards ; Research Design ; Practice Guidelines as Topic ; }, abstract = {Patient-reported outcomes (PROs) are often collected in cancer clinical trials. Data obtained from trials with PROs are essential in evaluating participant experiences relating to symptoms, financial toxicity, or health-related quality of life. Although most features of clinical trial design, implementation, and analyses apply to trials with PROs, several considerations are unique. In this paper, we focus on specific issues such as selection of the tool, timing and frequency of assessments, and data collection methods. We discuss how the estimand framework can be used in connection with PROs, properties of common estimation methods, and handling of missing outcomes. With a plethora of literature available, we aim to summarize best practices and pragmatic approaches to the design and analysis of the studies incorporating PROs.}, }
@article {pmid39989035, year = {2025}, author = {Dressler, EV and Pugh, SL and Gunn, HJ and Unger, JM and Zahrieh, DM and Snavely, AC}, title = {Practical design considerations for cluster randomized controlled trials: lessons learned in community oncology research.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {68}, pages = {56-64}, pmid = {39989035}, issn = {1745-6614}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; //ECOG/ ; R01CA207158/CA/NCI NIH HHS/United States ; UG1CA189824/CA/NCI NIH HHS/United States ; UG1CA189961//University of Rochester/ ; UG1 CA189823/CA/NCI NIH HHS/United States ; U10CA180822//Wake Forest NCORP/ ; //SWOG NCORP RB/ ; 5UG1CA189955-11//Children's Oncology Group/ ; UG1 CA189867/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; R01HS025194//Agency for Healthcare Research and Quality/ ; U10CA180882//NRG Oncology/ ; U10 CA180882/CA/NCI NIH HHS/United States ; UG1CA189974//Alliance for Clinical Trials in Oncology/ ; UG1CA189824//Wake Forest University/ ; /NH/NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1CA189867//NCI Community Oncology Research Program/ ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1CA189828//ACRIN/ ; R01 CA207158/CA/NCI NIH HHS/United States ; R01 HS025194/HS/AHRQ HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/standards ; *Research Design ; *Medical Oncology/methods ; United States ; *Neoplasms/therapy ; Cluster Analysis ; National Cancer Institute (U.S.) ; }, abstract = {Cancer care delivery research trials conducted within the National Cancer Institute (NCI) Community Oncology Research Program (NCORP) routinely implement interventions at the practice or provider level, necessitating the use of cluster randomized controlled trials (cRCTs). The intervention delivery requires cluster-level randomization instead of participant-level, affecting sample size calculation and statistical analyses to incorporate correlation between participants within a practice. Practical challenges exist in the conduct of these cRCTs due to unique trial network infrastructures, including the possibility of unequal participant accrual totals and rates and staggered study initiation by clusters, potentially with differences between randomized arms. Execution of cRCT designs can be complex, ie, if some clusters do not accrue participants, unintended cluster-level crossover occurs, how best to identify appropriate cluster-level stratification, timing of randomization, and multilevel eligibility criteria considerations. This article shares lessons learned with potential mitigation strategies from 3 NCORP cRCTs.}, }
@article {pmid39988778, year = {2025}, author = {Stamatatos, L}, title = {The Germline Targeting Vaccine Concept: Overview and Updates from HIV Pre-Clinical and Clinical Trials.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570162X358302250206074255}, pmid = {39988778}, issn = {1873-4251}, abstract = {An effective HIV-1 vaccine should elicit diverse immune responses, including broadly neutralizing antibodies (bNAbs). Such antibodies recognize regions of the viral envelope glyco-protein (Env) that are conserved among the diverse HIV-1 clades and strains. They are isolated from people living with HIV-1 to protect animals from experimental viral exposure and reduce HIV-1 acquisition in clinical settings. However, despite efforts spanning several decades, bNAbs have not been elicited through immunization. The HIV Env efficiently binds bNAbs, but not their unmutated (germline, gl) precursors. In contrast, Env readily engages the germline precursors of antibodies with no, or very narrow, cross-neutralizing activities (non-neutralizing antibodies, nnAbs). That, in part, explains why Env-based immunogens consistently elicit nnAbs, but not bNAbs. In the past decade, Env-derived proteins have been specifically designed to engage the germline precursors of diverse bNAbs. These 'germline-targeting' Env immunogens activate the corresponding naive B cells in vivo, but are unable to guide their proper maturation towards their broadly neutralizing forms. For this, immunizations with currently not well-defined heterologous Envs are required. Here, we discuss the development of germline-targeting Env immunogens, their in vivo evaluation, and the strategies currently under evaluation that aim to rapidly guide the mat-uration of germline-precursor BCRs into their broadly neutralizing forms.}, }
@article {pmid39987960, year = {2025}, author = {Ross, WL and Santiago-Rivera, Y and Tan, MT and Roy, MM and Bryant, S and Appel, BE and Casillas, J and Demedis, J and Smitherman, AB and Horwitz, LI and Hurtado-de-Mendoza, A and Mendoza, JA and Santacroce, SJ and Kadan-Lottick, NS}, title = {Design and methods of a multi-level intervention to improve adherence to childhood cancer survivorship care by partnering with primary care providers: The BRIDGES randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {152}, number = {}, pages = {107859}, doi = {10.1016/j.cct.2025.107859}, pmid = {39987960}, issn = {1559-2030}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Young Adult ; *Cancer Survivors ; Equivalence Trials as Topic ; *Guideline Adherence ; *Neoplasms/therapy ; Patient Education as Topic/organization & administration/methods ; *Primary Health Care/organization & administration ; Prospective Studies ; *Survivorship ; Telemedicine/organization & administration ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: Despite heightened risk of chronic health conditions, <20 % of childhood cancer survivors (CCS) receive guideline-recommended surveillance for late effects. Barriers include avoidance of reminders, lack of knowledge, and costs. The goal of the BRIDGES Study is to evaluate the effects of a multi-level, remote intervention on adherence to guideline-recommended surveillance among CCS by partnering with primary care providers (PCPs).
METHODS: This ongoing study is a multi-site, two-arm, prospective, parallel design, 1:1 randomized controlled non-inferiority trial (N = 240; n = 120/group). Eligibility criteria are: cancer diagnosis at age < 21 years, 2.0-4.0 years post-cancer therapy, and no previous specialty survivorship clinic care. The intervention includes: 1) patient survivorship education via telehealth with a cancer center nurse, including discussion of patient's individualized survivorship care plan (SCP), 2) ongoing patient-tailored health education within the electronic health record's patient portal, 3) a structured interactive phone call between the cancer center nurse and PCP, including discussion of patient's SCP, and 4) an in-person PCP visit for survivorship care. Patients randomized to the comparison group are contacted to schedule an in-person visit at their cancer center-based survivorship clinic. Adherence to guideline-recommended surveillance tests (primary outcome) is assessed at 1-year post-randomization (primary follow-up time point) and 2-years post-randomization (for durability). Patient knowledge, self-efficacy, and activation; PCP knowledge and self-efficacy; and process outcomes are also assessed.
CONCLUSION: Models of survivorship care that overcome existing barriers are needed. If efficacious, this scalable, remote intervention would be a valuable strategy to address barriers and bridge gaps in care to reach more CCS.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05448560.}, }
@article {pmid39986828, year = {2025}, author = {Lange, PH and Schellhammer, PF}, title = {Tribute to Michael Droller MD.}, journal = {Urologic oncology}, volume = {43}, number = {2}, pages = {94}, doi = {10.1016/j.urolonc.2024.05.008}, pmid = {39986828}, issn = {1873-2496}, }
@article {pmid39985691, year = {2025}, author = {Viskochil, RH and Lin, T and Gigic, B and Himbert, C and Bandera, VM and Skender, S and Holowatyj, AN and Schrotz-King, P and Steindorf, K and Strehli, I and Mutch, MG and Chao, D and Toriola, AT and Shibata, D and Siegel, EM and Li, CI and Hardikar, S and Peoples, AR and Figueiredo, JC and Schneider, M and Ulrich, CM and Ose, J}, title = {Sedentary behavior and physical activity one year after colorectal cancer diagnosis: results from the ColoCare Study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {39985691}, issn = {1932-2267}, abstract = {PURPOSE: Physical activity plays key roles in colorectal cancer survivorship; however, the impact of different clinicodemographic outcomes on cross-sectional and longitudinal objectively measured physical activity 12 and 24 months post-diagnosis are unclear.
METHODS: ColoCare study participants (n = 165) wore an Actigraph GT3x accelerometer for 4-10 consecutive days to objectively assess activity levels 12 and 24 months after colorectal cancer diagnosis and resection. Associations between these clinical/demographic exposures and physical activity outcomes and longitudinal changes were determined using t-test, ANOVA F-test, and linear regression modeling, adjusting for common confounders (e.g., sex, age, stage).
RESULTS: Key physical activity and sedentary behavior variables significantly differed by demographic status, including minutes of weekly exercise by sex and age (age < 50: 364 min ± 303 min; age 50-70: 232 min ± 263 min; age > 70: 93 min ± 135 min, p < 0.001) and (%) daily sedentary time by age (age < 50: 64 ± 10%; age 50-70: 67 ± 7%; age > 70: 71 ± 7%, p = 0.003). Within the multivariate model, age was the primary measure consistently associated with activity differences. Participants who wore accelerometers 12- and 24-month post-resection (n = 52) significantly increased weekly exercise minutes (214 min ± 208 min vs. 288 min ± 316 min, p = 0.04).
CONCLUSION: Age is the primary clinicodemographic determinant separating physical activity levels in colorectal cancer survivors, and increases in exercise from 12 to 24 months are likely due to consolidation of sporadic daily physical activity into bouts of exercise.
Colorectal cancer survivors experience different volumes and changes in accelerometer-derived physical activity based on some (e.g., age) but not all (e.g., stage) clinicodemographic variables.}, }
@article {pmid39984572, year = {2025}, author = {Ahmed, SR and Befano, B and Egemen, D and Rodriguez, AC and Desai, KT and Jeronimo, J and Ajenifuja, KO and Clark, C and Perkins, R and Campos, NG and Inturrisi, F and Wentzensen, N and Han, P and Guillen, D and Norman, J and Goldstein, AT and Madeleine, MM and Donastorg, Y and Schiffman, M and de Sanjose, S and Kalpathy-Cramer, J and , }, title = {Generalizable deep neural networks for image quality classification of cervical images.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {6312}, pmid = {39984572}, issn = {2045-2322}, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/diagnostic imaging/diagnosis ; *Cervix Uteri/diagnostic imaging/pathology ; *Neural Networks, Computer ; *Deep Learning ; *Image Processing, Computer-Assisted/methods ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {Successful translation of artificial intelligence (AI) models into clinical practice, across clinical domains, is frequently hindered by the lack of image quality control. Diagnostic models are often trained on images with no denotation of image quality in the training data; this, in turn, can lead to misclassifications by these models when implemented in the clinical setting. In the case of cervical images, quality classification is a crucial task to ensure accurate detection of precancerous lesions or cancer; this is true for both gynecologic-oncologists' (manual) and diagnostic AI models' (automated) predictions. Factors that impact the quality of a cervical image include but are not limited to blur, poor focus, poor light, noise, obscured view of the cervix due to mucus and/or blood, improper position, and over- and/or under-exposure. Utilizing a multi-level image quality ground truth denoted by providers, we generated an image quality classifier following a multi-stage model selection process that investigated several key design choices on a multi-heterogenous "SEED" dataset of 40,534 images. We subsequently validated the best model on an external dataset ("EXT"), comprising 1,340 images captured using a different device and acquired in different geographies from "SEED". We assessed the relative impact of various axes of data heterogeneity, including device, geography, and ground-truth rater on model performance. Our best performing model achieved an area under the receiver operating characteristics curve (AUROC) of 0.92 (low quality, LQ vs. rest) and 0.93 (high quality, HQ vs. rest), and a minimal total %extreme misclassification (%EM) of 2.8% on the internal validation set. Our model also generalized well externally, achieving corresponding AUROCs of 0.83 and 0.82, and %EM of 3.9% when tested out-of-the-box on the external validation ("EXT") set. Additionally, our model was geography agnostic with no meaningful difference in performance across geographies, did not exhibit catastrophic forgetting upon retraining with new data, and mimicked the overall/average ground truth rater behavior well. Our work represents one of the first efforts at generating and externally validating an image quality classifier across multiple axes of data heterogeneity to aid in visual diagnosis of cervical precancer and cancer. We hope that this will motivate the accompaniment of adequate guardrails for AI-based pipelines to account for image quality and generalizability concerns.}, }
@article {pmid39983446, year = {2025}, author = {Ficarra, S and Kang, DW and Wilson, RL and Gonzalo-Encabo, P and Christopher, CN and Normann, AJ and Lopez, P and Lakićević, N and Dieli-Conwright, CM}, title = {Exercise medicine for individuals diagnosed with Lung Cancer: A systematic review and meta-analysis of health outcomes.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {201}, number = {}, pages = {108413}, doi = {10.1016/j.lungcan.2025.108413}, pmid = {39983446}, issn = {1872-8332}, mesh = {Humans ; Cardiorespiratory Fitness ; *Exercise Therapy/methods ; *Lung Neoplasms/therapy/diagnosis/rehabilitation ; Quality of Life ; }, abstract = {Consensus exists regarding the need to provide exercise interventions to individuals diagnosed with lung cancer (LC). Exercise interventions for this populations usually include multidisciplinary approaches, making the attempt to understand the effects of exercise a real challenge. Therefore, we designed a systematic review to identify the effects of exercise interventions among individuals with a LC diagnosis. Following the PRISMA guidelines, studies across 5 different databases were systematically screened. Eligible studies were randomised and non-randomised trials, including individuals with a LC diagnosis, administering exercise-only interventions. Three-level meta-analyses were performed for cardiorespiratory fitness, strength, physical function, anxiety, depression, and health-related quality of life. Differences between exercise types were also explored. The Cochrane Risk of Bias (RoB) II tool for randomised controlled trials and the RoB in non-randomised studies - of interventions were used to assess study quality. A total of 36,304 records were screened and 13 studies, including 547 LC survivors, were considered eligible. Randomised and non-randomised trials were mainly judged as "some concern" and at "serious" RoB, respectively. Meta-analyses reported significant improvements on physical function among exercise groups compared to control (ES = 0.62; 95 % CI: 0.10 to 1.15; p = 0.03), and no significant changes for all other variables. There is moderate evidence that exercise interventions appear to be an effective tool to improve physical function among individuals diagnosed with LC. Further studies are still needed to determine exercise prescription effectiveness on health outcomes, differences across exercise types and enhance individualized interventions.}, }
@article {pmid39982694, year = {2025}, author = {Alduhayh, S and Laskar, RS and Jiang, X and Zhu, Z and Vincent, EE and Constantinescu, AE and Buchanan, DD and Grant, RC and Phipps, AI and Brenner, H and Huang, WY and Kweon, SS and Li, L and Pearlman, R and Castellví-Bel, S and Gruber, SB and Li, CI and Pellatt, A and Platz, EA and Van Guelpen, B and Zheng, W and Chan, AT and Figueiredo, JC and Ogino, S and Ulrich, CM and Gunter, MJ and Haycock, P and Severi, G and Murphy, N and Dimou, N}, title = {Association of Genetic Liability to Allergic Diseases with Overall and Early-Onset Colorectal Cancer Risk: A Mendelian Randomization Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {5}, pages = {722-736}, pmid = {39982694}, issn = {1538-7755}, support = {R01 CA067941/CA/NCI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; U01 CA067941/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; C18281/A29019//Cancer Research UK (CRUK)/ ; U01 HG004438/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; RF20190208587//Fondation ARC pour la Recherche sur le Cancer (ARC)/ ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; 2020-076//Institut National Du Cancer (INCa)/ ; T32 ES013678/ES/NIEHS NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Mendelian Randomization Analysis ; *Hypersensitivity/genetics/epidemiology ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Risk Factors ; Female ; Male ; Age of Onset ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: The tumor immunosurveillance theory supports that allergic conditions could decrease cancer risk. However, observational evidence yielded inconsistent results for the association between allergic diseases and colorectal cancer risk. We used Mendelian randomization (MR) to examine potential causal associations of allergies with the risk of overall and early-onset colorectal cancer.
METHODS: Genome-wide association study summary statistical data were used to identify genetic variants associated with allergic diseases (Nvariants = 65) and individual allergic conditions (asthma, hay fever/allergic rhinitis, and eczema). Using two-sample MR, we examined these variants in relation to incident overall (Ncases = 52,775 cases) and early-onset colorectal cancer (Ncases = 6,176). The mediating role of white blood cells was examined using multivariable MR.
RESULTS: In inverse-variance-weighted models, genetic liability to allergic diseases was inversely associated with overall {OR per log (odds) = 0.90 [95% confidence interval (CI), 0.85-0.96]; P < 0.01} and early-onset colorectal cancer [OR = 0.83 (95% CI, 0.73-0.95); P = 0.01]. Similar inverse associations were found for hay fever/allergic rhinitis or eczema, whereas no evidence of association was found between liability to asthma-related phenotypes and colorectal cancer risk. Multivariable MR adjustment for eosinophils weakened the inverse associations for liability to allergic diseases for overall [OR = 0.96 (95% CI, 0.89-1.03); P = 0.26] and early-onset colorectal cancer [OR = 0.86 (95% CI, 0.73-1.01); P = 0.06].
CONCLUSIONS: Our study supports a potential causal association between liability to allergic diseases, specifically hay fever/allergic rhinitis or eczema, and colorectal cancer, possibly at least in part mediated via eosinophil counts.
IMPACT: Our results provide evidence that allergic responses may also have a role in immunosurveillance against colorectal cancer.}, }
@article {pmid39982410, year = {2025}, author = {Burfeind, KG and Funahashi, Y and Su, XT and Lackey, AE and Hagen, MW and Blanche, S and Emathinger, JM and Hebert, JF and McDonough, AA and Gurley, SB and Nelson, JW and Hutchens, MP}, title = {Kidney cell response to acute cardiorenal and isolated kidney ischemia-reperfusion injury.}, journal = {Physiological genomics}, volume = {57}, number = {4}, pages = {266-278}, pmid = {39982410}, issn = {1531-2267}, support = {20CDA35320169//American Heart Association (AHA)/ ; I01BX004288//U.S. Department of Veterans Affairs (VA)/ ; KL2 TR002370/TR/NCATS NIH HHS/United States ; TL1TR002371//HHS | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; K01 DK121737/DK/NIDDK NIH HHS/United States ; K01DK121737//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; I01 BX004288/BX/BLRD VA/United States ; 24CDA1269598//American Heart Association (AHA)/ ; R01 DK098382/DK/NIDDK NIH HHS/United States ; TL1 TR002371/TR/NCATS NIH HHS/United States ; KL2TR002370//HHS | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; W81XWH2010196/PR191304//U.S. Department of Defense (DOD)/ ; //Collins Medical Trust (CMT)/ ; }, mesh = {Animals ; *Cardio-Renal Syndrome/genetics/pathology/metabolism ; *Reperfusion Injury/genetics/pathology/metabolism ; Mice ; *Kidney/pathology/metabolism ; Male ; Transcriptome/genetics ; Humans ; Cardiopulmonary Resuscitation ; Mice, Inbred C57BL ; Heart Arrest/genetics ; Kidney Tubules, Proximal/metabolism/pathology ; Disease Models, Animal ; Gene Expression Profiling ; Acute Kidney Injury/genetics ; }, abstract = {Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We used single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in comparison to ischemia-reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of acute kidney injury (AKI) highly correlated with a dataset of human biopsies from patients diagnosed with AKI. This comprehensive single-nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.NEW & NOTEWORTHY Cardiac dysfunction is a common cause of acute kidney injury in a malady called acute cardiorenal syndrome. In a mouse model of acute cardiorenal syndrome called cardiac arrest/cardiopulmonary resuscitation, we characterized, for the first time, the kidney transcriptional landscape at the single-cell level. We developed a novel method for quantifying cell response to injury and found that cells adapted through dedifferentiation, the magnitude of which varied depending on cell type.}, }
@article {pmid39981705, year = {2025}, author = {Taylor, MR and Bradford, MC and Zhou, C and Fladeboe, KM and Wittig, JF and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Heart Rate Variability as a Digital Biomarker in Adolescents and Young Adults Receiving Hematopoietic Cell Transplantation.}, journal = {Cancer medicine}, volume = {14}, number = {4}, pages = {e70609}, pmid = {39981705}, issn = {2045-7634}, support = {//American Cancer Society/ ; }, mesh = {Humans ; Adolescent ; *Hematopoietic Stem Cell Transplantation/adverse effects/psychology ; Male ; Female ; Young Adult ; *Heart Rate/physiology ; Quality of Life ; Biomarkers ; Anxiety/physiopathology ; Child ; Patient Reported Outcome Measures ; Adult ; Prospective Studies ; Depression/physiopathology ; }, abstract = {INTRODUCTION: Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk for poor psychosocial outcomes. Heart rate variability (HRV), a surrogate for autonomic nervous system activity, is a promising digital biomarker that has been linked to important outcomes. The objectives of this study were to prospectively describe the trajectory of HRV among AYAs receiving HCT and explore the association between HRV and patient-reported outcomes (PROs).
METHODS: This was a multi-site study embedded in a randomized trial among AYAs receiving HCT (NCT03640325). We collected sequential 24-h HRV metrics, including the standard deviation of normal-to-normal beats (SDNN), root-mean-square of successive differences (RMSSD), as well as frequency domain measures. PRO surveys queried anxiety, depression, quality of life, hope, and resilience at baseline and 3 months. We summarized outcomes using descriptive statistics, and Pearson correlation coefficients were used to examine the relationship between HRV and PROs.
RESULTS: Thirty-nine HRV recordings were collected from n = 16 participants aged 12-21 years. There was a moderately strong correlation between inferior baseline HRV and higher anxiety and depression (anxiety: r = -0.35 (p = 0.18) for SDNN, r = -0.47 (p = 0.07) for RMSSD; depression: r = -0.26 (p = 0.34) for SDNN, r = -0.39 (p = 0.14) for RMSSD). Among participants with elevated baseline anxiety, higher HRV suggested greater improvement in anxiety over time (r = -0.66 (p = 0.08) for SDNN, r = -0.31 (p = 0.45) for RMSSD).
CONCLUSIONS: There was a correlation between HRV and PROs in this study, and among those with elevated anxiety, HRV predicted improvement over time. Digital biomarkers may augment behavioral intervention design and implementation.}, }
@article {pmid39980037, year = {2025}, author = {Nikolaienko, O and Anderson, GL and Chlebowski, RT and Jung, SY and Harris, HR and Knappskog, S and Lønning, PE}, title = {MGMT epimutations and risk of incident cancer of the colon, glioblastoma multiforme, and diffuse large B cell lymphomas.}, journal = {Clinical epigenetics}, volume = {17}, number = {1}, pages = {28}, pmid = {39980037}, issn = {1868-7083}, mesh = {Humans ; Female ; *DNA Repair Enzymes/genetics ; *Lymphoma, Large B-Cell, Diffuse/genetics/epidemiology ; *Tumor Suppressor Proteins/genetics ; *DNA Modification Methylases/genetics ; Middle Aged ; DNA Methylation ; Aged ; Case-Control Studies ; *Glioblastoma/genetics/epidemiology ; *Colonic Neoplasms/genetics/epidemiology ; Promoter Regions, Genetic ; Incidence ; Mutation ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: Constitutional BRCA1 epimutations (promoter hypermethylation) are associated with an elevated risk of triple-negative breast cancer and high-grade serous ovarian cancer. While MGMT epimutations are frequent in colon cancer, glioblastoma, and B-cell lymphoma, it remains unknown whether constitutional MGMT epimutations are associated with risk of any of these malignancies.
METHODS: We designed a nested case-control study, assessing potential associations between MGMT epimutations in blood from healthy individuals and subsequent risk of incident cancer. The study cohort was drawn from postmenopausal women, participating in the Women's Health Initiative (WHI) study, who had not been diagnosed with either colon cancer, glioblastoma, or B-cell lymphoma prior to study entry. The protocol included n = 400 women developing incident left-sided and n = 400 women developing right-sided colon cancer, n = 400 women developing diffuse large B-cell lymphomas, all matched on a 1:2 basis with cancer-free controls, and n = 195 women developing incident glioblastoma multiforme, matched on a 1:4 basis. All cancers were confirmed in centralized medical record review. Blood samples, collected at entry, were analyzed for MGMT epimutations by massive parallel sequencing. Associations between MGMT methylation and incident cancers were analyzed by Cox proportional hazards regression.
RESULTS: Analyzing epimutations affecting the key regulatory area of the MGMT promoter, the hazard ratio (HR) was 1.07 (95% CI 0.79-1.45) and 0.80 (0.59-1.08) for right- and left-sided colon cancer, respectively, 1.13 (0.78-1.64) for glioblastoma, and 1.11 (0.83-1.48) for diffuse large B-cell lymphomas. Sensitivity analyses limited to subregions of the MGMT promoter and to individuals with different genotypes of a functional SNP in the MGMT promoter (rs16906252), revealed no significant effect on HR for any of the cancer forms. Neither did we observe any effect of rs16906252 status on HR for any of the cancer forms among individuals methylated or non-methylated at the MGMT promoter.
CONCLUSIONS: Constitutional MGMT promoter methylation in normal tissue is not associated with an increased risk of developing colon cancer, glioblastoma, or B-cell lymphoma.}, }
@article {pmid39979638, year = {2025}, author = {Toghani, D and Gupte, S and Zeng, S and Mahammadov, E and Crosse, EI and Seyedhassantehrani, N and Burns, C and Gravano, D and Radtke, S and Kiem, HP and Rodriguez, S and Carlesso, N and Pradeep, A and Georgiades, A and Lucas, F and Wilson, NK and Kinston, SJ and Göttgens, B and Zong, L and Beerman, I and Park, B and Janssens, DH and Jones, D and Toghani, A and Nerlov, C and Pietras, EM and Mesnieres, M and Maes, C and Kumanogoh, A and Worzfeld, T and Cheong, JG and Josefowicz, SZ and Kharchenko, P and Scadden, DT and Scialdone, A and Spencer, JA and Silberstein, L}, title = {Author Correction: Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.}, journal = {Nature aging}, volume = {5}, number = {4}, pages = {720}, doi = {10.1038/s43587-025-00837-x}, pmid = {39979638}, issn = {2662-8465}, }
@article {pmid39979464, year = {2025}, author = {Briney, CA and Henriksen, JC and Lin, C and Jones, LA and Benner, L and Rains, AB and Gutierrez, R and Gafken, PR and Rissland, OS}, title = {Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase.}, journal = {EMBO reports}, volume = {26}, number = {6}, pages = {1647-1669}, pmid = {39979464}, issn = {1469-3178}, support = {5T32GM141742//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM128680/GM/NIGMS NIH HHS/United States ; CAREER 2056136//National Science Foundation (NSF)/ ; P40 OD010949/OD/NIH HHS/United States ; T32 GM141742/GM/NIGMS NIH HHS/United States ; 5T32GM136444//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32 GM136444/GM/NIGMS NIH HHS/United States ; S10 OD030225/CD/ODCDC CDC HHS/United States ; R35GM128680//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 2P40OD010949//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; S10 OD030225/OD/NIH HHS/United States ; }, mesh = {Animals ; *Drosophila Proteins/metabolism/genetics ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Gene Expression Regulation, Developmental ; *RNA-Binding Proteins/metabolism/genetics ; *Drosophila melanogaster/embryology/genetics/metabolism ; Embryo, Nonmammalian/metabolism ; Protein Binding ; Substrate Specificity ; Female ; DEAD-box RNA Helicases ; }, abstract = {The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies because Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting the degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental regulation of the CTLH complex is multi-pronged, including transcriptional control by OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate is a substrate adaptor for the Drosophila CTLH complex. Finally, we find that Muskelin has few targets beyond the three known RNA-binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, during which time it regulates three important RNA-binding proteins.}, }
@article {pmid39977705, year = {2025}, author = {Boiko, JR and Ensbey, KS and Waltner, OG and Jenkins, IC and Bhise, SS and MacDonald, KPA and Blazar, BR and Hall, AM and Gooley, TA and Minnie, SA and Lee, SJ and Furlan, SN and Hill, GR}, title = {Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease.}, journal = {Blood}, volume = {145}, number = {19}, pages = {2214-2228}, doi = {10.1182/blood.2024025337}, pmid = {39977705}, issn = {1528-0020}, mesh = {*Graft vs Host Disease/genetics/pathology/etiology/immunology ; *Interleukin-17/genetics ; Animals ; Mice ; *Macrophage Colony-Stimulating Factor/genetics ; Humans ; Chronic Disease ; Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; *Transcriptome ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; }, abstract = {Chronic graft-versus-host disease (cGVHD) remains the leading cause of nonrelapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutic agents targeting dysregulated cytokines including interleukin-17 (IL-17) and colony-stimulating factor 1 (CSF-1) have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent US Food and Drug Administration approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the United States, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single-cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, nonintuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocyte populations within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 after HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and nonresponders to relevant therapeutics targeting these pathways.}, }
@article {pmid39976968, year = {2025}, author = {Umoren, RA and Ezeaka, C and Berkelhamer, SK and Hippe, DS and Asangansi, IE and Cook, MW and Fajolu, IB and Olawuyi, O and Adeboboye, C and Ekhalufoh, OO and Fashola, OS and Feltner, J and Fisher, JD and James, JM and Imoukhuede, OM and Park, N and Quach, V and Stiffler, AK and Engmann, CM}, title = {Essential Newborn Care Virtual Simulations for Skills Retention in Newborn Care.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2460565}, pmid = {39976968}, issn = {2574-3805}, support = {R21 HD107984/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Infant, Newborn ; Female ; *Clinical Competence ; Male ; *Simulation Training/methods ; Nigeria ; Adult ; *Infant Care/methods ; Cohort Studies ; *Health Personnel/education ; Midwifery/education ; }, abstract = {IMPORTANCE: Newborn mortality accounts for approximately 47% of all mortality of children under the age of 5 years. Virtual simulation may be a viable approach to support retention of essential newborn care knowledge and skills among health care professionals in low- and middle-income countries.
OBJECTIVE: To evaluate the association between mobile virtual simulation using Virtual Essential Newborn Care (vENC) and knowledge and skills retention in early newborn care in low-resource settings and to propose a frequency of virtual simulation use for among health care professionals who care for newborns in low-resource settings.
This cohort study was conducted at 23 primary, secondary, and tertiary health care facilities in Lagos, Nigeria, for 6 months between December 1, 2022, and June 30, 2023. Participants included nurses and midwives who participated in deliveries and provided newborn care. Potential participants who attended a Helping Babies Breathe or Essential Newborn Care (ENC) course within the past 1 year were excluded.
EXPOSURES: All participants received in-person training using the World Health Organization ENC 1 and ENC 2 curricula along with virtual simulation practice at variable recommended frequencies for 6 months after course completion.
MAIN OUTCOMES AND MEASURES: Primary outcomes included assessments of bag-valve-mask (BVM) ventilation skills, and performance on ENC 1 and ENC 2 case A and B scenarios conducted by trained research assistants before, immediately after, and 6 months after the in-person course. All scores ranged from 0% to 100%, with higher scores indicating better performance.
RESULTS: Of 70 enrolled participants (67 of 69 [97%] female), 62 (89%) completed the 6-month follow-up. Immediate posttraining performance (median [IQR] scores: BVM ventilation skills, 93% [86%-100%]; ENC 1 case scenario A, 72% [61%-78%]; ENC 1 case scenario B, 76% [68%-88%]; ENC 2 case scenario A, 80% [73%-87%]; and ENC 2 case scenario B, 88% [70%-95%]) improved compared with pretraining performance for all skill assessments (median [IQR] scores: BVM ventilation skills, 57% [29%-64%]; ENC 1 case scenario A, 39% [28%-50%]); ENC 2 case scenario A, 33% [20%-45%]) (all P < .001). There were further gains in performance at the 6-month follow-up assessment for BVM ventilation (median [IQR], 100% [86%-100%]; P = .04) and the ENC1 and ENC2 assessments by case scenario (case scenario A: ENC 1 median [IQR] score, 78% [72%-83%]; P = .001 and ENC 2 median [IQR] score, 87% [80%-93%]; P = .008; and case scenario B: ENC 1 median [IQR] score, 88% [76%-92%]; P = .009 and ENC 2 median [IQR] score, 93% [80%-100%]; P = .004) relative to the immediate postcourse assessment scores.
CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that the app-based simulations may be effective in supporting the retention of knowledge and skills following ENC training and may contribute to further performance gains for health care professionals in low- and middle-income countries. More clinical and implementation research is needed to explore the impact of virtual simulations on health professionals' clinical practices and neonatal outcomes.}, }
@article {pmid39976936, year = {2025}, author = {DeVine, A and Landier, W and Hudson, MM and Constine, LS and Bhatia, S and Armenian, SH and Gramatges, MM and Chow, EJ and Friedman, DN and Ehrhardt, MJ}, title = {The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers: A Review.}, journal = {JAMA oncology}, volume = {11}, number = {5}, pages = {544-553}, pmid = {39976936}, issn = {2374-2445}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors ; Adolescent ; Child ; Young Adult ; *Neoplasms/therapy ; *Practice Guidelines as Topic ; Follow-Up Studies ; }, abstract = {IMPORTANCE: Since 2003, the Children's Oncology Group (COG) has developed and disseminated the Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. These guidelines have benchmarked the standard of care for long-term survivors of childhood cancer in North America and beyond. Since their inception, they have evolved in depth, scope, and contributors to maintain fidelity toward continually emerging evidence related to cancer survivorship. They are intended to inform care for individuals who survived 2 or more years from completion of childhood, adolescent, and young adult cancer-directed therapy and receiving care in either specialty or primary care environments. The guidelines are updated on a 5-year cycle, during which comprehensive literature searches pertaining to guideline-specific questions are performed, evidence abstracted from pertinent publications, and recommendations determined and scored following expert deliberation.
OBSERVATIONS: Version 6.0 of the guidelines, released in October 2023, comprised 165 sections and 45 health links and represents the cooperative efforts of 220 individuals. Major changes include the addition of recommendations regarding surveillance for genetic cancer predisposition, surveillance following the use of novel cancer treatment modalities, and routine vaccination practices during long-term follow-up. In addition, surveillance echocardiograms were omitted for those at low risk of cardiomyopathy.
CONCLUSIONS AND RELEVANCE: This narrative review outlines the historical evolution of the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, current methods guiding their development, and key recommendations from version 6.0. The guidelines are publicly available in their entirety online. The COG guidelines continue to set the standard for surveillance practices for long-term survivors of childhood, adolescent, and young adult cancer. The growing body of evidence supporting these recommendations will continue to guide their evolution to inform optimal survivorship care practices.}, }
@article {pmid39976415, year = {2025}, author = {Dumm, W and Ralph, D and DeWitt, W and Vora, A and Araki, T and Victora, GD and Matsen Iv, FA}, title = {Leveraging DAGs to improve context-sensitive and abundance-aware tree estimation.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {380}, number = {1919}, pages = {20230315}, pmid = {39976415}, issn = {1471-2970}, support = {/NH/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; //James S. McDonnell Foundation/ ; /RI/ORIP NIH HHS/United States ; }, mesh = {*Phylogeny ; *Models, Genetic ; Receptors, Antigen, B-Cell/genetics ; }, abstract = {The phylogenetic inference package GCtree uses abundance of sampled sequences to improve the performance of parsimony-based inference, using a branching process model. Our previous work showed that GCtree performs competitively on B-cell receptor data, compared with other similar tools. In this article, we describe recent enhancements to GCtree, including an efficient tree storage data structure that discovers additional diversity of parsimonious trees with negligible additional computational cost. We also describe a suite of new objective functions that can be used to rank these trees, including a Poisson context likelihood function that models sequence evolution in a context-sensitive way. We validate these additions to GCtree with simulated B-cell receptor data, and benchmark performance against other phylogenetic inference tools.This article is part of the theme issue '"A mathematical theory of evolution": phylogenetic models dating back 100 years'.}, }
@article {pmid39975454, year = {2025}, author = {Xie, T and Richman, H and Gao, J and Matsen, FA and Zhang, C}, title = {PhyloVAE: Unsupervised Learning of Phylogenetic Trees via Variational Autoencoders.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39975454}, issn = {2331-8422}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Learning informative representations of phylogenetic tree structures is essential for analyzing evolutionary relationships. Classical distance-based methods have been widely used to project phylogenetic trees into Euclidean space, but they are often sensitive to the choice of distance metric and may lack sufficient resolution. In this paper, we introduce phylogenetic variational autoencoders (PhyloVAEs), an unsupervissed learning framework designed for representation learning and generative modeling of tree topologies. Leveraging an efficient encoding mechanism inspired by autoregressive tree topology generation, we develop a deep latent-variable generative model that facilitates fast, parallelized topology generation. PhyloVAE combines this generative model with a collaborative inference model based on learnable topological features, allowing for high-resolution representations of phylogenetic tree samples. Extensive experiments demonstrate PhyloVAE's robust representation learning capabilities and fast generation of phylogenetic tree topologies.}, }
@article {pmid39975340, year = {2025}, author = {Jochim, BE and Topalidou, I and Lehrbach, NJ}, title = {Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975340}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, abstract = {The Nrf/NFE2L family of transcription factors regulates redox balance, xenobiotic detoxification, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is primarily responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. Nrf2/NFE2L2 is mainly involved in activating oxidative stress responses and promoting xenobiotic detoxification. Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively, and share an identical DNA binding domain. Thus, the extent to which SKN-1A/Nrf1 and SKN-1C/Nrf2 functions are distinct or overlapping has been unclear. Regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term 'sequence editing'. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We confirm that activation of proteasome subunit genes is strictly dependent on sequence editing. In addition, we find that sequence edited SKN-1A can also activate genes linked to redox homeostasis and xenobiotic detoxification that are also regulated by SKN-1C, but the extent of these genes' activation is antagonized by sequence editing. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that both isoforms promote optimal oxidative stress resistance, acting as effectors for distinct signaling pathways. These findings suggest that sequence editing governs SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.}, }
@article {pmid39975229, year = {2025}, author = {Shi, Z and Tsuge, M and Collier, N and Takeuchi, Y and Uchida, T and Rutter, CM and Teraoka, Y and Uprichard, S and Ishida, Y and Tateno, C and Ozik, J and Dahari, H and Chayama, K}, title = {Modeling of hepatitis B virus infection spread in primary human hepatocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975229}, issn = {2692-8205}, support = {R01 AI144112/AI/NIAID NIH HHS/United States ; R01 AI146917/AI/NIAID NIH HHS/United States ; }, abstract = {Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHH) over 32 days post-inoculation (pi) and used agent-based modeling (ABM) to gain insights into HBV lifecycle and spread. Parallel PHH cultures were mock-treated or HBV entry inhibitor Myr-preS1 (6.25 μg/mL) was initiated 24h pi. In untreated PHH, 3 viral DNA kinetic patterns were identified: (1) an initial decline, followed by (2) rapid amplification, and (3) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 hours. After the eclipse phase, the viral production rate increases over time, starting with a slow production cycle of 1 virion per day, which gradually accelerates to 1 virion per hour after 3 days. Approximately 4 days later, virion production reaches a steady state production rate of 4 virions/hour. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar of those predicted in uPA/SCID mice with human livers.}, }
@article {pmid39975131, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, A and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975131}, issn = {2692-8205}, support = {DP5 OD029630/OD/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid39975072, year = {2025}, author = {Radford, CE and Bloom, JD}, title = {Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975072}, issn = {2692-8205}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, abstract = {Antibodies capable of neutralizing many strains of HIV are being explored as prophylactic and therapeutic agents, but viral escape mutations pose a major challenge. Efforts have been made to experimentally define the escape mutations from specific antibodies in specific viral strains, but it remains unclear how much the effects of mutations on neutralization differ among HIV strains. Here, we use pseudovirus deep mutational scanning to comprehensively map escape mutations from the V3 loop targeting antibody 10-1074 and the CD4-binding site targeting antibody 3BNC117 for both a clade A (BF520) and a clade B (TRO.11) HIV Envelope (Env). Mutations that escape neutralization by antibody 10-1074 are largely similar for the two Envs, but mutations that escape 3BNC117 differ greatly between Envs. Some differences in the effects of mutations on escape between Envs can be explained by strain-to-strain variation in mutational tolerance or glycosylation patterns, but other mutations have different effects on escape for unclear reasons. Overall, the extent that measurements of mutational effects on antibody neutralization can be generalized across HIV strains differs among antibodies.}, }
@article {pmid39974149, year = {2025}, author = {Bhardwaj, S and Galanter, N and Berenbrok, LA and Shah, PD and Bacci, JL}, title = {Pediatric vaccination in pharmacies is not associated with delayed well-child visits among commercially insured children.}, journal = {Health affairs scholar}, volume = {3}, number = {2}, pages = {qxaf028}, pmid = {39974149}, issn = {2976-5390}, abstract = {Pediatric vaccination rates in the United States lag national goals. Policies that expand pharmacy-based vaccinations among children could help improve vaccination rates. Opponents argue, however, that such policies will result in delayed or missed well-child visits as most children receive routine vaccinations in primary care settings. We evaluated the likelihood of having a timely well-child visit following a routine vaccination in pharmacies and primary care settings among children aged 4-17 years. We conducted a retrospective cohort analysis with commercial claims data from 2016-2019, using conditional logistic regression models. A timely well-child visit was defined as one within 12 months after a preceding well-child visit for primary analysis and 15 months for secondary analysis. Approximately 95% of the sample consisted of children with influenza among their index vaccine(s). The odds of having a timely well-child visit were similar between children who received vaccines in pharmacies and those who received them in primary care settings. Findings suggest that guardians or parents who choose pharmacy-based pediatric vaccinations for their commercially insured children do not forgo well-child visits and may actually be more likely to obtain a timely well-child visit. Extending pharmacy-based vaccinations to patients of all ages can help improve pediatric vaccination rates.}, }
@article {pmid39974143, year = {2025}, author = {Park, MS and Kumar, RD and Ovadiuc, C and Folta, A and McEwen, AE and Snyder, A and Fowler, DM and Rubin, AF and Shirts, BH and Starita, LM and Stergachis, AB}, title = {Insights on improving accessibility and usability of functional data to unlock its potential for variant interpretation.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39974143}, support = {R01 HG013025/HG/NHGRI NIH HHS/United States ; UM1 HG011969/HG/NHGRI NIH HHS/United States ; }, abstract = {INTRODUCTION: Variant-level functional data is a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUS). However, the usage of functional data by genetics professionals is currently unknown.
METHODS: An online survey was developed and distributed in spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses.
RESULTS: 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting and overall respondents felt confident in assessing functional data. However, 67% indicated that functional data for variants of interest was rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to its use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions.
DISCUSSION: The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.}, }
@article {pmid39973981, year = {2025}, author = {Gustav, M and van Treeck, M and Reitsam, NG and Carrero, ZI and Loeffler, CML and Meneghetti, AR and Märkl, B and Boardman, LA and French, AJ and Goode, EL and Gsur, A and Brezina, S and Gunter, MJ and Murphy, N and Hönscheid, P and Sperling, C and Foersch, S and Steinfelder, R and Harrison, T and Peters, U and Phipps, A and Kather, JN}, title = {Assessing Genotype-Phenotype Correlations with Deep Learning in Colorectal Cancer: A Multi-Centric Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39973981}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA107333/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN261201000032C/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Deep Learning (DL) has emerged as a powerful tool to predict genetic biomarkers directly from digitized Hematoxylin and Eosin (H&E) slides in colorectal cancer (CRC). However, few studies have systematically investigated the predictability of biomarkers beyond routinely available alterations such as microsatellite instability (MSI), and BRAF and KRAS mutations.
METHODS: Our primary dataset comprised H&E slides of CRC tumors across five cohorts totaling 1,376 patients who underwent comprehensive panel sequencing, with an additional 536 patients from two public datasets for validation. We developed a DL model using a single transformer model to predict multiple genetic alterations directly from the slides. The model's performance was compared against conventional single-target models, and potential confounders were analyzed.
FINDINGS: The multi-target model was able to predict numerous biomarkers from pathology slides, matching and partly exceeding single-target transformers. The Area Under the Receiver Operating Characteristic curve (AUROC, mean ± std) on the primary external validation cohorts was: BRAF (0·78 ± 0·01), hypermutation (0·88 ± 0·01), MSI (0·93 ± 0·01), RNF43 (0·86 ± 0·01); this biomarker predictability was mirrored across metrics and co-occurrence analyses. However, biomarkers with high AUROCs largely correlated with MSI, with model predictions depending considerably on MSI-associated morphology upon pathological examination.
INTERPRETATION: Our study demonstrates that multi-target transformers can predict the biomarker status for numerous genetic alterations in CRC directly from H&E slides. However, their predictability is mainly associated with MSI phenotype, despite indications of slight biomarker-inherent contributions to a phenotype. Our findings underscore the need to analyze confounders in AI-based oncology biomarkers. To enable this, we developed a validated model applicable to other cancers and larger, diverse datasets.
FUNDING: The German Federal Ministry of Health, the Max-Eder-Programme of German Cancer Aid, the German Federal Ministry of Education and Research, the German Academic Exchange Service, and the EU.}, }
@article {pmid39973220, year = {2025}, author = {Meanley, S and Rodriguez Garcia, L and Lisha, NE and Ahmed, A and Korolkova, A and Figueroa, T and Nguyen, E and J Peluso, M and Cohn, LB and Deeks, S and Dubé, K and Sauceda, J}, title = {Exploring Stigma and Self-Image: Mixed-Methods Insights from HIV Cure-Related Research Participants Undergoing Analytical Treatment Interruptions.}, journal = {AIDS patient care and STDs}, volume = {39}, number = {4}, pages = {151-159}, pmid = {39973220}, issn = {1557-7449}, support = {R01 MH126768/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Anti-HIV Agents/therapeutic use/administration & dosage ; *HIV Infections/psychology/drug therapy ; Interviews as Topic ; Qualitative Research ; San Francisco ; *Self Concept ; *Social Stigma ; }, abstract = {This mixed-methods study explored self-image among people with HIV participating in an HIV cure-related study involving analytical treatment interruptions (ATIs). Using both quantitative and qualitative approaches, we described how self-image emerged across study participation, focusing on internalized stigma, emotional strengths, and the psychosocial dimensions of study participation. Data come from the SCOPE-ATI substudy (NCT00187512) of the University of California San Francisco SCOPE cohort (NCT04359186). Quantitative data were collected at three timepoints: pre-ATI (n = 15), post-ATI (n = 12), and end of the study (n = 14). We observed a general decline in self-image scores over time. However, participants maintained a moderately high agreement with statements about contributing to reducing HIV stigma through their involvement in the study. Qualitative interviews were collected pre-ATI (n = 11), during ATI (n = 8), and post-ATI (n = 6). Qualitative findings revealed two major themes shaping self-image: (1) experiencing and reconciling internalized HIV stigma and (2) self-evaluations in relation to life purpose. Many participants expressed disappointment at having to resume antiretroviral therapy, viewing it as a reminder of their HIV status and its associated stigma. Nevertheless, some found purpose and pride in their participation, motivated by altruistic contributions to improving future HIV control options. The findings highlight the emotional complexities of participating in HIV cure research and underscore the need for psychosocial support throughout ATI studies. While most participants experienced a decline in self-image, some derived meaning and empowerment from their involvement. This study suggests that addressing emotional well-being and reinforcing participants' contributions to science can enhance their experience in future research.}, }
@article {pmid39970314, year = {2025}, author = {Theodore, DA and Neradilek, M and Gillespie, K and Edupuganti, S and Hinojosa, JC and Lama, JR and De La Grecca, R and Wu, YH and Davis, A and Mangini, D and Andrew, P and Marovich, MA and Zwerski, S and Broder, G and Andrasik, MP and Castor, D and Roxby, AC and Cohen, M and Huang, Y and Karuna, ST and Sobieszczyk, ME}, title = {Brief Report: Associations Between Gender and Solicited Adverse Events After Passive Infusion of VRC01 or Placebo in HVTN 704/HPTN 085.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {98}, number = {4}, pages = {340-345}, doi = {10.1097/QAI.0000000000003582}, pmid = {39970314}, issn = {1944-7884}, support = {//HIV Vaccine Trials Network/ ; }, mesh = {Humans ; Male ; Female ; *HIV Infections/prevention & control ; Adult ; Transgender Persons ; Young Adult ; Middle Aged ; Sex Factors ; Sexual and Gender Minorities ; }, abstract = {BACKGROUND: Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Gender minority (GM) individuals are understudied in clinical trials.
SETTING: HVTN 704/HIV Prevention Trials Network 085, a phase 2b randomized HIV prevention trial, enrolled MSM and transgender participants from Brazil, Peru, Switzerland, and the United States to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg, or placebo. Solicited adverse events (AEs) were recorded for 3 days after each infusion.
METHODS: Gender was defined by self-report and sex assigned-at-birth. Multivariate mixed logistic models were used to estimate the association between gender (cisgender men [CM] vs. GM participants [transgender women, transgender men, or another gender]) and solicited AE frequency and severity.
RESULTS: GM participants reported more solicited AEs than CM among all participants (adjusted OR 1.59, 95% CI: 1.20 to 2.10, P = 0.001) and among placebo recipients (1.72, 1.05 to 2.81, P = 0.031). The severity of solicited AEs (occurrence of grade 2 and higher event) did not significantly differ overall (1.83, 0.79 to 4.20, P = 0.174) or among placebo recipients (3.05, 0.76 to 12.32, P = 0.112). Grade 2 events were reported after 1% and 2% of total infusions among CM and GM participants, respectively. Grade 3-4 events were rare overall (<0.1%). Completion of 10 infusions was high (78.6%) and slightly higher in CM (79.2%) than GM participants (73%).
CONCLUSIONS: This is the first report of associations between gender and solicited AEs after monoclonal antibody infusion. GM participants reported more events; severity was low. HIV prevention trials must engage and support GM individuals to best evaluate tolerability of novel agents.}, }
@article {pmid39969870, year = {2025}, author = {Chen, J and Raymundo, C and Martinez, A and Lee, SJ and Stevenson, PA and Shinohara, MM}, title = {Histopathologic Grading of Acute Cutaneous Graft-vs-Host Disease and Nonrelapse Mortality.}, journal = {JAMA dermatology}, volume = {161}, number = {4}, pages = {438-440}, pmid = {39969870}, issn = {2168-6084}, }
@article {pmid39969427, year = {2025}, author = {Levy, C and Naik, H and Overbey, J and Hedstrom, K and Wang, K and McDonough, C and Freeman, M and Keel, SB and Erwin, AL and Dickey, AK and Leaf, RK and Quigley, J and Mazepa, M and Wang, B and Phillips, J and Parker, C and McGuire, B and Kazamel, M and Bonkovsky, H and Rudnick, S and Anderson, KE and Moghe, A and Thapar, M and Saberi, B and Wheeden, K and Desnick, R and Balwani, M and , }, title = {Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria.}, journal = {Hepatology communications}, volume = {9}, number = {3}, pages = {}, pmid = {39969427}, issn = {2471-254X}, mesh = {Humans ; *Protoporphyria, Erythropoietic/complications/pathology ; Female ; Male ; Adult ; *Liver/pathology ; Middle Aged ; Young Adult ; Adolescent ; Longitudinal Studies ; Protoporphyrins ; *Genetic Diseases, X-Linked/complications ; Child ; }, abstract = {BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed.
METHODS: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described.
RESULTS: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at enrollment was 33.3 years. Liver chemistries were available for 235 patients, and 132 (56.2%) had abnormalities, mostly mild. Abnormal liver enzymes were associated with higher erythrocyte protoporphyrin levels. Eleven patients had advanced protoporphyric hepatopathy. In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died. At least 4 deaths were caused by liver failure due to protoporphyric hepatopathy, 2 were complications of bone marrow transplant, and 1 from HCC, which developed in a patient with EPP without cirrhosis. Patients with XLP were more likely to develop liver-related complications compared to EPP.
CONCLUSIONS: Liver abnormalities are common in patients with EPP and XLP. In this national registry, only 3.4% had protoporphyric hepatopathy, with most requiring a transplant. Of the deaths, 62.5% were attributable to liver disease. Further observations are needed for guiding hepatic evaluation and management of patients with protoporphyria with or without initial hepatic abnormalities.}, }
@article {pmid39969207, year = {2025}, author = {Mehta, RS and Lee, SJ and Gooley, T and Thur, L and Dahlberg, A and Delaney, C and Gyurkocza, B and Vo, P and Deeg, HJ and Milano, F}, title = {Long-term outcomes and quality of life with treosulfan-based conditioning in hematological malignancies.}, journal = {Blood advances}, volume = {9}, number = {11}, pages = {2691-2694}, pmid = {39969207}, issn = {2473-9537}, }
@article {pmid39966732, year = {2025}, author = {Chawana, TD and Walsh, SR and Stranix-Chibanda, L and Chirenje, ZM and Yu, C and Zhang, L and Seaton, KE and Heptinstall, J and Zhang, L and Paez, CA and Gamble, T and Karuna, ST and Andrew, P and Hanscom, B and Sobieszczyk, ME and Edupuganti, S and Gay, CL and Mannheimer, SB and Hurt, CB and Stephenson, KE and Polakowski, LL and Spiegel, H and Yacovone, M and Regenold, S and Yen, C and Baumblatt, JA and Gama, L and Barouch, DH and Piwowar-Manning, E and Koup, RA and Tomaras, GD and Hyrien, O and Roxby, AC and Huang, Y and , }, title = {Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV.}, journal = {BMC immunology}, volume = {26}, number = {1}, pages = {8}, pmid = {39966732}, issn = {1471-2172}, support = {P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Adult ; *HIV Antibodies/immunology/therapeutic use ; Male ; Female ; *HIV Infections/immunology/prevention & control ; Middle Aged ; *Antibodies, Monoclonal/pharmacokinetics/therapeutic use ; *Broadly Neutralizing Antibodies ; *HIV-1/immunology ; *Antibodies, Neutralizing/therapeutic use ; Young Adult ; }, abstract = {VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone ('single'; n = 100) or in combination with 1 or 2 other mAbs ('combined'; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.}, }
@article {pmid39966627, year = {2025}, author = {Bock, TJ and Colonne, CK and Fiorenza, S and Turtle, CJ}, title = {Outcome correlates of approved CD19-targeted CAR T cells for large B cell lymphoma.}, journal = {Nature reviews. Clinical oncology}, volume = {22}, number = {4}, pages = {241-261}, pmid = {39966627}, issn = {1759-4782}, mesh = {Humans ; *Immunotherapy, Adoptive/methods/adverse effects ; *Antigens, CD19/immunology ; *Lymphoma, Large B-Cell, Diffuse/therapy/immunology/mortality ; *Receptors, Chimeric Antigen/immunology/therapeutic use ; *Receptors, Antigen, T-Cell/immunology/therapeutic use ; Treatment Outcome ; Biological Products ; }, abstract = {CD19-targeted chimeric antigen receptor (CAR) T cells have provided a breakthrough in the treatment of patients with relapsed and/or refractory large B cell lymphoma (LBCL). Currently, three CD19-targeted CAR T cell products are approved by the FDA and various other regulators for the treatment of patients with LBCL: axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel. Response rates following infusion of these CD19-targeted CAR T cells have been promising; however, approximately half of treated patients show relapse within 2 years. Furthermore, receiving these agents can be associated with serious toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this Review, we summarize the factors associated with the efficacy, including response and survival outcomes, and toxicity of CD19-targeted CAR T cells in pivotal clinical trials and large real-world datasets describing the outcomes of patients with LBCL who received treatment with these products.}, }
@article {pmid39965886, year = {2025}, author = {Attygalle, AD and Karube, K and Jeon, YK and Cheuk, W and Bhagat, G and Chan, JKC and Naresh, KN}, title = {The fifth edition of the WHO classification of mature T cell, NK cell and stroma-derived neoplasms.}, journal = {Journal of clinical pathology}, volume = {78}, number = {4}, pages = {217-232}, doi = {10.1136/jcp-2025-210074}, pmid = {39965886}, issn = {1472-4146}, mesh = {Humans ; World Health Organization ; *Killer Cells, Natural/pathology ; *T-Lymphocytes/pathology ; *Stromal Cells/pathology ; *Hematologic Neoplasms/classification/pathology/genetics/diagnosis ; }, abstract = {The fifth edition of the WHO Classification of Haematolymphoid Tumors (WHO-HAEM5) introduces significant advancements in the understanding and diagnosis of mature T cell and NK cell, and stroma-derived neoplasms, and incorporates molecular and genetic data/findings accrued over the past years. The classification has been reorganised using a hierarchical system, employed across the fifth edition of the WHO classification of tumours of all organ systems. This review highlights recent developments, evolving concepts, and key updates since the revised fourth edition (WHO-HAEM4R). It enumerates the minimal/essential criteria necessary for diagnosis and classification, constituting not only the importance of clonality analysis in the workup of certain T cell neoplasms and the detection of infectious agents and specific genetic alterations in a subset of entities but also the applicability of these criteria in resource-constrained settings. 'Stroma-derived neoplasms of lymphoid tissues discussed in this review is a new category introduced in HAEM5 that encompasses mesenchymal tumours occurring exclusively in lymph nodes and spleen and mesenchymal dendritic cell neoplasms previously classified as 'histiocytic/dendritic cell neoplasms'.}, }
@article {pmid39965175, year = {2025}, author = {Hansen, DK and Peres, LC and Dima, D and Richards, A and Shune, L and Afrough, A and Midha, S and Dhakal, B and Kocoglu, MH and Atrash, S and Ferreri, C and Castaneda, O and Davis, JA and Bhurtel, E and McGuirk, J and Wagner, C and Bansal, R and Costello, P and Smith, K and Lieberman-Cribbin, A and De Avila, G and Purvey, S and Hosoya, H and Mikkilineni, L and Oswald, LB and Kaur, G and Pasvolsky, O and Gaballa, M and Herr, MM and Forsberg, P and Janakiram, M and Htut, M and Asoori Maringanti, S and Kalariya, N and Hashmi, H and Reshef, R and Sborov, DW and Nadeem, O and Anwer, F and Khouri, J and Raza, S and Atanackovic, D and Alsina, M and Freeman, CL and Locke, FL and Voorhees, P and Anderson, LD and Richard, S and Martin, T and Lin, Y and Patel, KK and Sidana, S and , }, title = {Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {13}, pages = {1597-1609}, pmid = {39965175}, issn = {1527-7755}, support = {R01 CA281756/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy/therapy/mortality/immunology/pathology ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; *Immunotherapy, Adoptive/methods/adverse effects ; Standard of Care ; *Neoplasm Recurrence, Local ; Aged, 80 and over ; *Antigens, CD19/therapeutic use ; Adult ; Receptors, Chimeric Antigen ; }, abstract = {PURPOSE: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel.
METHODS: Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type.
RESULTS: A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade ≥3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (≥complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (≥March 2022).
CONCLUSION: Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.}, }
@article {pmid39964269, year = {2025}, author = {Lawson, MB and Zhu, W and Miglioretti, DL and Onega, T and Henderson, LM and Rauscher, GH and Kerlikowske, K and Sprague, BL and Bowles, EJA and O'Meara, ES and Tosteson, ANA and diFlorio-Alexander, RM and Hubbard, RA and Lee, JM and Lee, CI}, title = {Disparities in Standard-of-Care, Advanced, and Same-Day Diagnostic Services among Patients with Abnormal Screening Mammography.}, journal = {Radiology}, volume = {314}, number = {2}, pages = {e241673}, pmid = {39964269}, issn = {1527-1315}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; R01 CA266377/CA/NCI NIH HHS/United States ; R50 CA211115/CA/NCI NIH HHS/United States ; U54 GM115516/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; Aged ; *Mammography/statistics & numerical data/methods ; *Breast Neoplasms/diagnostic imaging ; Retrospective Studies ; Adult ; *Healthcare Disparities/statistics & numerical data/ethnology ; Aged, 80 and over ; United States ; Early Detection of Cancer ; *Health Services Accessibility/statistics & numerical data ; Biopsy ; }, abstract = {Background Diagnostic imaging and biopsy are used to evaluate abnormal screening mammography. Differences in on-site availability and receipt of these diagnostic services may contribute to disparities in breast cancer outcomes across sociodemographic groups. Purpose To identify multilevel factors associated with on-site availability and receipt of diagnostic imaging and biopsy after screening mammography. Materials and Methods This retrospective study included female patients (age range, 40-89 years) who underwent screening mammography at 136 facilities in the United States from January 2010 to December 2020. The primary exposure variables were race and ethnicity and neighborhood-level educational attainment, household income, and rurality. The adjustment variables were age, breast density, breast biopsy history, personal and family history of breast cancer, time from prior mammographic examination to screening mammography, screening modality, facility academic affiliation, and screening examination year. The relative risk (RR) of factors for on-site availability at screening facilities and undergoing standard-of-care imaging (ie, mammography and/or US) and advanced diagnostic imaging (ie, digital breast tomosynthesis, MRI) and biopsy, and undergoing any same-day diagnostic service and biopsy were estimated using modified Poisson regression. Results In total, 1 123 177 female patients (median age, 59 years; IQR, 51-67 years) underwent 3 519 502 screening mammographic examinations: 10.3% Asian patients (362 440 of 3 519 502), 12.7% Black patients (447 777 of 3 519 502), 6.5% Hispanic patients (227 177 of 3 519 502), 68.3% White patients (2 403 159 of 3 519 502), and 2.2% all other races and ethnicities (78 949 of 3 519 502). In most fully adjusted models, race or ethnicity and neighborhood-level socioeconomic status were not associated with on-site diagnostic service availability. However, compared with White patients, patients belonging to racial and ethnic minority groups were less likely to undergo same-day diagnostic services after abnormal screening mammography (Asian patients: RR, 0.74 [95% CI: 0.64, 0.85]; Black patients: RR, 0.56 [95% CI: 0.49, 0.63]; Hispanic patients: RR, 0.61 [95% CI: 0.52, 0.71]). Black patients were less likely to undergo same-day biopsies after an abnormal diagnostic workup (RR, 0.46; 95% CI: 0.33, 0.65). Conclusion Although no evidence existed that on-site diagnostic service availability varied by race and ethnicity in most models, patients in racial and ethnic minority groups were less likely to be provided same-day diagnostic services and Black patients were less likely to undergo same-day biopsy. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Mullen in this issue.}, }
@article {pmid39963309, year = {2025}, author = {Wadden, E and Lai, C and Grivas, P and Bhatia, S and Portuguese, AJ and Salem, JE and Moslehi, JJ and Cheng, RK}, title = {Successful treatment of immune checkpoint inhibitor-associated fulminant myocarditis with abatacept and ruxolitinib: a case report.}, journal = {European heart journal. Case reports}, volume = {9}, number = {2}, pages = {ytaf019}, pmid = {39963309}, issn = {2514-2119}, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy with growing indications for treatment of various malignancies. Immune checkpoint inhibitors are monoclonal antibodies that block inhibitory pathways in immune cells, including cytotoxic T lymphocyte antigen-4 (CTLA4), programmed death 1 receptor (PD1), and programmed cell death ligand-1 (PDL1), to activate the immune system. However, these agents can disrupt self-tolerance and lead to immune-related adverse events. Fulminant myocarditis, a feared complication of ICIs, can be highly fatal, and there is a need for effective treatment options.
CASE SUMMARY: A 70-year-old patient with recurrent metastatic disease of urothelial carcinoma subsequently developed fulminant myocarditis after receiving eight cycles of pembrolizumab. He developed cardiogenic shock and required inotropes and a percutaneous microaxial flow pump placement for temporary mechanical circulatory support. He received methylprednisolone initially and then was started on second-line immunosuppression agents, ruxolitinib and abatacept, for steroid-refractory myocarditis. Abatacept is thought to inhibit activation of T-cell CTLA4 and PD1/PDL1 pathways and reverse ICI-activated pathways. Ruxolitinib is a Janus kinase inhibitor that impairs immune activation through suppressing cytokine sensing and production and T-cell activation. After these treatments, the patient subsequently clinically improved and his myocarditis resolved.
DISCUSSION: This case highlights ICI myocarditis refractory to corticosteroids leading to treatment with second-line immunosuppression. As immunotherapies are increasingly applied to a broader range of cancers, further research is needed to evaluate the optimal treatment strategy for ICI-related myocarditis and other immune-related adverse events.}, }
@article {pmid39962532, year = {2025}, author = {Hunter, NB and Peterson, LM and Specht, JM and Mankoff, DA and Muzi, M and Chen, DL and Gwin, WR and Vinayak, S and Davidson, NE and Linden, HM}, title = {Fluoroestradiol (FES) and Fluorodeoxyglucose (FDG) PET imaging in patients with ER+, HER2-positive or HER2-negative metastatic breast cancer.}, journal = {Breast cancer research : BCR}, volume = {27}, number = {1}, pages = {23}, pmid = {39962532}, issn = {1465-542X}, support = {P01 CA042045/CA/NCI NIH HHS/United States ; R50 CA211270/CA/NCI NIH HHS/United States ; CA42045/NH/NIH HHS/United States ; CA72064/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/pathology/metabolism/mortality ; *Fluorodeoxyglucose F18 ; *Receptor, ErbB-2/metabolism ; *Receptors, Estrogen/metabolism ; Middle Aged ; Retrospective Studies ; *Positron-Emission Tomography/methods ; Adult ; Aged ; *Estradiol/analogs & derivatives ; Radiopharmaceuticals ; Neoplasm Metastasis ; Aged, 80 and over ; Prognosis ; }, abstract = {BACKGROUND: [18]F-Fluorodeoxyglucose (FDG) and [18]F-Fluorestradiol (FES) have been FDA approved for measuring tumor glycolytic activity and estrogen receptor (ER) uptake, respectively, in clinical positron emission tomography (PET) imaging for patients with hormone-receptor (HR) positive metastatic breast cancer (MBC), but little is known about its utility in patients with breast tumors that overexpress human epidermal growth factor 2 (HER2). We hypothesize that comparing patterns of FDG and FES uptake in patients with HER2-positive versus HER2-negative MBC can guide further biologic and clinical studies into the HR/HER2-positive phenotype.
METHODS: We conducted a retrospective study examining uptake in matched lesions for FES and FDG-PET scans, assessing these parameters in 213 patients with ER-positive/HER2-positive (n = 33) versus ER-positive/HER2-negative MBC (n = 180). We employed log-rank and t-tests to assess the association of HER2 status with outcome variables and the hypotheses that patients expressing HER2-positive disease lived longer than patient with HER2-negative disease.
RESULTS: No difference in FES or FDG avidity was observed between patients with HER2-negative or HER2-positive tumor status. Limited data also suggests that patients with HER2-positive disease had better overall survival (p = 0.024), than those with HER2-negative disease, but not time-to-progression between the same patient cohorts.
CONCLUSION: This retrospective analysis suggests that there is a possible role for future trials using FES-PET in helping to select patients with ER+/HER2-positive primary tumors who retain ER expression at all sites of disease and may benefit from endocrine therapy.}, }
@article {pmid39962220, year = {2025}, author = {Gang, M and Othus, M and Sandmaier, BM and Davis, C and Basom, RS and Walter, RB}, title = {Modulators of relapse risk in adults allografted for acute myeloid leukemia in measurable residual disease-positive remission.}, journal = {Bone marrow transplantation}, volume = {60}, number = {5}, pages = {705-707}, pmid = {39962220}, issn = {1476-5365}, support = {T32-HL007093//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; T32 HL007093/HL/NHLBI NIH HHS/United States ; P30-CA015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA018029//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA078902//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA078902/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, }
@article {pmid39961473, year = {2025}, author = {Munshi, PN and Olin, RL and Wall, S and McCurdy, SR and Al-Juhaishi, T and Baker, J and Bhatt, VR and Chokr, N and Dahi, P and DeFilipp, Z and Espinoza-Gutarra, M and Farhan, S and Gowda, L and Hamilton, BK and Inamoto, Y and Jayani, R and Kharfan-Dabaja, MA and Lin, R and Meyers, G and Mishra, A and Murthy, HS and Nawas, M and Rosko, AE and Ruiz, M and Sorror, ML and Sung, AD and Carpenter, PA and Hamadani, M and Artz, AS}, title = {US Geriatric Assessment Practices for Older Adults Undergoing Hematopoietic Cell Transplantation or Chimeric Antigen Receptor T Cell Therapy: An American Society for Transplantation and Cellular Therapy Physician Survey from the Aging Special Interest Group and Committee on Practice Guidelines.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {5}, pages = {285-296}, doi = {10.1016/j.jtct.2025.02.014}, pmid = {39961473}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Aged ; Cross-Sectional Studies ; United States ; Surveys and Questionnaires ; *Geriatric Assessment/methods ; Male ; *Immunotherapy, Adoptive/methods ; Practice Guidelines as Topic ; Female ; *Receptors, Chimeric Antigen ; *Practice Patterns, Physicians' ; Middle Aged ; Physicians ; *Cell- and Tissue-Based Therapy/methods ; Societies, Medical ; }, abstract = {Geriatric assessment (GA) may identify vulnerabilities and promote risk-stratification in older adults predisposed to toxicities after autologous (auto), allogeneic (allo) hematopoietic cell transplantation (HCT) and chimeric antigen T-cell therapies (CAR T). With increased utilization cellular therapies for older adults the American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines and its Special Interest Group for Aging (SIG) conducted an online cross-sectional survey between April 2023 and August 2023 to determine transplantation and cellular therapy physicians' practice patterns regarding GA in older patients receiving HCT and CAR T-cell therapies. E-mail surveys were sent to 1168 ASTCT physician members and only 96 (8.2%) respondents completed the survey. Most (86%) were affiliated with university/teaching centers and 70% had a combined HCT and cellular therapy practice. More than 50% of respondents were interested in pursuing GA but 68% described barriers. The top two recognized barriers to GA were lack of time (96%) and clinical support staff (90%). Despite interest, only 15% respondents reported to know the domains of GA 'well'. Among those using GA, the minimum age used for routine GA was 65 years for allo-HCT and CAR T in over 91% respondents. Taken together, we recommend the HCT community leadership and GA experts combine efforts to address the gap in GA uptake and implementation.}, }
@article {pmid39960754, year = {2025}, author = {Estevam, GO and Linossi, E and Rao, J and Macdonald, CB and Ravikumar, A and Chrispens, KM and Capra, JA and Coyote-Maestas, W and Pimentel, H and Collisson, EA and Jura, N and Fraser, JS}, title = {Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39960754}, issn = {2050-084X}, support = {GM145238/GM/NIGMS NIH HHS/United States ; R01 CA239604/CA/NCI NIH HHS/United States ; LM013434/NH/NIH HHS/United States ; S10 OD028511/OD/NIH HHS/United States ; R35 GM145238/GM/NIGMS NIH HHS/United States ; CA239604/CA/NCI NIH HHS/United States ; R01 LM013434/LM/NLM NIH HHS/United States ; }, mesh = {*Proto-Oncogene Proteins c-met/genetics/antagonists & inhibitors/metabolism/chemistry ; Humans ; *Protein Kinase Inhibitors/pharmacology ; *Drug Resistance, Neoplasm/genetics ; *Mutation ; Protein Domains ; }, abstract = {Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We validate previously identified resistance mutations, pinpoint common resistance sites across type I, type II, and type I ½ inhibitors, unveil unique resistance and sensitizing mutations for each inhibitor, and verify non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.}, }
@article {pmid39959858, year = {2025}, author = {Ninga, X and Sun, Y and Pan, Y and Gilbert, PB}, title = {Regression analysis of semiparametric Cox-Aalen transformation models with partly interval-censored data.}, journal = {Electronic journal of statistics}, volume = {19}, number = {1}, pages = {240-290}, pmid = {39959858}, issn = {1935-7524}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Partly interval-censored data, comprising exact and intervalcensored observations, are prevalent in biomedical, clinical, and epidemiological studies. This paper studies a flexible class of the semiparametric Cox-Aalen transformation models for regression analysis of such data. These models offer a versatile framework by accommodating both multiplicative and additive covariate effects and both constant and time-varying effects within a transformation, while also allowing for potentially time-dependent covariates. Moreover, this class of models includes many popular models such as the semiparametric transformation model, the Cox-Aalen model, the stratified Cox model, and the stratified proportional odds model as special cases. To facilitate efficient computation, we formulate a set of estimating equations and propose an Expectation-Solving (ES) algorithm that guarantees stability and rapid convergence. Under mild regularity assumptions, the resulting estimator is shown to be consistent and asymptotically normal. The validity of the weighted bootstrap is also established. A supremum test is proposed to test the time-varying covariate effects. Finally, the proposed method is evaluated through comprehensive simulations and applied to analyze data from a randomized HIV/AIDS trial.}, }
@article {pmid39956433, year = {2025}, author = {Wilson, MH and Harrington, J and Suh, J and Fearon, C and Reavis, M and Srisatidnarakul, S and Swetky, M and Warren, N and Badalucco, A and Adams Barker, CM and Nandakumar, S and Pergam, SA}, title = {Isolation precautions associated with COVID-19 infections among immunocompromised populations: A multicenter study of nine National Cancer Institute--designated Comprehensive Cancer Centers.}, journal = {American journal of infection control}, volume = {53}, number = {5}, pages = {596-601}, doi = {10.1016/j.ajic.2025.02.002}, pmid = {39956433}, issn = {1527-3296}, mesh = {Humans ; *COVID-19/prevention & control ; *Immunocompromised Host ; *Patient Isolation/methods ; United States ; SARS-CoV-2 ; National Cancer Institute (U.S.) ; *Cancer Care Facilities ; *Infection Control/methods ; Neoplasms/complications ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Nine Comprehensive Cancer Centers sought to understand COVID-19 infection management experiences to improve future immunocompromised host guidelines.
METHODS: Volunteers from Comprehensive Cancer Center Infection Prevention and Control (C3IC) completed 2 surveys on COVID-19 practices from March 2020 to December 2023. Three reviewers independently validated qualitative analysis of findings. Virtual meetings were leveraged to discuss findings and identify themes.
RESULTS: 100% (9/9) of respondents changed COVID-19-associated isolation discontinuation guidance at least once. All (9/9) included patient immune status as criterion. All (9/9) required clearance testing at some point in the pandemic, 6 of 9 (66%) continued to require clearance testing at the time of the survey. Only 1 of 9 (11%) allowed antigen testing to meet criteria. Seven isolation titles were noted across 9 institutions, despite near agreement on measures employed.
DISCUSSION: Variability existed in COVID-19 management among study participants, despite serving similar populations, which may stem from limited data supporting understanding of viral transmissibility in immunocompromised hosts.
CONCLUSIONS: Guideline development for immunocompromised hosts, potential drivers for viral evolution, can lack clarity for consistent management of the population. Engaging subject matters in specialty populations with future guideline development will improve infection prevention in health care settings.}, }
@article {pmid39955465, year = {2025}, author = {Chow, EJ and Blythe, NA and Cushing-Haugen, KL and Duggan, C and Baker, KS and Cole, AM and Green, S and Guiterrez, AI and Lee, E and Linden, HM and Mendoza, JA and Ohlsen, TJD and Ortblad, KF and Schwartz, SM and Yung, RL and Ceballos, RM}, title = {Enhancing survivorship care among Hispanic/Latino cancer survivors via lay health educators: results of a pilot randomized trial.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {39955465}, issn = {1932-2267}, support = {CA015704/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; 75N91020C00005/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; CA015704/NH/NIH HHS/United States ; HHSN261201800004I/NH/NIH HHS/United States ; CA258105/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Assess the feasibility, acceptability, and preliminary efficacy of lay health educators to enhance Hispanic/Latino survivors' knowledge of their cancer history, screening needs, and health-related self-efficacy.
METHODS: Hispanic/Latino survivors diagnosed within 5 years were recruited from three clinics and a regional cancer registry. Survivors were randomized to receive a personalized survivorship care plan (SCP; control) or SCP plus telephone session with a bilingual-bicultural lay health educator (intervention). Survivors were reassessed after 3 months. Primary outcomes were feasibility (meeting accrual, n = 60-100) and acceptability of the SCP and education session. Secondary outcomes were changes in survivors' knowledge of their cancer history, screening needs, and health-related self-efficacy.
RESULTS: Ninety-fine survivors (median age 55 years, 78% female, 56% low/marginal health literacy) were randomized (n = 48 intervention). Seventy-nine completed the study; most found the SCP useful (82% intervention; 68% control); 84% of the intervention group rated the education session useful. Over time, both groups had improved knowledge of their cancer history (accuracy increased from 71.5 ± 16.4% to 73.8 ± 15.0%; p = 0.19) although differences over time and between groups were not statistically significant. At follow-up compared with baseline, participants were more likely to report plans for future screening: cervical (57% versus 31%, p = 0.002); colorectal (39% versus 26%, p = 0.10). Although the change in self-efficacy did not differ between study groups, self-efficacy significantly improved within the control group over time (0.3; 95% CI 0.1, 0.5).
CONCLUSIONS: Hispanic/Latino survivors found the SCP and education session acceptable. SCPs alone may improve knowledge and adherence to cancer screening.
Provision of a SCP may benefit Hispanic/Latino survivors.
CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT04081779.}, }
@article {pmid39954698, year = {2025}, author = {Ortblad, KF and Ngure, K}, title = {Safety of dapivirine vaginal rings during breastfeeding.}, journal = {The lancet. HIV}, volume = {12}, number = {3}, pages = {e164-e165}, doi = {10.1016/S2352-3018(24)00342-4}, pmid = {39954698}, issn = {2352-3018}, }
@article {pmid39954697, year = {2025}, author = {Noguchi, LM and Owor, M and Mgodi, NM and Gati Mirembe, B and Dadabhai, S and Horne, E and Gundacker, H and Richardson, BA and Bunge, K and Scheckter, R and Song, M and Marzinke, MA and Anderson, PL and Livant, E and Jacobson, C and Piper, JM and Chakhtoura, N and Hillier, SL and Balkus, JE and , }, title = {Safety and drug quantification of the dapivirine vaginal ring and oral pre-exposure prophylaxis in breastfeeding mother-infant pairs (MTN-043): a phase 3B, open-label, randomised trial.}, journal = {The lancet. HIV}, volume = {12}, number = {3}, pages = {e180-e190}, doi = {10.1016/S2352-3018(24)00306-0}, pmid = {39954697}, issn = {2352-3018}, mesh = {Humans ; Female ; *HIV Infections/prevention & control ; *Breast Feeding ; Adult ; *Pre-Exposure Prophylaxis/methods ; Infant ; *Anti-HIV Agents/administration & dosage/adverse effects ; *Infectious Disease Transmission, Vertical/prevention & control ; *Contraceptive Devices, Female/adverse effects ; Young Adult ; *Pyrimidines/administration & dosage/adverse effects ; Infant, Newborn ; Administration, Oral ; South Africa ; Uganda ; }, abstract = {BACKGROUND: In 2021, WHO recommended dapivirine vaginal rings (DVRs) for HIV prevention, but noted evidence gaps for breastfeeding populations. This trial aimed to describe safety profiles associated with DVRs and oral pre-exposure prophylaxis (PrEP) use during breastfeeding and to summarise study-drug quantification and concentrations for mothers and infants.
METHODS: Microbicide Trials Network (MTN)-043 was a phase 3b, open-label, randomised trial in which mother-infant pairs were recruited from local health facilities and enrolled at four HIV clinical trial sites in Malawi, South Africa, Uganda, and Zimbabwe. Eligible mothers (aged ≥18 years) were HIV-negative, exclusively breastfeeding one infant (aged 6-12 weeks, birthweight ≥2000 g), and had not been exposed to HIV post-exposure prophylaxis in the previous 6 months. Mother-infant pairs were randomly assigned (3:1) via a computer-generated sequence to 12 weeks of 25 mg monthly DVR or daily oral PrEP (200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate), with stratification by site using a permuted block design. Participants and staff were aware of study product assignment. Primary outcomes were maternal and infant safety (all serious adverse events and grade 3 or worse adverse events) and drug concentrations, which were measured in maternal plasma, maternal blood, breastmilk, infant plasma, and infant blood. All mother-infant pairs who received at least one dose of study product were included in the primary safety analysis, and those with at least one post-enrolment drug concentration result were included in the drug quantification analysis. The trial was registered at ClinicalTrials.gov (NCT04140266).
FINDINGS: Between Sept 24, 2020, and July 29, 2021, 197 mother-infant pairs enrolled (148 on DVR and 49 on PrEP), all of whom received at least one dose of study product and were included in the primary safety analysis. Two (1%) of 148 mothers in the DVR group had serious adverse events, and three (2%) in the DVR group and two (4%) in the oral PrEP group had a grade 3 or worse adverse event; four (3%) of 148 infants in the DVR group had a serious adverse event, and ten (7%) in the DVR group and one (2%) in the oral PrEP group had a grade 3 or worse adverse event. No mother or infant in the oral PrEP group had a serious adverse event. No HIV infections were detected. 144 participants in the DVR group and 48 in the oral PrEP group had at least one post-enrolment drug concentration result. Quantifiable median dapivirine concentrations ranged from 656·0 (IQR 407·0-878·0) pg/mL at week 1 to 558·5 (282·0-778·0) pg/mL at month 3, but were observed infrequently (5-15%) in specimens from infants, with median concentrations below the limit of quantification at all visits. Median tenofovir diphosphate concentrations ranged from 263·0 (193·0-363·0) fmol/punch at week 1 to 777·0 (381·0-1241·0) fmol/punch at month 3, but were not observed in specimens from infants, with all concentrations below the limit of quantification at all visits.
INTERPRETATION: Increased risk of HIV acquisition in the postnatal period, favourable product safety profile, and low drug exposures among infants support the recommendation for DVRs as an additional HIV prevention choice during breastfeeding.
FUNDING: US National Institutes of Health.}, }
@article {pmid39953849, year = {2025}, author = {Dontchos, BN and Phelps, MD and Rahbar, H and Lam, DL}, title = {Pre-Treatment Breast MRI: Clinical Indications, Outcomes, and Future Directions.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {}, number = {}, pages = {}, doi = {10.1002/jmri.29741}, pmid = {39953849}, issn = {1522-2586}, abstract = {Breast MRI is the most sensitive modality for assessing the extent of disease in patients with newly-diagnosed breast cancer because it identifies clinically- and mammographically-occult breast cancers. Though highly sensitive, breast MRI has lower specificity that may result in false positive findings and potential overestimation of disease if additional MRI findings are not biopsied prior to surgery. It had been anticipated that the superior cancer detection rate of pre-treatment MRI would translate to improved immediate (surgical re-excision) and long-term patient outcomes such as breast cancer recurrence and survival rates, but studies have not necessarily supported this assumption. In this review, current recommendations and utilization of breast MRI for pre-treatment local staging of breast cancer will be presented, with an emphasis on specific clinical scenarios for patient selection and its impact on short- and long-term patient clinical outcomes. We will also present new evidence that pre-treatment MRI may support de-escalation of treatment and discuss emerging advanced MRI techniques that may improve diagnostic performance.}, }
@article {pmid39953405, year = {2025}, author = {Soussand, F and Abdou, AY and Sanchez, M and Huynh, BT and Giese, C and Tran-Kiem, C and Béraud, G and Guillemot, D and Cauchemez, S and Opatowski, L and Bosetti, P}, title = {Evolution of social contacts patterns in France over the SARS-CoV-2 pandemic: results from the SocialCov survey.}, journal = {BMC infectious diseases}, volume = {25}, number = {1}, pages = {224}, pmid = {39953405}, issn = {1471-2334}, mesh = {Humans ; France/epidemiology ; *COVID-19/epidemiology/transmission/prevention & control ; Adult ; Middle Aged ; Male ; Female ; Surveys and Questionnaires ; SARS-CoV-2 ; Young Adult ; Aged ; Adolescent ; *Contact Tracing/statistics & numerical data ; Pandemics ; Child ; Infant ; }, abstract = {BACKGROUND: Non-pharmaceutical measures such as lockdowns, curfews and place closures were implemented in France during 2020-2022 to reduce contacts in the population, to limit the spread of SARS-CoV-2 and reduce COVID-19 healthcare burden. Individuals also changed their behaviours as a response to the pandemic. Here, we present the results of the SocialCov survey that characterise the evolution of contacts in France between December 2020 and May 2022 to better understand the short and long term impact of these interventions on social mixing.
METHODS: A questionnaire was advertised over six independent communication campaigns through the governmental application TousAntiCovid between December 2020 and June 2022. Participants were asked to detail social contacts in the previous day, including contact age, location, duration and type (physical/conversational).
RESULTS: Over the six distinct campaigns, 44,396 individuals participated in the survey, declaring 300,735 contacts in total. The patterns of contacts strongly evolved over time, along with the progressive easing of national mitigation measures. The number of contacts in the French population increased from 5.3 contacts per day on average in December 2020 to 9.7 in May 2022. Mixing patterns were affected by age of participants, holidays and weekends. Healthcare workers declared 18.4 contacts on average during working days, roughly twice more than other workers. Reported risk perception changed throughout the two year period.
CONCLUSIONS: Results provide a detailed picture of contact evolution over the years 2020-2022 in France. In addition to a major evolution of contact density over time, this study highlights strong heterogeneities in contact patterns according to age, employment and weekend/vacation periods. The contact matrices provided here can be used to inform age-stratified transmission models of respiratory pathogens in the context of implementation of multiple non-pharmaceutical measures.}, }
@article {pmid39951615, year = {2025}, author = {Pierson, SK and Brandstadter, JD and Torigian, DA and Bagg, A and Lechowicz, MJ and Alapat, D and Casper, C and Chadburn, A and Chandrakasan, S and Dispenzieri, A and Fosså, A and Hoffmann, C and Ide, M and Kurzrock, R and Mukherjee, S and Nasta, S and Navarro, JT and Noy, A and Oksenhendler, E and Bustamante, MS and Shyamsundar, S and Streetly, M and Wong, RSM and Zhang, L and Lim, MS and Srkalovic, G and van Rhee, F and Fajgenbaum, DC}, title = {Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry.}, journal = {Blood advances}, volume = {9}, number = {8}, pages = {1952-1965}, pmid = {39951615}, issn = {2473-9537}, support = {R01 FD007632/FD/FDA HHS/United States ; R01 HL141408/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Castleman Disease/diagnosis/pathology/etiology/classification/epidemiology ; Registries ; Female ; Male ; Adult ; Middle Aged ; Phenotype ; Aged ; Young Adult ; Adolescent ; }, abstract = {Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8-negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm-driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have "oligocentric" lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.}, }
@article {pmid39951468, year = {2025}, author = {Chen, KY and Toro-Moreno, M and Subramaniam, AR}, title = {GitHub enables collaborative and reproducible laboratory research.}, journal = {PLoS biology}, volume = {23}, number = {2}, pages = {e3003029}, pmid = {39951468}, issn = {1545-7885}, support = {R01 AT012826/AT/NCCIH NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; }, mesh = {*Software ; *Laboratories ; Workflow ; Reproducibility of Results ; Cooperative Behavior ; Humans ; }, abstract = {GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into "wet" lab workflows.}, }
@article {pmid39951264, year = {2025}, author = {Chung, DH and Caverly, TJ and Schipper, MJ and Hofer, TP and Gulati, R and Rose, BS and Caram, MEV and Tsao, PA and Stensland, KD and Elliott, D and Saini, SD and Bryant, AK}, title = {Prostate Cancer Mortality in Men Aged 70 Years Who Recently Underwent Prostate-Specific Antigen Screening.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459766}, pmid = {39951264}, issn = {2574-3805}, mesh = {Humans ; Male ; Aged ; *Prostatic Neoplasms/mortality/blood/diagnosis ; *Prostate-Specific Antigen/blood ; *Early Detection of Cancer/statistics & numerical data ; United States/epidemiology ; Cohort Studies ; Risk Assessment ; Mass Screening/statistics & numerical data ; }, abstract = {IMPORTANCE: Continuing prostate-specific antigen (PSA) screening after age 70 years might benefit men at high risk of prostate cancer-specific mortality (PCSM) or metastatic prostate cancer (mPCa), but the relative value of clinical factors (race and ethnicity, competing mortality, and PSA history) in identifying men at higher vs lower risk is unknown.
OBJECTIVE: To examine the value of PSA levels, race and ethnicity, and competing mortality in risk stratification for PCSM and mPCa in men after age 70 years.
In this cohort study, clinical data of all men receiving health care through the Veterans Health Administration who turned age 70 years between 2008 and 2020 and had a normal screening PSA value between age 65 and 69 years (<4 ng/mL [baseline PSA]) and no prior history of prostate cancer or biopsy were examined. The data cutoff date was December 26, 2023.
EXPOSURE: The most recent screening PSA value from age 65 to 69 years, self-reported race and ethnicity, and competing mortality risk derived from a machine learning model.
MAIN OUTCOME AND MEASURES: The 10-year absolute risk of PCSM and mPCa were determined using regression modeling.
RESULTS: The cohort included 921 609 men who turned 70 years between 2008 and 2020; 11% of whom self-reported as Black and 82% as White race. Between age 65 and 70 years, 45% of patients had a baseline PSA of less than 1.00 ng/mL, and 32% had a baseline PSA of 1.00 to 1.99 ng/mL. Most patients (87%) continued to undergo screening past age 70 years, with little variation by competing mortality risk or race and ethnicity. The 10-year cumulative incidence of PCSM was 0.26% overall, and 95% of men had a 10-year risk less than 0.73%. Higher baseline PSA level between age 65 and 69 years was associated with 10-year PCSM risk (0.79% for 3.00-3.99 ng/mL vs 0.10% for 0.20-0.99 ng/mL), race and ethnicity (0.36% for Black vs 0.25% for White), and competing mortality (0.24% for the highest quintile vs 0.21% for the lowest quintile). Similar results were found for mPCa. Low PSA (0.20-0.99 ng/mL) was associated with very low PCSM and mPCa risk, even among Black men in the healthiest quintile of competing mortality risk (10-year PCSM risk, 0.08% [95% CI, 0.01%-0.44%]; 10-year mPCa risk 0.24% [95% CI, 0.10%-0.52%]).
CONCLUSIONS AND RELEVANCE: In this cohort study, the findings suggest that most men receiving care through the VHA continue PSA screening after age 70 years despite low absolute 10-year PCSM risks. The PSA values from age 65 to 69 years may be highly informative for adverse prostate cancer outcomes after age 70 years, with a PSA less than 1 ng/mL associated with a very low risk of long-term PCSM and mPCa.}, }
@article {pmid39950338, year = {2025}, author = {Iyer, KR and Clarke, SL and Guarischi-Sousa, R and Gjoni, K and Heath, AS and Young, EP and Stitziel, NO and Laurie, C and Broome, JG and Khan, AT and Lewis, JP and Xu, H and Montasser, ME and Ashley, KE and Hasbani, NR and Boerwinkle, E and Morrison, AC and Chami, N and Do, R and Rocheleau, G and Lloyd-Jones, DM and Lemaitre, RN and Bis, JC and Floyd, JS and Kinney, GL and Bowden, DW and Palmer, ND and Benjamin, EJ and Nayor, M and Yanek, LR and Kral, BG and Becker, LC and Kardia, SLR and Smith, JA and Bielak, LF and Norwood, AF and Min, YI and Carson, AP and Post, WS and Rich, SS and Herrington, D and Guo, X and Taylor, KD and Manson, JE and Franceschini, N and Pollard, KS and Mitchell, BD and Loos, RJF and Fornage, M and Hou, L and Psaty, BM and Young, KA and Regan, EA and Freedman, BI and Vasan, RS and Levy, D and Mathias, RA and Peyser, PA and Raffield, LM and Kooperberg, C and Reiner, AP and Rotter, JI and Jun, G and de Vries, PS and Assimes, TL}, title = {Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.}, journal = {Journal of the American Heart Association}, volume = {14}, number = {4}, pages = {e036499}, pmid = {39950338}, issn = {2047-9980}, support = {K26 DK138425/DK/NIDDK NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Coronary Artery Disease/genetics/diagnosis ; Genome-Wide Association Study ; Male ; Female ; Genetic Predisposition to Disease ; Middle Aged ; Aged ; Polymorphism, Single Nucleotide ; Case-Control Studies ; *Genomic Structural Variation ; Whole Genome Sequencing ; Chromosomes, Human, Pair 6/genetics ; Phenotype ; Risk Factors ; }, abstract = {BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear.
METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits.
CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.}, }
@article {pmid39947884, year = {2025}, author = {Chen, X and Patkar, N and Tembhare, P and Papagudi, S and Yeung, C and Kanagal Shamanna, R and Gujral, S and Wood, B and Naresh, KN}, title = {Fifth edition WHO classification: myeloid neoplasms.}, journal = {Journal of clinical pathology}, volume = {78}, number = {5}, pages = {335-345}, doi = {10.1136/jcp-2024-210022}, pmid = {39947884}, issn = {1472-4146}, mesh = {Humans ; World Health Organization ; *Biomarkers, Tumor/genetics ; *Myelodysplastic Syndromes/classification/genetics/diagnosis/pathology ; *Myeloproliferative Disorders/classification/genetics/diagnosis/pathology ; *Hematologic Neoplasms/classification/genetics/diagnosis/pathology ; *Leukemia, Myeloid, Acute/classification/genetics/diagnosis ; Genetic Predisposition to Disease ; }, abstract = {The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant advancements in the understanding and diagnosis of myeloid neoplasms, emphasising molecular and genetic insights. This review highlights key updates from the revised fourth edition (WHO-HEM4R), particularly the integration of genetic criteria for disease classification. Many entities are now defined by specific genetic abnormalities, enhancing diagnostic precision and prognostic assessment. Notably, the elimination of the 20% blast threshold for acute myeloid leukaemia (AML) with specific defining genetic alterations reflects a shift towards genomic-driven diagnostics. Additional updates include the refined subclassification of myelodysplastic neoplasms (MDS) and MDS/myeloproliferative neoplasms, as well as the recognition of novel entities such as clonal haematopoiesis and MDS with biallelic TP53 inactivation, further expanding the spectrum of myeloid neoplasms. WHO-HEM5 illustrates the diagnostic utility of morphology, flow cytometry, immunohistochemistry and next-generation sequencing in resource-rich settings. However, its implementation in low-income and middle-income countries (LMICs) remains challenging due to limited access to advanced diagnostic tools. This review explores strategies to optimise diagnosis in resource-constrained environments, where morphology and immunophenotyping remain fundamental. By integrating molecular diagnostics with traditional methods, WHO-HEM5 aims to refine classification and facilitate risk stratification in the era of personalised medicine, providing haematopathologists and clinicians with an essential framework to navigate the complexities of myeloid neoplasms. The emphasis on advancing haematopathology practices worldwide, including in LMICs, demonstrates the ongoing commitment to improving global outcomes in haematological malignancies.}, }
@article {pmid39946483, year = {2025}, author = {Henikoff, S and Zheng, Y and Paranal, RM and Xu, Y and Greene, JE and Henikoff, JG and Russell, ZR and Szulzewsky, F and Thirimanne, HN and Kugel, S and Holland, EC and Ahmad, K}, title = {RNA polymerase II at histone genes predicts outcome in human cancer.}, journal = {Science (New York, N.Y.)}, volume = {387}, number = {6735}, pages = {737-743}, pmid = {39946483}, issn = {1095-9203}, support = {K99 HG012797/HG/NHGRI NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Female ; Humans ; Mice ; Aneuploidy ; *Breast Neoplasms/diagnosis/genetics ; Chromatin ; *Glioma/diagnosis/genetics ; *Histones/genetics ; *Meningioma/diagnosis/genetics ; Paraffin Embedding ; Prognosis ; Receptor, ErbB-2/genetics ; *RNA Polymerase II/genetics ; *Transcription, Genetic ; }, abstract = {Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)-cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.}, }
@article {pmid39943310, year = {2025}, author = {Jyoti, D and Reeves, D and Gordon-Wylie, S and Eskey, C and Weaver, J}, title = {Improving Stroke Treatment Using Magnetic Nanoparticle Sensors to Monitor Brain Thrombus Extraction.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {3}, pages = {}, pmid = {39943310}, issn = {1424-8220}, support = {K25 AI155224/AI/NIAID NIH HHS/United States ; R43 NS129419/NS/NINDS NIH HHS/United States ; 1R43NS129419//1R43NS129419 and AI155224/ ; }, mesh = {Humans ; *Magnetite Nanoparticles/chemistry ; *Thrombosis/therapy/surgery ; *Thrombectomy/methods ; *Stroke/therapy ; *Biosensing Techniques ; Stents ; Brain/pathology ; }, abstract = {(1) Background: Mechanical thrombectomy (MT) successfully treats ischemic strokes by extracting the thrombus, or clot, using a stent retriever to pull it through the blood vessel. However, clot slippage and/or fragmentation can occur. Real-time feedback to a clinician about attachment between the stent and clot could enable more complete removal. We propose a system whereby antibody-targeted magnetic nanoparticles (NPs) are injected via a microcatheter to coat the clot, oscillating magnetic fields excite the particles, and a small coil attached to the catheter picks up a signal that determines the proximity of the clot to the stent. (2) Methods: We used existing simulation code to model the signal from NPs distributed on a hemispherical clot with three orthogonally applied magnetic fields. An in vitro apparatus was built that applied fields and read out signals from a 1.5 mm pickup coil at a variable distance and orientation angle from a sample of 100 nm iron oxide core/shell NPs. (3) Results: Our simulations suggest that the sum of the voltages induced in the pickup coil from three orthogonal applied fields could localize a clot to within 180 µm, regardless of the exact orientation of the pickup coil, with further precision added via rotation-correction formulae. Our experimental system validated simulations; we estimated an in vitro distance recovery precision of 41 µm with a pickup coil 1 mm from the clot. (4) Conclusions: Magnetic NP sensing could be a safe and real-time method to estimate whether a clot is attached to the stent retriever during MT.}, }
@article {pmid39939790, year = {2025}, author = {Adli, M and Przybyla, L and Burdett, T and Burridge, PW and Cacheiro, P and Chang, HY and Engreitz, JM and Gilbert, LA and Greenleaf, WJ and Hsu, L and Huangfu, D and Hung, LH and Kundaje, A and Li, S and Parkinson, H and Qiu, X and Robson, P and Schürer, SC and Shojaie, A and Skarnes, WC and Smedley, D and Studer, L and Sun, W and Vidović, D and Vierbuchen, T and White, BS and Yeung, KY and Yue, F and Zhou, T and , }, title = {MorPhiC Consortium: towards functional characterization of all human genes.}, journal = {Nature}, volume = {638}, number = {8050}, pages = {351-359}, pmid = {39939790}, issn = {1476-4687}, support = {R01 CA222833/CA/NCI NIH HHS/United States ; U24 HG012674/HG/NHGRI NIH HHS/United States ; UM1 HG012651/HG/NHGRI NIH HHS/United States ; UM1 HG012654/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; Alleles ; *Genome, Human/genetics ; *Genomics ; Phenotype ; }, abstract = {Recent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium's initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated-including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools-will be made available to the broader research community to facilitate deeper insights into human gene functions.}, }
@article {pmid39939524, year = {2025}, author = {Adil, M and Kolarova, TR and Doebley, AL and Chen, LA and Tobey, CL and Galipeau, P and Rosen, S and Yang, M and Colbert, B and Patton, RD and Persse, TW and Kawelo, E and Reichel, JB and Pritchard, CC and Akilesh, S and Lockwood, CM and Ha, G and Shree, R}, title = {Preeclampsia risk prediction from prenatal cell-free DNA screening.}, journal = {Nature medicine}, volume = {31}, number = {4}, pages = {1312-1318}, pmid = {39939524}, issn = {1546-170X}, support = {HL150169//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 GM007454/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; HD086620//U.S. Department of Health & Human Services | NIH | NICHD | National Center for Medical Rehabilitation Research (NCMRR)/ ; CA237746//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; K22 CA237746/CA/NCI NIH HHS/United States ; T32GM007454//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; DP2 CA280624/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; U01 HL152401/HL/NHLBI NIH HHS/United States ; K08 HL150169/HL/NHLBI NIH HHS/United States ; CA280624//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21 HD086620/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; *Pre-Eclampsia/genetics/diagnosis/blood ; Pregnancy ; *Cell-Free Nucleic Acids/genetics/blood ; Placenta/metabolism/pathology ; Adult ; Nucleosomes/metabolism/genetics ; *Prenatal Diagnosis/methods ; Whole Genome Sequencing ; ROC Curve ; Risk Factors ; }, abstract = {Preeclampsia is characterized by placental dysfunction and results in significant morbidity, but reliable early prediction remains challenging. We investigated whether clinically obtained prenatal cell-free DNA (cfDNA) screening (PDNAS) using whole-genome sequencing (WGS) data can be leveraged to predict preeclampsia risk early in pregnancy (≤16 weeks). Using 1,854 routinely collected clinical PDNAS samples (median, 12.1 weeks) with low-coverage (0.5×) WGS data, we developed a framework to quantify maternal and fetal tissue signatures using nucleosome accessibility, revealing early placental and endothelial dysfunction. These signatures informed a prediction model for preeclampsia risk, which achieved a validation performance of 0.85 area under the receiver operating characteristic curve (AUC) (81% sensitivity at 80% specificity) for preterm phenotypes several months prior to disease onset in a separate cohort of 831 consecutively collected samples, and subsequently confirmed in an external cohort of 141 samples (AUC 0.84, 79% sensitivity). We demonstrate that assessment of cfDNA nucleosome accessibility from early-pregnancy cfDNA sequence data enables the detection of early placental and endothelial-tissue aberrations and may aid in the determination of preeclampsia risk.}, }
@article {pmid39939078, year = {2025}, author = {Hsieh, RW and Symonds, LK and Siu, J and Cohen, SA}, title = {Identification of circulating tumor DNA as a biomarker for diagnosis and response to therapies in cancer patients.}, journal = {International review of cell and molecular biology}, volume = {391}, number = {}, pages = {43-93}, doi = {10.1016/bs.ircmb.2024.08.006}, pmid = {39939078}, issn = {1937-6448}, mesh = {Humans ; *Circulating Tumor DNA/blood/genetics ; *Neoplasms/diagnosis/therapy/genetics/blood ; *Biomarkers, Tumor/blood/genetics ; Treatment Outcome ; }, abstract = {The sampling of circulating biomarkers provides an opportunity for non-invasive evaluation and monitoring of cancer activity. In modern day practice, this has typically been in the form of circulating tumor DNA (ctDNA) detected in plasma. The field of ctDNA has been a burgeoning technology, with prominent applications for blood-based cancer screening and in disease status assessment, especially after curative-intent surgery to evaluate for minimal residual disease (MRD). Clinical applications for the latter show an incredibly high sensitivity in certain cancer types with a need for additional studies to determine how much clinical decision-making should be adapted based on ctDNA results and which cancer types, stages, and treatments are best informed by ctDNA results. This chapter provides an overview of ctDNA detection as tool for cancer screening, detecting MRD, and/or molecularly characterizing a cancer, highlighting the rapidly amassing research as a prognostic biomarker and emerging data on ctDNA as a predictive biomarker.}, }
@article {pmid39938471, year = {2025}, author = {Colevas, AD and Cmelak, AJ and Pfister, DG and Spencer, S and Adkins, D and Birkeland, AC and Brizel, DM and Busse, PM and Caudell, JJ and Durm, G and Fakhry, C and Galloway, T and Geiger, JL and Gillison, ML and Glastonbury, C and Haddad, RI and Hicks, WL and Hitchcock, YJ and Jimeno, A and Juloori, A and Kase, M and Leizman, D and Maghami, E and Mell, LK and Mittal, BB and Pinto, HA and Price, K and Rocco, JW and Rodriguez, CP and Schwartz, D and Shah, JP and Sher, D and John, MS and Wang, H and Weinstein, G and Worden, F and Bruce, JY and Yom, SS and Zhen, W and Montgomery, S and Darlow, SD}, title = {NCCN Guidelines® Insights: Head and Neck Cancers, Version 2.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {2}, pages = {2-11}, doi = {10.6004/jnccn.2025.0007}, pmid = {39938471}, issn = {1540-1413}, mesh = {Humans ; *Head and Neck Neoplasms/therapy/diagnosis/pathology ; Practice Guidelines as Topic ; Education, Medical, Continuing ; }, abstract = {The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.}, }
@article {pmid39938467, year = {2025}, author = {Inaba, H and Teachey, D and Annesley, C and Batra, S and Beck, J and Colace, S and Cooper, S and Dallas, M and Oliveira, S and Kelly, K and Kitko, C and Kohorst, M and Kutny, M and Lacayo, N and Lee-Miller, C and Ludwig, K and Madden, L and Maloney, K and Mangum, D and Massaro, S and McCall, D and Morocco, P and Muller, B and Murphy, L and Nardi, V and Rossoff, J and Schuettpelz, L and Shah, B and Sun, J and Wong, V and Yanik, G and Awotiwon, A and Stehman, K}, title = {Pediatric Acute Lymphoblastic Leukemia, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {2}, pages = {41-62}, doi = {10.6004/jnccn.2025.0006}, pmid = {39938467}, issn = {1540-1413}, mesh = {Humans ; Child ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/diagnosis/genetics ; *Medical Oncology/standards/methods ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.}, }
@article {pmid39938019, year = {2025}, author = {Chavez, JC and Dickinson, M and Munoz, J and Ulrickson, ML and Thieblemont, C and Oluwole, OO and Herrera, AF and Ujjani, CS and Lin, Y and Riedell, PA and Kekre, N and de Vos, S and Wulff, J and Williams, CM and Winters, J and Kloos, I and Xu, H and Neelapu, SS}, title = {Three-year follow-up analysis of first-line axicabtagene ciloleucel for high-risk large B-cell lymphoma: the ZUMA-12 study.}, journal = {Blood}, volume = {145}, number = {20}, pages = {2303-2311}, doi = {10.1182/blood.2024027347}, pmid = {39938019}, issn = {1528-0020}, mesh = {Humans ; Middle Aged ; Male ; Female ; Adult ; Follow-Up Studies ; *Immunotherapy, Adoptive/methods/adverse effects ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality ; Aged ; *Antigens, CD19/immunology/therapeutic use ; Receptors, Chimeric Antigen ; *Biological Products/therapeutic use ; Aged, 80 and over ; Young Adult ; *Tissue Extracts/therapeutic use/adverse effects ; }, abstract = {ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel-related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.}, }
@article {pmid39938007, year = {2025}, author = {Samples, L and Sadrzadeh, H and Frigault, MJ and Jacobson, CA and Hamadani, M and Gurumurthi, A and Strati, P and Shouval, R and Noy, A and Riedell, PA and Dahiya, S and Maloney, DG and Till, BG and Hirayama, AV and Gauthier, J and Gopal, AK and Smith, SD and Poh, C and Lynch, R and Ujjani, C and Di, M and Raghunathan, V and Shakib-Azar, M and Naresh, KN and Gooley, TA and Yared, J and Jain, MD and Locke, FL and Leslie, LA and Epperla, N and Ghosh, M and Skarbnik, A and Hill, BT and Kamdar, MK and Ortiz-Maldonado, V and Martinez-Cibrian, N and Shune, L and Shadman, M}, title = {Outcomes among adult recipients of CAR T-cell therapy for Burkitt lymphoma.}, journal = {Blood}, volume = {145}, number = {23}, pages = {2762-2767}, doi = {10.1182/blood.2024026831}, pmid = {39938007}, issn = {1528-0020}, mesh = {Humans ; *Burkitt Lymphoma/therapy/mortality/immunology ; *Immunotherapy, Adoptive/adverse effects/methods ; Adult ; Male ; Female ; Middle Aged ; Retrospective Studies ; Young Adult ; Aged ; *Receptors, Chimeric Antigen ; Adolescent ; Antigens, CD19/immunology ; Treatment Outcome ; Receptors, Antigen, T-Cell ; Cytokine Release Syndrome/etiology ; }, abstract = {Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that is associated with poor outcomes in patients with relapsed/refractory disease. This multicenter, retrospective study evaluated real-world CD19 chimeric antigen receptor (CAR) T-cell therapy outcomes in patients with relapsed/refractory BL using data abstracted from the medical records. In total, 31 patients received CAR T cells after a median of 3 previous therapies (range, 1-6). Patients received axicabtagene ciloleucel (n = 19), lisocabtagene maraleucel (n = 4), tisagenlecleucel (n = 4), or other agents (n = 4). Grade 1 to 2 cytokine release syndrome occurred in 83.9% of patients (grade ≥3, 65%), and grade 1 to 2 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 29% of patients (grade ≥3, 19.4%). The 28-day mortality rate was 16.1%, including 1 patient who died from grade 5 ICANS. The overall response rate at 1 month was 58.0% with a complete response (CR) rate of 41.9%; however, the 6-month CR rate was only 19.4%. The median progression-free survival was 2.3 months (95% confidence interval, 1.0-9.0), and the median overall survival was 6.0 months (95% confidence interval, 1.9-11.5). Three patients (9.7%) received consolidative allogeneic stem cell transplants, but all subsequently relapsed. In conclusion, CD19 CAR T-cell therapy infrequently delivers long-term disease control in BL. Further investigation is needed to determine the most effective alternative management strategy for these patients.}, }
@article {pmid39935960, year = {2025}, author = {Zane, GK and Barbee, LA and Duerr, A and Golden, MR and Manhart, LE and Dimitrov, D and Khosropour, C}, title = {High Incidence and Duration of Antibiotic Use Among a Cohort of Men Who Have Sex With Men in Seattle, Washington.}, journal = {Open forum infectious diseases}, volume = {12}, number = {2}, pages = {ofaf051}, pmid = {39935960}, issn = {2328-8957}, support = {K23 AI113185/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Doxycycline postexposure prophylaxis (doxy-PEP) effectively prevents bacterial sexually transmitted infections (STIs) but may increase antibiotic pressure. Little is known about longitudinal antibiotic use among men who have sex with men (MSM), a key population for doxy-PEP.
METHODS: We analyzed data from a prospective cohort of MSM in Seattle, Washington, from 2016 to 2018, prior to the introduction of doxy-PEP. Antibiotic use and reason for prescription were self-reported in weekly surveys and extracted from medical records. We characterized antibiotic use across 49 weeks of follow-up, stratified by specific antibiotics of interest and reasons for prescription. Incidence rates (IRs) were calculated for the number of incident events of antibiotic initiation per 100 person-years (PY) at risk. We assessed factors associated with antibiotic initiation using negative binomial regression to estimate adjusted incidence rate ratios (IRRs).
RESULTS: Among 140 participants, 68.6% (n = 96) received at least 1 antibiotic during follow-up, resulting in an overall IR of 264.5 events of antibiotic initiation per 100 PY and 1696 total days of antibiotic use. STI treatment was the most common reason for antibiotic initiation (IR, 153.5 events per 100 PY; 462 days); however, treatment for other conditions contributed most to overall days of antibiotic use (IR, 42.6 events per 100 PY; 947 days). An age of 25-39 years (IRR, 1.54 [95% confidence interval {CI}, 1.02-2.32]) and a history of bacterial STIs <12 months prior to enrollment (IRR, 1.81 [95% CI, 1.12-2.93]) were significantly associated with higher incidence of antibiotic initiation.
CONCLUSIONS: Antibiotic consumption among this population was very high. Our analysis provides a necessary foundation for assessing the potential impacts of doxy-PEP.}, }
@article {pmid39934055, year = {2025}, author = {Powles, T and Tagawa, S and Vulsteke, C and Gross-Goupil, M and Park, SH and Necchi, A and De Santis, M and Duran, I and Morales-Barrera, R and Guo, J and Sternberg, CN and Bellmunt, J and Goebell, PJ and Kovalenko, M and Boateng, F and Sierecki, M and Wang, L and Sima, CS and Waldes, J and Loriot, Y and Grivas, P}, title = {Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {5}, pages = {561-571}, doi = {10.1016/j.annonc.2025.01.011}, pmid = {39934055}, issn = {1569-8041}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage ; *Camptothecin/analogs & derivatives/adverse effects/therapeutic use/administration & dosage ; *Immunoconjugates/adverse effects/therapeutic use/administration & dosage ; *Carcinoma, Transitional Cell/drug therapy/pathology/mortality ; *Urologic Neoplasms/drug therapy/pathology/mortality ; Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged, 80 and over ; Paclitaxel/administration & dosage ; Progression-Free Survival ; Vinblastine/analogs & derivatives/administration & dosage ; Docetaxel/administration & dosage ; }, abstract = {BACKGROUND: Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, demonstrated efficacy and manageable toxicity in the phase II TROPHY-U-01 study in pretreated advanced urothelial carcinoma (aUC). We report the results from final analysis of the global open-label randomized phase III TROPiCS-04 study (NCT04527991) in pretreated aUC.
PATIENTS AND METHODS: Patients with aUC whose disease had progressed on prior platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1 : 1 to receive SG or treatment of physician's choice (TPC; paclitaxel, docetaxel, or vinflunine). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by investigator and blinded independent committee review, as well as safety.
RESULTS: Overall, 711 patients were randomized. After a median follow-up of 9.2 months, the primary endpoint was not met [median OS for SG versus TPC: 10.3 months versus 9.0 months, hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.02, P = 0.087]. Median PFS with SG and TPC was 4.2 months and 3.6 months, respectively (HR 0.86, 95% CI 0.72-1.03); ORR (95% CI) was 23% (18% to 27%) and 14% (10% to 18%). The most common grade ≥3 treatment-related adverse event (TRAE) with SG was neutropenia (35%, including 12% with febrile neutropenia). Incidence of grade ≥3 TRAEs (67% versus 35%) and grade 5 treatment-emergent adverse events (TEAEs; 7% versus 2%) was higher with SG versus TPC. In the SG group, 16/25 grade 5 TEAEs were infections with neutropenia mostly occurring early in the treatment course of patients with multiple risk factors for febrile neutropenia. Primary prophylactic granulocyte colony-stimulating factor (G-CSF) usage with SG and TPC was 21% and 22%, respectively.
CONCLUSIONS: SG did not result in a significant improvement in OS or PFS compared with TPC in pretreated aUC, although SG activity was demonstrated by a higher ORR. Early toxicity-related complications with SG may have impacted efficacy outcomes.}, }
@article {pmid39932777, year = {2025}, author = {Patel, SH and Colby, S and Sohal, D and Guthrie, KA and Kachnic, LA and Chiorean, EG and Lowy, AM and Rocha, FG and Hochster, HS and Philip, PA and Ahmad, SA}, title = {Chemotherapy dose density is prognostic for overall survival in patients with resectable pancreas cancer: A landmark analysis of SWOG 1505.}, journal = {Cancer}, volume = {131}, number = {4}, pages = {e35759}, pmid = {39932777}, issn = {1097-0142}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; U10CA180819/NH/NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/drug therapy/mortality/surgery/pathology ; Female ; Male ; Aged ; Middle Aged ; *Carcinoma, Pancreatic Ductal/drug therapy/surgery/mortality/pathology ; Prognosis ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/therapeutic use ; Adult ; Chemotherapy, Adjuvant ; }, abstract = {BACKGROUND: Chemotherapy is required to improve the overall survival (OS) of patients with resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose density (DD) on survival is difficult as a result of confounding. The objective of this study was to determine the impact of chemotherapy DD on OS in patients with resectable PDAC.
METHODS: This was a secondary analysis of SWOG 1505, a randomized phase 2 trial of perioperative chemotherapy in resectable PDAC. DD was defined as the percentage of chemotherapy dose received of the total planned. Two landmark time points for OS were used: after surgery and at 40 weeks (which encompassed the entire treatment period).
RESULTS: Of the 102 eligible patients enrolled, 73 (71%) underwent surgery, and median preoperative chemotherapy DD was 89%. Patients with ≥85% DD had higher OS compared to those with <85% DD (median, 38.1 vs. 17.2 months; p = .039). Of the 82 patients who survived to 40 weeks postrandomization, 67 underwent surgery, and median DD for all perioperative chemotherapy was 67%. In this cohort, DD ≥70% was associated with better OS (median, 32.2 vs. 14.0 months; p = .017). Perioperative DD was not significantly associated with pathologic response, margin status, or lymph node negativity.
CONCLUSIONS: This is the first study to identify a prognostic association of chemotherapy DD with OS in patients undergoing perioperative chemotherapy and surgery for resectable PDAC. Patients who received ≥85% DD preoperatively and/or ≥70% DD perioperatively survived longer than those receiving a smaller proportion of protocol therapy.}, }
@article {pmid39930085, year = {2025}, author = {Hoffmann, TJ and Graff, RE and Madduri, RK and Rodriguez, AA and Cario, CL and Feng, K and Jiang, Y and Wang, A and Klein, RJ and Pierce, BL and Eggener, S and Tong, L and Blot, W and Long, J and Goss, LB and Darst, BF and Rebbeck, T and Lachance, J and Andrews, C and Adebiyi, AO and Adusei, B and Aisuodionoe-Shadrach, OI and Fernandez, PW and Jalloh, M and Janivara, R and Chen, WC and Mensah, JE and Agalliu, I and Berndt, SI and Shelley, JP and Schaffer, K and Machiela, MJ and Freedman, ND and Huang, WY and Li, SA and Goodman, PJ and Till, C and Thompson, I and Lilja, H and Ranatunga, DK and Presti, J and Van Den Eeden, SK and Chanock, SJ and Mosley, JD and Conti, DV and Haiman, CA and Justice, AC and Kachuri, L and Witte, JS}, title = {Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups.}, journal = {Nature genetics}, volume = {57}, number = {2}, pages = {334-344}, pmid = {39930085}, issn = {1546-1718}, support = {RC2 AG036607/AG/NIA NIH HHS/United States ; OT2 OD026556/OD/NIH HHS/United States ; R01 CA241410/CA/NCI NIH HHS/United States ; P30 CA014599/CA/NCI NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; R01 CA244948/CA/NCI NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; U01 CA261339/CA/NCI NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; R00 CA246076/CA/NCI NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R01 CA175491/CA/NCI NIH HHS/United States ; U01 CA266535/CA/NCI NIH HHS/United States ; U01 CA184374/CA/NCI NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; R01 GM130791/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Humans ; Male ; Middle Aged ; Asian People/genetics ; Cohort Studies ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Hispanic or Latino/genetics ; Multifactorial Inheritance/genetics ; Polymorphism, Single Nucleotide/genetics ; *Prostate-Specific Antigen/genetics/blood ; *Prostatic Neoplasms/genetics/blood/ethnology ; White People/genetics ; Black People/genetics ; }, abstract = {We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10[-8]) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.}, }
@article {pmid39929823, year = {2025}, author = {Raeisi Dehkordi, S and Wong, IT and Ni, J and Luebeck, J and Zhu, K and Prasad, G and Krockenberger, L and Xu, G and Chowdhury, B and Rajkumar, U and Caplin, A and Muliaditan, D and Gnanasekar, A and Coruh, C and Jin, Q and Turner, K and Teo, SX and Pang, AWC and Alexandrov, LB and Chua, CEL and Furnari, FB and Maciejowski, J and Paulson, TG and Law, JA and Chang, HY and Yue, F and DasGupta, R and Zhao, J and Mischel, PS and Bafna, V}, title = {Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1497}, pmid = {39929823}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U24 CA264379/CA/NCI NIH HHS/United States ; P50 CA168504/CA/NCI NIH HHS/United States ; R35 CA210057/CA/NCI NIH HHS/United States ; OT2 CA278635/CA/NCI NIH HHS/United States ; R01 GM114362/GM/NIGMS NIH HHS/United States ; OT2 CA278688/CA/NCI NIH HHS/United States ; P01 CA091955/CA/NCI NIH HHS/United States ; CGCATF-2021/100025//Cancer Research UK (CRUK)/ ; }, mesh = {Humans ; *Oncogenes/genetics ; *Gene Amplification ; Cell Line, Tumor ; Animals ; *Neoplasms/genetics/pathology ; Mice ; Algorithms ; Whole Genome Sequencing ; *Genetic Heterogeneity ; }, abstract = {Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remains poorly understood due to detection challenges with DNA sequencing. We introduce an algorithm, OM2BFB, designed to detect and reconstruct BFB amplifications using optical genome mapping (OGM). OM2BFB demonstrates high precision (>93%) and recall (92%) in identifying BFB amplifications across cancer cell lines, patient-derived xenograft models, and primary tumors. Comparisons using OGM reveal that BFB detection with our AmpliconSuite toolkit for short-read sequencing also achieves high precision, though with reduced sensitivity. We identify 371 BFB events through whole genome sequencing of 2557 primary tumors and cancer cell lines. BFB amplifications are prevalent in cervical, head and neck, lung, and esophageal cancers, but rare in brain cancers. Genes amplified through BFB exhibit lower expression variance, with limited potential for regulatory adaptation compared to ecDNA-amplified genes. Tumors with BFB amplifications (BFB(+)) show reduced structural heterogeneity in amplicons and delayed resistance onset relative to ecDNA(+) tumors. These findings highlight ecDNA and BFB amplifications as distinct oncogene amplification mechanisms with differing biological characteristics, suggesting distinct avenues for therapeutic intervention.}, }
@article {pmid39928955, year = {2025}, author = {Petty, NE and Radtke, S and Kanestrom, G and Fields, E and Humbert, O and Fiorenza, S and Llewellyn, MJ and Laszlo, GS and Thomas, J and Burger, Z and Swing, K and Zhu, H and Jerome, KR and Turtle, CJ and Walter, RB and Kiem, HP}, title = {Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in rhesus macaques.}, journal = {Blood advances}, volume = {9}, number = {10}, pages = {2367-2378}, pmid = {39928955}, issn = {2473-9537}, mesh = {Animals ; Macaca mulatta ; *Hematopoietic Stem Cells/metabolism/cytology/immunology ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism/immunology ; *Hematopoietic Stem Cell Transplantation ; *T-Lymphocytes/metabolism/immunology ; *Receptors, Chimeric Antigen/metabolism/genetics/immunology ; Gene Editing ; Humans ; *Immunotherapy, Adoptive/methods ; }, abstract = {The treatment of monogenetic disorders, such as hemoglobinopathies and lysosomal storage diseases, has markedly improved with the advent of cell and gene therapies, particularly allogeneic or gene-modified autologous stem cell transplantations. However, therapeutic efficacy is reliant on maintaining engraftment above a critical threshold. To maintain such engraftment levels, we and others have pursued approaches to shield edited cells from antibody or chimeric antigen receptor (CAR) T-cell-mediated selection. Here, we focused on CD33, which is expressed early on hematopoietic stem and progenitor cells (HSPCs) as well as on myeloid progenitors. Rhesus macaques were engrafted with HSPCs edited to ablate CD33 using either CRISPR/CRISPR-associated protein 9 or adenine base editor. Both editing strategies showed similar post-transplant recovery kinetics and yielded equivalent levels of engraftment. We then created a V-set domain-specific CAR construct (CAR33), validated its functionality in vitro, and treated both animals with autologous CAR33 T cells. CAR33 T cells expanded after infusion and caused specific depletion of CD33WT but not CD33null progeny, leading to a transient enrichment for gene-edited cells in the blood. No depletion was seen in the bone marrow stem cell compartment with CD34+CD90+ HSCs expressing lower levels of CD33 in comparison to monocytes. Thus, we show proof of concept and safety of an epitope editing-based enrichment/protection strategy in macaques.}, }
@article {pmid39928141, year = {2025}, author = {Papadopoulos, A and Kyriakou, I and Matsuya, Y and Cortés-Giraldo, MA and Galocha-Oliva, M and Plante, I and Stewart, RD and Tran, NH and Li, W and Daglis, IA and Santin, G and Nieminen, P and Incerti, S and Emfietzoglou, D}, title = {Analytic and Monte Carlo calculations of dose-mean lineal energy for 1 MeV-1 GeV protons with application to radiation protection quality factor.}, journal = {Radiation and environmental biophysics}, volume = {64}, number = {1}, pages = {117-135}, pmid = {39928141}, issn = {1432-2099}, support = {4000132935/21/NL/CRS//European Space Agency (ESA)/ ; }, mesh = {*Monte Carlo Method ; *Protons ; *Radiation Dosage ; *Radiation Protection ; Radiometry ; }, abstract = {Radiation quality for determining biological effects is commonly linked to the microdosimetric quantity lineal energy (y) and to the dose-mean lineal energy (y D). Calculations of y D are typically performed by specialised Monte Carlo track-structure (MCTS) codes, which can be time-intensive. Thus, microdosimetry-based analytic models are potentially useful for practical calculations. Analytic model calculations of proton y D and radiation protection quality factor (Q) values in sub-micron liquid water spheres (diameter 10-1000 nm) over a broad energy range (1 MeV-1 GeV) are compared against MCTS simulations by PHITS, RITRACKS, and Geant4-DNA. Additionally, an improved analytic microdosimetry model is proposed. The original analytic model of Xapsos is refined and model parameters are updated based on Geant4-DNA physics model. Direct proton energy deposition is described by an alternative energy-loss straggling distribution and the contribution of secondary electrons is calculated using the dielectric formulation of the relativistic Born approximation. MCTS simulations of proton y D values using the latest versions of the PHITS, RITRACKS, and Geant4-DNA are reported along with the Monte Carlo Damage Simulation (MCDS) algorithm. The y D datasets are then used within the Theory of Dual Radiation Action (TDRA) to illustrate variations in Q with proton energy. By a careful selection of parameters, overall differences at the ~ 10% level between the proposed analytic model and the MCTS codes can be attained, significantly improving upon existing models. MCDS estimates of y D are generally much lower than estimates from MCTS simulations. The differences of Q among the examined methods are somewhat smaller than those of y D . Still, estimates of proton Q values by the present model are in better agreement with MCTS-based estimates than the existing analytic models. An improved microdosimetry-based analytic model is presented for calculating proton y D values over a broad range of proton energies (1 MeV-1 GeV) and target sizes (10-1000 nm) in very good agreement with state-of-the-art MCTS simulations. It is envisioned that the proposed model might be used as an alternative to CPU-intensive MCTS simulations and advance practical microdosimetry and quality factor calculations in medical, accelerator, and space radiation applications.}, }
@article {pmid39927451, year = {2025}, author = {Sears, E and Dahlquist, J and Stayman, S and Ko, C and Konnick, EQ and Cole, A and Zhang, Y and Kohn, M and Henderson, V and Knerr, S}, title = {Feasibility of using patient navigation to improve identification of hereditary cancer syndromes in newly diagnosed patients with colorectal cancer.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {27}, number = {5}, pages = {101372}, doi = {10.1016/j.gim.2025.101372}, pmid = {39927451}, issn = {1530-0366}, mesh = {Humans ; *Colorectal Neoplasms/genetics/diagnosis ; *Patient Navigation ; Genetic Testing/methods ; *Neoplastic Syndromes, Hereditary/diagnosis/genetics ; Feasibility Studies ; Genetic Counseling ; Genetic Predisposition to Disease ; }, abstract = {PURPOSE: Germline genetic testing to identify hereditary cancer syndromes in patients newly diagnosed with colorectal cancer (CRC) carries substantial benefits. We examined the feasibility of using patient navigation, an evidence-based approach to reduce structural barriers to recommended care, to improve test completion by increasing pretest counseling attendance.
METHODS: We conducted key informant interviews with representatives from organizations providing cancer care to CRC patients. Interviews included questions derived from the Consolidated Framework for Implementation Research, which delineates barriers and facilitators to implementing evidence-based practices. We used an inductive-deductive coding approach to identify themes related to program feasibility.
RESULTS: We interviewed 19 participants across 13 organizations. Key feasibility barriers included funding to implement and sustain a navigation program, staffing and supervising the navigator role, health information technology needs, gaining administrators' buy-in, and evolving genetic service delivery models. Participants suggested multiple strategies to address implementation barriers, but most would prefer other approaches to improve genetic test completion over implementing a genomics-focused patient navigation program.
CONCLUSION: Stakeholders across a range of health care organizations saw limited value in improving the identification of hereditary CRC syndromes by implementing a program designed to increase pretest genetic counseling attendance. The need to scale up genetic testing has shifted interest toward delivery models better integrated in established care pathways, requiring fewer resources and providing broader reach.}, }
@article {pmid39926260, year = {2025}, author = {Wu, X and Lazris, D and Wong, R and Tykodi, SS}, title = {Belzutifan for the treatment of renal cell carcinoma.}, journal = {Therapeutic advances in medical oncology}, volume = {17}, number = {}, pages = {17588359251317846}, pmid = {39926260}, issn = {1758-8340}, abstract = {Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. It is the first FDA-approved drug to target hypoxia-inducible factor 2 alpha (HIF-2α). By inhibiting the HIF-2α transcription factor, belzutifan prevents HIF-2α from dimerizing with HIF-1β, thereby preventing the transcription of downstream oncogenes. Most clear cell renal cell carcinoma (ccRCC) tumors are associated with VHL deletion or inactivation resulting in HIF-2α overexpression that represents a key contributor to tumorigenesis, thereby making belzutifan a uniquely optimal drug for targeting ccRCC. Belzutifan has demonstrated activity in clinical trials as a front- and later-line therapy, and in combination with tyrosine kinase inhibitors. It has been largely well tolerated, although anemia represents a common on-target side effect and, along with hypoxia, requires monitoring during treatment. Ongoing phase III trials are investigating belzutifan in combination regimens in the relapsed/refractory, front-line, and adjuvant settings. Future studies will focus on identifying predictive biomarkers and resistance pathways.}, }
@article {pmid39925467, year = {2025}, author = {Mediano, MFF and Mok, Y and Ballew, SH and Gonzalez, F and Sotres-Alvarez, D and Mossavar-Rahmani, Y and Kaplan, R and Carlson, JA and Alver, SK and Daviglus, M and Garcia-Bedoya, O and Evenson, KR and Schrack, JA and Matsushita, K}, title = {The association of physical activity fragmentation with all-cause mortality in Hispanics: a prospective cohort study.}, journal = {Lancet regional health. Americas}, volume = {42}, number = {}, pages = {100996}, pmid = {39925467}, issn = {2667-193X}, support = {R01 HL146132/HL/NHLBI NIH HHS/United States ; HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HG/NHGRI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Physical activity fragmentation represents the frequency of transitioning from an active to sedentary state. The prognostic information of physical activity fragmentation is unclear in Hispanics/Latinos. This study examined the association of PA fragmentation with all-cause mortality in Hispanic/Latino adults.
METHODS: We investigated 11,992 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (18-74 yr; 52.2% women), from four United States urban communities (Bronx, New York; Chicago, Illinois; Miami, Florida; San Diego, California), that wore an accelerometer for one week. Physical activity fragmentation was calculated using the active-to-sedentary transition probability (ASTP) as the reciprocal of the average active bout duration. Daily total log-transformed activity count (TLAC) was used as a measure of total physical activity. The residual of ASTP regressed on TLAC (TLAC-adjusted ASTP) was explored to investigate the association of ASTP independent of total physical activity. Deaths were identified from annual follow-up interviews, obituary searches, or matches to the National Death Index through December 31, 2021. Cox regression models were fitted according to physical activity fragmentation.
FINDINGS: There were 745 deaths (6.2%) over a mean follow-up of 11.2 (SD 2.2) years. The highest compared to the lowest tertile of ASTP showed a HR of 1.45 (95% CI 1.10-1.92) of all-cause mortality after accounting for confounders. The mortality risk also increased for each 0.10-unit increase of ASTP, as a continuous variable, by 22% (HR 1.22; 95% CI 1.07-1.39). The results were similar considering TLAC-adjusted ASTP.
INTERPRETATION: Among Hispanic/Latino adults, more fragmented physical activity was associated with elevated all-cause mortality, independent of total physical activity volume.
FUNDING: HCHS/SOL was supported by the National Institutes of Health.}, }
@article {pmid39925094, year = {2025}, author = {Bovee, LB and Gooley, TA and Perlman, JE and Hirsch, IB}, title = {The Role of a Continuous Glucose Monitoring-Derived Glycation Ratio in the Development of Microvascular Complications.}, journal = {Diabetes technology & therapeutics}, volume = {27}, number = {7}, pages = {553-557}, doi = {10.1089/dia.2024.0580}, pmid = {39925094}, issn = {1557-8593}, mesh = {Humans ; Middle Aged ; Retrospective Studies ; Male ; Female ; *Glycated Hemoglobin/metabolism/analysis ; *Diabetic Retinopathy/blood/epidemiology ; *Blood Glucose/metabolism/analysis ; *Diabetic Nephropathies/blood/epidemiology/etiology ; Adult ; Blood Glucose Self-Monitoring ; *Diabetic Angiopathies/blood ; *Diabetes Mellitus, Type 2/blood/complications ; *Diabetes Mellitus, Type 1/blood/complications ; Aged ; Glycosylation ; Logistic Models ; Continuous Glucose Monitoring ; }, abstract = {Background: Previous studies have evaluated the associations between HbA1c discordance and diabetes complications using indices of glycation. The ideal index would allow for identification of those at increased risk for microvascular complications. This analysis evaluates the association of a newly published index, the glycation ratio (GR), with diabetic retinopathy (DR) and diabetic kidney disease (DKD). Methods: This is a retrospective review of 661 patients with diabetes seen at the University of Washington. All patients used continuous glucose monitoring (CGM) before the study. Diabetes duration was greater than 20 years in 59%. Median age was 45 years. GR was defined as the ratio of the glucose management indicator (GMI) to the HbA1c. The associations of GR with microvascular complications were each assessed using logistic regression. Results: Modeling GR as a continuous linear variable, each increase in GR of 0.20 units was associated with a 38% relative reduction in the odds of DR (adjusted odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.45-0.86, P = 0.004] and a similar reduction in the odds of DKD (OR = 0.61; 95% CI: 0.41-0.93, P = 0.02). Conclusions: GR may be a useful marker for risk of diabetic microvascular complications. Longitudinal assessment will be required to see how well GR compares with GMI or HbA1c alone.}, }
@article {pmid39924630, year = {2025}, author = {Daniel, LC and Lubas, MM and Wang, H and Szklo-Coxe, M and Ness, KK and Williams, AM and Mulrooney, DA and Howell, R and Leisenring, W and Yasui, Y and Robison, LL and Armstrong, GT and Chow, EJ and Krull, KR and Brinkman, TM}, title = {Frailty and Sleep in Adult Survivors of Childhood Cancer: A Childhood Cancer Survivor Study Report.}, journal = {Psycho-oncology}, volume = {34}, number = {2}, pages = {e70098}, pmid = {39924630}, issn = {1099-1611}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; //St. Jude Children's Research Hospital/ ; //American Lebanese Syrian Associated Charities/ ; }, mesh = {Humans ; *Cancer Survivors/statistics & numerical data/psychology ; Male ; Female ; Adult ; *Neoplasms/epidemiology ; *Sleep Wake Disorders/epidemiology ; *Frailty/epidemiology ; Middle Aged ; *Sleep Quality ; Young Adult ; Child ; }, abstract = {BACKGROUND: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.
AIMS: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.
METHODS: This study utilized data from 9044 participants (> 5 years from diagnosis, Mage = 40.8 years [SD = 9.5]) in the Childhood Cancer Survivor Study. Survivors' frailty status, chronic health conditions (CHC), health behaviors, mental health, and pain were collected in 2014-2016, and self-reported sleep quality in 2017-2019. Multivariable logistic regression models examined frailty status as a predictor of clinically significant poor sleep. All models were adjusted for age at diagnosis, age at survey, sex, race/ethnicity, smoking, risky/heavy alcohol use, and physical inactivity. Separate models included treatment-related variables, CHC burden (number/severity), and emotional health/pain as co-variates.
RESULTS: Frail survivors had 6-fold (95% CI 4.48-7.96) increased odds of future poor sleep quality. Little attenuation of this association was observed when accounting for cancer diagnosis (Odds Ratio [OR] 5.80, 95% CI 4.47-7.52), treatment exposures (OR 5.80, 95% CI 4.43-7.71), or chronic health condition burden (OR 5.12, 95% CI 3.98-6.59), but adjustment for emotional health/pain (OR 2.88, 95% CI 2.18-3.82) attenuated the association appreciably.
CONCLUSIONS: Frail childhood cancer survivors have a higher prevalence of clinically significant poor sleep quality. Addressing poor physiologic reserve may impact sleep in frail childhood cancer survivors.}, }
@article {pmid39924174, year = {2025}, author = {Landsburg, DJ and Frigault, MJ and Heim, M and Foley, SR and Hill, B and Schofield, G and Jacobson, CA and Jaglowski, S and Locke, FL and Ram, R and Riedell, PA and Shah, G and Popplewell, LL and Tiwari, R and Lim, S and Majdan, M and Masood, A and Pasquini, M and Turtle, CJ}, title = {Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {2}, pages = {}, pmid = {39924174}, issn = {2051-1426}, support = {R01 AI158861/AI/NIAID NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; U01 AI126612/AI/NIAID NIH HHS/United States ; U24 HL157560/HL/NHLBI NIH HHS/United States ; R01 HL155741/HL/NHLBI NIH HHS/United States ; U01 HL128568/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; R01 AI150999/AI/NIAID NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 CA152108/CA/NCI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; R01 CA231141/CA/NCI NIH HHS/United States ; UM1 CA121947/CA/NCI NIH HHS/United States ; U24 CA233032/CA/NCI NIH HHS/United States ; R01 CA262899/CA/NCI NIH HHS/United States ; R01 HL131731/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Registries ; Adult ; Aged ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/mortality ; *Receptors, Antigen, T-Cell/therapeutic use ; Treatment Outcome ; Young Adult ; *Immunotherapy, Adoptive/methods ; Adolescent ; }, abstract = {BACKGROUND: Tisagenlecleucel, a CD19 chimeric antigen receptor T-cell therapy, is approved for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) after ≥2 lines of therapy. When used in real-world settings, tisagenlecleucel has shown similar efficacy and improved safety compared with previous clinical trials. However, long-term data on real-world outcomes are lacking.
METHODS: Clinical data from a cohort of patients treated with tisagenlecleucel in a real-world setting were captured in the Center for International Blood and Marrow Transplant Research registry. The main clinical outcomes analysed included response rate, duration of response, survival, adverse events and clinicopathologic and treatment characteristics that may affect those outcomes.
RESULTS: As of May 2022, 1159 patients with R/R DLBCL/HGBCL received tisagenlecleucel. The overall response rate was 59.5%, and the complete response rate was 44.5%. With a median follow-up of 23.2 months in the efficacy set (n=968), the 24 month rates of progression-free survival, ongoing response and overall survival were 28.4%, 52.6% and 43.6%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 6% and 7.4% of patients, respectively. Patients with DLBCL (vs HGBCL), complete response before infusion, prior autologous or allogeneic haematopoietic stem cell transplant and lactate dehydrogenase (LDH) within normal limits experienced more favourable efficacy outcomes, and those with Eastern Cooperative Oncology Group performance status of ≥2, ≥3 prior lines of therapy, elevated LDH and fludarabine-based lymphodepleting chemotherapy experienced less favourable safety outcomes.
CONCLUSIONS: This real-world study of tisagenlecleucel for patients with R/R DLBCL/HGBCL shows consistent efficacy and better safety outcomes than the pivotal trial. This study also identifies baseline disease characteristics and prior or concurrent treatments that may affect clinical outcomes.Tisagenlecleucel, a CD19 chimeric antigen receptor T-cell therapy, is approved for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) after ≥2 lines of therapy. When used in real-world settings, tisagenlecleucel has shown similar efficacy and improved safety compared with previous clinical trials. However, long-term data on real-world outcomes are lacking.Clinical data from a cohort of patients treated with tisagenlecleucel in a real-world setting were captured in the Center for International Blood and Marrow Transplant Research registry. The main clinical outcomes analysed included response rate, duration of response, survival, adverse events, and clinicopathologic and treatment characteristics that may affect those outcomes.As of May 2022, 1159 patients with R/R DLBCL/HGBCL received tisagenlecleucel. The overall response rate was 59.5%, and the complete response rate was 44.5%. With a median follow-up of 23.2 months in the efficacy set (n=968), the 24 month rates of progression-free survival, ongoing response, and overall survival were 28.4%, 52.6%, and 43.6%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 6% and 7.4% of patients, respectively. Patients with DLBCL (vs HGBCL), complete response before infusion, prior autologous or allogeneic haematopoietic stem cell transplant, and lactate dehydrogenase (LDH) within normal limits experienced more favourable efficacy outcomes, and those with Eastern Cooperative Oncology Group performance status ≥2, ≥3 prior lines of therapy, elevated LDH, and fludarabine-based lymphodepleting chemotherapy experienced less favourable safety outcomes.In conclusion, this real-world study of tisagenlecleucel for patients with R/R DLBCL/HGBCL shows consistent efficacy and better safety outcomes than the pivotal trial. This study also identifies baseline disease characteristics and prior or concurrent treatments that may affect clinical outcomes.}, }
@article {pmid39923937, year = {2025}, author = {El Jurdi, N and Hamilton, BK and Pidala, JA and Onstad, L and Mun, C and Jain, S and Lee, SJ}, title = {Longitudinal Tear Cytokine Biomarkers: An Analysis from the Close Assessment and Testing for Chronic Graft-Versus-Host Disease (CATCH) Protocol.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {4}, pages = {226.e1-226.e9}, pmid = {39923937}, issn = {2666-6367}, support = {U01 CA118953/CA/NCI NIH HHS/United States ; U01 CA236229/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Biomarkers/metabolism ; Chronic Disease ; *Cytokines/metabolism ; *Graft vs Host Disease/diagnosis/metabolism/etiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Longitudinal Studies ; *Tears/metabolism ; Prospective Studies ; }, abstract = {BACKGROUND: Ocular graft-versus-host disease (oGVHD) is one of the most common initial manifestations of chronic GVHD (cGVHD) leading to significant morbidity and reduced quality of life. Early detection of oGVHD using susceptibility/risk biomarkers is urgently needed to enable preemptive therapy.
OBJECTIVES: In this subset analysis of patients enrolled on the CATCH Study (NCT04188912), we tested whether changes in tear film cytokines or ocular symptoms, as assessed by the Lee symptom scale (LSS) eye subscale, can predict oGVHD onset.
STUDY DESIGN: LSS eye subscores, Inflammadry (MMP9) and conjunctival washing samples were collected before hematopoietic cell transplantation (HCT) and every 2 months (mos) until 12 mos. A custom-designed 13-plex human cytokine magnetic bead panel was used to measure: IL-10, IL-17A, IL-1Ra, IL-1α, ELA2, IL-1β, LIGHT/TNFSF14, NGAL, OSM, IL-8, IP-10, TNF-α, and VEGF-A. Cytokine levels at the pre-HCT visit were compared across the groups using the Kruskal-Wallis test. Fold change (FC) of the cytokines, defined as post-HCT value divided by pre-HCT value, was calculated and FC ≥ 2 was used in further analyses. oGVHD diagnosis was based on the NIH diagnostic criteria and having an eye score ≥1. Cox regression models were used to examine the longitudinal relationships between potential predictors and oGVHD development.
RESULTS: Of the 44 patients included, 18 developed oGVHD, 11 had cGVHD without oGVHD, and 15 did not have any cGVHD. Median age was 64.5 years, median time from HCT to cGVHD was 6.4 mos and to oGVHD was 8.3 mos. There were no significant differences in baseline cytokine levels among groups. None of the tear cytokines or the InflammaDry MMP9 test predicted oGVHD onset. Clinically meaningful change in LSS eye score was associated with subsequent oGVHD development when compared to cGVHD without eye involvement (HR 2.5, 95% CI 1.2-5.1, P = .01); and when compared to controls (HR 3.0, 95% CI 1.4-6.0, P = .004) but the PPV of LSS change ≥15 points was low (27.6%), with a higher NPV (89.4%).
CONCLUSIONS: This is the first prospective longitudinal study of tear cytokines and symptoms in a cohort of patients observed closely through HCT for development of cGVHD. We were not able to identify any biological susceptibility/risk markers for oGVHD. Patient-reported symptoms as measured by the LSS are associated with oGVHD development but the low PPV and overlap with diagnostic criteria limit its usefulness as a biomarker to guide preemptive treatment studies.}, }
@article {pmid39923936, year = {2025}, author = {Douglas, AP and Lamoth, F and John, TM and Groll, AH and Shigle, TL and Papanicolaou, GA and Chemaly, RF and Carpenter, PA and Dadwal, SS and Walsh, TJ and Kontoyiannis, DP}, title = {American Society of Transplantation and Cellular Therapy Series: #8-Management and Prevention of Non-Aspergillus Molds in Hematopoietic Cell Transplantation Recipients.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {4}, pages = {194-223}, doi = {10.1016/j.jtct.2025.01.892}, pmid = {39923936}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Mycoses/prevention & control/etiology ; Risk Factors ; Antifungal Agents/therapeutic use ; *Cell- and Tissue-Based Therapy ; *Fungi ; United States ; }, abstract = {The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to create a guideline focusing on non-Aspergillus invasive molds, which are uncommon yet lethal invasive fungal diseases in the peri-hematopoietic cell transplant (HCT) period. We used a compendium-style approach by dissecting this broad, heterogeneous, and highly complex topic into a series of standalone frequently asked questions (FAQs) and tables. Adult and pediatric infectious diseases and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations. All the evidence for non-Aspergillus invasive mold infection is non-RCT and mostly level III, therefore there are no recommendation grades, and instead key references are provided. Through this format, this "8th" topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to rare mold infections in the pre- and post-transplant periods.}, }
@article {pmid39921591, year = {2025}, author = {Schleicher, TK and Cohen, M and Graf, SA}, title = {The preclinical discovery and development of zanubrutinib for the treatment of chronic lymphocytic leukemia.}, journal = {Expert opinion on drug discovery}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/17460441.2025.2465365}, pmid = {39921591}, issn = {1746-045X}, abstract = {INTRODUCTION: The history of treating chronic lymphocytic leukemia (CLL) inflected in 2014 with the Food and Drug Administration's (FDA) approval of ibrutinib, the first-in-class small molecule inhibitor of the Bruton's tyrosine kinase (BTK). Zanubrutinib is a 2[nd] generation covalent BTK inhibitor developed and manufactured by BeiGene.
AREAS COVERED: In this review, the authors trace the arc of zanubrutinib development from the preclinical phase through the two landmark phase 3 studies in the CLL space, ALPINE and SEQUOIA. The authors cover contemporary management strategies in CLL and highlight the areas of need that zanubrutinib was designed to mitigate.
EXPERT OPINION: Zanubrutinib entered a fray of novel, exciting therapies for CLL. As the second of two 2[nd] generation covalent BTK inhibitors its path to prominence in CLL management was narrow. Emphasis during development on kinase selectivity and enhanced bioavailability identified a molecule with superior efficacy and tolerability; hierarchical endpoints in trial design allowed for efficient acquisition of comparative data. Zanubrutinib is endorsed by the National Comprehensive Cancer Network as a preferred, category 1 recommended treatment choice for CLL. Future efforts in combination therapies and response-directed treatment breaks will hopefully lead to still further improvements in use.}, }
@article {pmid39921375, year = {2025}, author = {Olivieri, DJ and Gopal, AK and Uldrick, TS and Menon, MP}, title = {Exclusion of People Living with HIV in Aggressive B-Cell Non-Hodgkin Lymphoma Studies: A Cross-Sectional Analysis of Clinical Trials from 2014 to 2024.}, journal = {Cancer investigation}, volume = {43}, number = {2}, pages = {141-148}, doi = {10.1080/07357907.2025.2462568}, pmid = {39921375}, issn = {1532-4192}, mesh = {Humans ; *HIV Infections/complications/epidemiology ; *Clinical Trials as Topic/statistics & numerical data ; Cross-Sectional Studies ; *Lymphoma, B-Cell/therapy ; *Patient Selection ; United States ; }, abstract = {BACKGROUND: Human immunodeficiency virus is associated with the development of various aggressive non-Hodgkin B-cell lymphomas (NHL). Despite this, people living with HIV (PLWH) are often excluded from clinical trials. Here we analyze the change in clinical trial exclusion among PLWH resulting from multilateral advocacy efforts since 2017.
METHODS: We identified all US-based clinical trials with the keyword "lymphoma" with start dates between January 01, 2014 and January 04, 2025 using the publicly available NIH Clinical Trial Database (https://www.clinicaltrials.gov/). All studies with aggressive B-cell NHL subtypes were included. Regression models were performed to analyze descriptive factors.
RESULTS: 1,973 US-based clinical trials were captured, of which 945 met criteria for further analysis. PLWH were excluded from 59% pre-2018 versus 48% post-2018. After multivariate adjustment, NIH-funded trials (24% exclusion rate, p < 0.001), other funders (64% exclusion rate), and studies initiated post-2018 (48% exclusion rate, p < 0.001) were associated with inclusion, while CAR-T-related studies (62% exclusion rate, p < 0.05) were associated with exclusion.
CONCLUSIONS: Likely partly due to advocacy from ASCO, NCI, and NCCN, there was a significant decrease in exclusion among PLWH in US-based NHL clinical trials. Future research should analyze the safety and efficacy of immunotherapy in PLWH to foster inclusion and reduce stigma among physicians and researchers.}, }
@article {pmid39921208, year = {2025}, author = {Alkhunaizi, M and Soto-Lanza, F and Leung, CH and Bhan, N and Bashoura, L and Dickey, BF and Sharifi, H and Cheng, GS and Yanik, GA and Rondon, G and Saliba, R and Chen, G and Al-Atrash, G and Hosing, C and Kebriaei, P and Popat, UR and Shpall, EJ and Champlin, RE and Li, L and Alousi, AM and Sheshadri, A}, title = {Restrictive Ventilatory Defects Following Hematopoietic Stem Cell Transplant Are Associated With Increased Mortality.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {4}, pages = {255.e1-255.e10}, doi = {10.1016/j.jtct.2025.02.001}, pmid = {39921208}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/mortality ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; *Hematologic Neoplasms/therapy/mortality ; Graft vs Host Disease/etiology/mortality ; Young Adult ; }, abstract = {INTRODUCTION: Hematopoietic cell transplantation (HCT) can potentially cure hematologic malignancies, but despite advancements in HCT regimens and graft-versus-host disease (GVHD) management, post-HCT complications, remain a major challenge. The epidemiology of post-HCT pulmonary impairment causing restrictive ventilatory defect (RVD) has not been examined. This study investigates the incidence, etiology, and impact of new-onset RVD following HCT on overall survival (OS) and non-relapse mortality (NRM).
METHODS: We conducted a retrospective review of adult patients who underwent their first allogeneic HCT for primary hematologic malignancies at The University of Texas MD Anderson Cancer Center between February 1999 and March 2018. RVD was defined by a total lung capacity (TLC) <5th percentile of the lower limit of normal. Patient data were analyzed using the Kaplan-Meier method, log-rank tests, and Cox regression models.
RESULTS: Among 3030 patients, 50 had pre-HCT RVD and 1275 developed new pulmonary impairment post-HCT, of which, we found 270 cases of new-onset RVD. The most common causes of post-HCT RVD were respiratory tract infections (23%), interstitial lung disease (15%) and truncal sclerosis (11%). Multivariate analysis indicated increased age (HR 1.03 per year, 95% CI 1.03-1.04, P < .001), matched unrelated donor transplant (HR 1.29, 95% CI 1.04-1.60, P = .02), mismatched related transplant (HR 2.04, 95% CI 1.33-3.14, P = .001), cord blood stem cell source (HR 3.02, 95% CI 2.26-4.05, P < .001), RVD (HR 2.27, 95% CI 1.77-2.90, P < .001) and cGVHD (HR 1.72, 95% CI 1.44-2.05, P < .001) were associated with higher mortality. More severe restriction (HR 4.04, 95% CI 2.83-5.77, P < .001), progressive RVD (5.04, 95% CI 1.88-13.52, P = .001), and RVD onset within 1 year of HCT (HR 2.61, 95% CI 1.72-3.98, P < .001) were associated with higher mortality.
CONCLUSION: New-onset RVD post-HCT is associated with increased mortality. These findings emphasize the importance of identifying RVD through proactive pulmonary function monitoring to improve post-HCT outcomes.}, }
@article {pmid39921094, year = {2025}, author = {Nagle, CM and Ibiebele, TI and Na, R and Bandera, EV and Cramer, D and Doherty, JA and Giles, GG and Goodman, MT and Hanley, GE and Harris, HR and Jensen, A and Kjaer, SK and Lee, A and McGuire, V and Milne, RL and Qin, B and Richardson, J and Sasamoto, N and Schildkraut, JM and Sieh, W and Terry, KL and Titus, L and Trabert, B and Wentzensen, N and Wu, AH and Berchuck, A and Pike, MC and Pearce, CL and Webb, PM and , }, title = {Diet and survival after a diagnosis of ovarian cancer: a pooled analysis from the Ovarian Cancer Association Consortium.}, journal = {The American journal of clinical nutrition}, volume = {121}, number = {4}, pages = {758-768}, pmid = {39921094}, issn = {1938-3207}, mesh = {Humans ; Female ; *Ovarian Neoplasms/mortality/diagnosis ; Middle Aged ; *Diet ; Aged ; Proportional Hazards Models ; Diet, Healthy ; }, abstract = {BACKGROUND: Prognosis after a diagnosis of invasive epithelial ovarian cancer is poor. Some studies have suggested modifiable behaviors, like diet, are associated with survival but the evidence is inconsistent.
OBJECTIVES: This study aims to pool data from studies conducted around the world to evaluate the relationships among dietary indices, foods, and nutrients from food sources and survival after a diagnosis of ovarian cancer.
METHODS: This analysis from the Multidisciplinary Ovarian Cancer Outcomes Group within the Ovarian Cancer Association Consortium included 13 studies with 7700 individuals with ovarian cancer, who completed food-frequency questionnaires regarding their prediagnosis diet. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) for associations with overall survival were estimated using Cox proportional hazards models.
RESULTS: Overall, there was no association between any of the 7 dietary indices (representing prediagnosis diet) evaluated and survival; however, associations differed by tumor stage. Although there were no consistent associations among those with advanced disease, among those with earlier stage (local/regional) disease, higher scores on the alternate Healthy Eating Index (aHR quartile 4 compared with 1 = 0.66, 95% CI: 0.50, 0.87), Healthy Eating Index-2015 (aHR: 0.75; 95% CI: 0.59, 0.97), and alternate Mediterranean diet (aHR: 0.76; 95% CI: 0.60, 0.98) were associated with better survival. Better survival was also observed for individuals with early-stage disease who reported higher intakes of dietary components that contribute to the healthy diet indices (aHR for Q4 compared with Q1: vegetables 0.71; 95% CI: 0.56, 0.91), tomatoes (aHR: 0.72; 95% CI: 0.57, 0.91) and nuts and seeds (aHR 0.71; 95% CI: 0.55, 0.92). In contrast, there were suggestions of worse survival with higher scores on 2 of the 3 inflammatory indices and higher intake of trans-fatty acids.
CONCLUSIONS: Adherence to a more healthy, less-inflammatory diet may confer a survival benefit for individuals with early-stage ovarian cancer.}, }
@article {pmid39920506, year = {2025}, author = {Li, X and Chen, H and Selvaraj, MS and Van Buren, E and Zhou, H and Wang, Y and Sun, R and McCaw, ZR and Yu, Z and Jiang, MZ and DiCorpo, D and Gaynor, SM and Dey, R and Arnett, DK and Benjamin, EJ and Bis, JC and Blangero, J and Boerwinkle, E and Bowden, DW and Brody, JA and Cade, BE and Carson, AP and Carlson, JC and Chami, N and Chen, YI and Curran, JE and de Vries, PS and Fornage, M and Franceschini, N and Freedman, BI and Gu, C and Heard-Costa, NL and He, J and Hou, L and Hung, YJ and Irvin, MR and Kaplan, RC and Kardia, SLR and Kelly, TN and Konigsberg, I and Kooperberg, C and Kral, BG and Li, C and Li, Y and Lin, H and Liu, CT and Loos, RJF and Mahaney, MC and Martin, LW and Mathias, RA and Mitchell, BD and Montasser, ME and Morrison, AC and Naseri, T and North, KE and Palmer, ND and Peyser, PA and Psaty, BM and Redline, S and Reiner, AP and Rich, SS and Sitlani, CM and Smith, JA and Taylor, KD and Tiwari, HK and Vasan, RS and Viali, S and Wang, Z and Wessel, J and Yanek, LR and Yu, B and , and Dupuis, J and Meigs, JB and Auer, PL and Raffield, LM and Manning, AK and Rice, KM and Rotter, JI and Peloso, GM and Natarajan, P and Li, Z and Liu, Z and Lin, X}, title = {A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {Nature computational science}, volume = {5}, number = {2}, pages = {125-143}, pmid = {39920506}, issn = {2662-8457}, support = {U01 DK085524/DK/NIDDK NIH HHS/United States ; R01 DK078616/DK/NIDDK NIH HHS/United States ; U01 HL054472/HL/NHLBI NIH HHS/United States ; R01 HL071025/HL/NHLBI NIH HHS/United States ; UL1 RR033176/RR/NCRR NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; K26 DK138425/DK/NIDDK NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; R01 HL113323/HL/NHLBI NIH HHS/United States ; U01-HG012064//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; N01-HC-95160//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01-HL071251//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35 CA197449/CA/NCI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; R01 HL104135/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01-DK117445//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL071251/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL087698/HL/NHLBI NIH HHS/United States ; R01 HL046380/HL/NHLBI NIH HHS/United States ; R01 HL071259/HL/NHLBI NIH HHS/United States ; N01-HC-95163//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U19 CA203654/CA/NCI NIH HHS/United States ; R01-HL071259//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UL1 TR001079/TR/NCATS NIH HHS/United States ; R01 HL175681/HL/NHLBI NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; U01 HG012064/HG/NHGRI NIH HHS/United States ; N01-HC-95169//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL087660/HL/NHLBI NIH HHS/United States ; DK063491//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AR048797/AR/NIAMS NIH HHS/United States ; R01-HL071205//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL092577/HL/NHLBI NIH HHS/United States ; N01-HC-95166//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 HL054509/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 HL153805/HL/NHLBI NIH HHS/United States ; R01 AG058921/AG/NIA NIH HHS/United States ; R01 HL071250/HL/NHLBI NIH HHS/United States ; R01-HL104135-04S1//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR-000040//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; N01-HC-95162//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UL1-TR001881//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 NS058700/NS/NINDS NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; R01 HL127564/HL/NHLBI NIH HHS/United States ; R01 HL076784/HL/NHLBI NIH HHS/United States ; N01-HC-95167//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01-HL113338//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL163972/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; R03-HL154284//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL142711//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; F32 HL085989/HL/NHLBI NIH HHS/United States ; R01 MH078111/MH/NIMH NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; U01 HL054464/HL/NHLBI NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; NHLBI TOPMed Fellowship 75N92021F00229//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; R01-HL071051//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL067348/HL/NHLBI NIH HHS/United States ; 1R01AG086379-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL142711/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01-HL071250//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35-CA197449//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U01 HL072524/HL/NHLBI NIH HHS/United States ; DK078616//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL071051/HL/NHLBI NIH HHS/United States ; HHSN268201800001I//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; N01 HC025195/HL/NHLBI NIH HHS/United States ; N01-HC-95161//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 HL054457/HL/NHLBI NIH HHS/United States ; M01 RR000052/RR/NCRR NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL049762/HL/NHLBI NIH HHS/United States ; HL046389//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P01 HL045522/HL/NHLBI NIH HHS/United States ; U01-HG009088//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; R00 HG012956/HG/NHGRI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; U01 HL072518/HL/NHLBI NIH HHS/United States ; U19-CA203654//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U01 DK078616/DK/NIDDK NIH HHS/United States ; N01-HC-95168//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; 1R35-HL135818//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01 HL137162/HL/NHLBI NIH HHS/United States ; M01 RR007122/RR/NCRR NIH HHS/United States ; R01 HL059684/HL/NHLBI NIH HHS/United States ; U54 HG013247/HG/NHGRI NIH HHS/United States ; R01 DK071891/DK/NIDDK NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; R01 AG086379/AG/NIA NIH HHS/United States ; R01 MH078143/MH/NIMH NIH HHS/United States ; R01 HG013163/HG/NHGRI NIH HHS/United States ; R01-MD012765//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HL071205/HL/NHLBI NIH HHS/United States ; U01 HL054481/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; R03 HL154284/HL/NHLBI NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; R00HG012956-02//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HL105756//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054472//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL151855/HL/NHLBI NIH HHS/United States ; U01 HG009088/HG/NHGRI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; R01 MH083824/MH/NIMH NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; N01-HC-95159//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; U01-HL054473//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC-95164//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG028321/AG/NIA NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; U01-HL054509//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR-001420//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01-HL054495//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL137162//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL071258//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; N01 HC095165/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; UL1-TR-001079//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UL1 TR001881/TR/NCATS NIH HHS/United States ; UL1-RR033176//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; N01-HC-95165//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 HL054495/HL/NHLBI NIH HHS/United States ; R01 HL071258/HL/NHLBI NIH HHS/United States ; R01-HL153805//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL055673/HL/NHLBI NIH HHS/United States ; R01-HL055673-18S1//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL092301/HL/NHLBI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; HL151855//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL127564//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL072524//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01 HC095160/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Whole Genome Sequencing/methods/statistics & numerical data ; *Genome-Wide Association Study ; *Genetic Variation ; Phenotype ; Genome, Human ; }, abstract = {Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.}, }
@article {pmid39920014, year = {2025}, author = {Raychaudhuri, R and Tuchayi, AM and Low, SK and Arafa, AT and Graham, LS and Gulati, R and Pritchard, CC and Montgomery, RB and Haffner, MC and Nelson, PS and Yu, EY and Hawley, JE and Cheng, HH and Mo, G and Chen, DL and Antonarakis, ES and Kilari, D and Hope, TA and Iravani, A and Schweizer, MT}, title = {Association of Prior PARP Inhibitor Exposure with Clinical Outcomes after [177]Lu-PSMA-617 in Men with Castration-resistant Prostate Cancer and Mutations in DNA Homologous Recombination Repair Genes.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.01.002}, pmid = {39920014}, issn = {2588-9311}, support = {R01 CA212148/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; K12 CA086913/CA/NCI NIH HHS/United States ; R01 CA235741/CA/NCI NIH HHS/United States ; R01 CA281801/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: The prostate-specific membrane antigen (PSMA) radioligand [177]Lu-PSMA-617 (LuPSMA) is approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARP inhibitors (PARPi) are approved for patients with mCRPC and mutations in homologous recombination repair (HRR) pathway genes. Both modalities induce DNA damage and therefore may share mechanisms of resistance. We investigated whether PARPi exposure would reduce the subsequent efficacy of LuPSMA.
METHODS: This retrospective study included 100 patients with a PARPi-qualifying HRR alteration treated with LuPSMA. Clinical outcomes on LuPSMA, including PSA50 response, PSA progression-free survival (PFS), and overall survival (OS), were compared between those who had not previously received PARPi (PARPi-N) and those who had (PARPi-T). Subgroup analyses were performed for the most frequent HRR alterations (BRCA2 and ATM).
KEY FINDINGS AND LIMITATIONS: PSA50 responses on LuPSMA were similar between PARPi-N (n = 47) and PARPi-T (n = 53), although PSA PFS was longer in the PARPi-N group (9.1 vs 4.8 mo; p = 0.037). Among patients with BRCA2 alterations, the PARPi-N group had a better PSA50 response rate (89% vs 35%; p = 0.009), PSA PFS (14 vs 2.9 mo; p = 0.026), and OS (19 vs 5.3 mo; p = 0.10). PARPi exposure did not influence LuPSMA outcomes among patients with ATM alterations. Limitations include the retrospective design and differences in prior lines of therapy between the groups.
PARPi exposure is associated with inferior LuPSMA outcomes, particularly for patients with BRCA2 alterations. These findings suggest potential cross-resistance and underscore the need for prospective studies assessing the optimal sequencing of these agents.}, }
@article {pmid39919997, year = {2025}, author = {Danilov, AV and Sauter, C and Phillips, T and Coombs, CC and Ip, A and Wang, Y and Rhodes, J and Leslie, L and Barrientos, J and Saeed, H and Strati, P and Barta, SK and Shadman, M}, title = {Perspectives on Current Challenges and Emerging Approaches for Lymphoma Management From the First Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {25}, number = {6}, pages = {e366-e373}, doi = {10.1016/j.clml.2025.01.005}, pmid = {39919997}, issn = {2152-2669}, mesh = {Humans ; *Multiple Myeloma/therapy ; Disease Management ; *Lymphoma/therapy/diagnosis ; *Leukemia/therapy ; }, abstract = {Recent years have brought a much-needed paradigm shift to the management and treatment of mature B-cell lymphomas. Pathophysiologic and clinical heterogeneity within the various subtypes have historically contributed to treatment challenges and differences in outcomes. Novel genomic tools and therapeutic modalities give promise for improved patient outcomes, but are also making treatment planning increasingly complex. To bridge the gaps between therapeutic advancements and clinical practice, an assembly of multidisciplinary hematologic oncology faculty convened to deliberate on the prevailing challenges, knowledge gaps, and controversies in B-cell lymphoma and chronic lymphocytic leukemia management. Many controversies and questions were identified regarding treatment selection, sequencing, and high-risk subtypes. There is a need for head-to-head trials in this therapeutic area to help answer some of these questions. The insights explored and the gaps in knowledge identified by this panel will inform a follow-up conference in 2025 that will employ the modified Delphi method to develop and publish formal consensus recommendations that can provide actionable guidance to practicing clinicians.}, }
@article {pmid39919043, year = {2025}, author = {Bender Ignacio, R and Kitahata, M and Montaño, M and Shapiro, A}, title = {Mpox in People with HIV: Prioritizing Interventions for those without HIV Viral Suppression.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf059}, pmid = {39919043}, issn = {1537-6591}, }
@article {pmid39916525, year = {2025}, author = {Brzezinski, JJ and Malkin, D}, title = {Knudson's "Two-Hit" Hypothesis and Cancer Predisposition: A Bit More Complicated but Still Going Strong.}, journal = {Cancer discovery}, volume = {15}, number = {2}, pages = {258-260}, doi = {10.1158/2159-8290.CD-24-1662}, pmid = {39916525}, issn = {2159-8290}, mesh = {Humans ; *Genetic Predisposition to Disease ; *Wilms Tumor/genetics ; *Kidney Neoplasms/genetics ; *Neoplasms/genetics ; }, abstract = {This study by Treger and colleagues is a comprehensive evaluation of the genome and epigenome of tumors and constitutional tissue from children with Wilms tumor predisposition syndromes that demonstrates that the molecular features of Wilms tumors are dependent on the constitutional milieu of the patient in which they develop. See related article by Treger et al., p. 286.}, }
@article {pmid39916421, year = {2025}, author = {Unger, JM}, title = {Financial toxicity: A ubiquitous condition in patients with cancer.}, journal = {Cancer}, volume = {131}, number = {4}, pages = {e35748}, doi = {10.1002/cncr.35748}, pmid = {39916421}, issn = {1097-0142}, }
@article {pmid39916344, year = {2024}, author = {Meisner, A and Xia, F and Chan, KCG and Mayer, K and Wheeler, D and Zangeneh, S and Donnell, D}, title = {Estimating the effect of pre-exposure prophylaxis in Black men who have sex with men.}, journal = {International journal of epidemiology}, volume = {54}, number = {1}, pages = {}, pmid = {39916344}, issn = {1464-3685}, support = {P30 MH123248/MH/NIMH NIH HHS/United States ; NIH U01 HL146242/NH/NIH HHS/United States ; }, mesh = {Humans ; Male ; *Pre-Exposure Prophylaxis/statistics & numerical data ; *HIV Infections/prevention & control/ethnology ; *Homosexuality, Male/statistics & numerical data ; *Black or African American/statistics & numerical data ; Adult ; *Anti-HIV Agents/therapeutic use/administration & dosage ; United States/epidemiology ; Middle Aged ; Young Adult ; Medication Adherence ; }, abstract = {BACKGROUND: Black men who have sex with men (MSM) are disproportionately burdened by the HIV epidemic in the USA. The effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection has been demonstrated through randomized placebo-controlled clinical trials in several populations. Importantly, no such trial has been conducted exclusively among Black MSM in the USA, and it would be unethical and infeasible to do so now.
METHODS: To estimate the causal effects of PrEP access, initiation, and adherence on HIV risk, we utilized causal inference methods to combine data from two non-randomized studies that exclusively enrolled Black MSM.
RESULTS: The estimated relative risks of HIV were: (i) 0.52 (95% confidence interval: 0.21, 1.22) for individuals with versus without PrEP access, (ii) 0.48 (0.12, 0.89) for individuals who initiated PrEP but were not adherent versus those who did not initiate, and (iii) 0.23 (0.02, 0.80) for individuals who were adherent to PrEP versus those who did not initiate.
CONCLUSION: Beyond addressing the knowledge gap around the effect of PrEP in Black MSM in the USA, which may have ramifications for public health, we have provided a framework to combine data from multiple non-randomized studies to estimate causal effects, which has broad utility.}, }
@article {pmid39915487, year = {2025}, author = {Xie, J and Chen, DG and Chour, W and Ng, RH and Zhang, R and Yuan, D and Choi, J and McKasson, M and Troisch, P and Smith, B and Jones, L and Webster, A and Rasheed, Y and Li, S and Edmark, R and Hong, S and Murray, KM and Logue, JK and Franko, NM and Lausted, CG and Piening, B and Algren, H and Wallick, J and Magis, AT and Watanabe, K and Mease, P and Greenberg, PD and Chu, H and Goldman, JD and Su, Y and Heath, JR}, title = {APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1402}, pmid = {39915487}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA264090/CA/NCI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSO10201600031C//U.S. Department of Health & Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; }, mesh = {*CD8-Positive T-Lymphocytes/immunology/metabolism ; Humans ; *Receptors, Antigen, T-Cell/immunology/metabolism/genetics ; *SARS-CoV-2/immunology ; *COVID-19/immunology/virology ; Phenotype ; *Antigens, Viral/immunology ; Single-Cell Analysis/methods ; HLA-A2 Antigen/immunology ; }, abstract = {Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8 T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.}, }
@article {pmid39915263, year = {2025}, author = {Ramaswami, R and Kask, AS and D'Amico, L and Menon, MP and Lurain, K and Yarchoan, R and Ekwede, I and Couey, P and Burnham, E and Angeldekao, A and Ha Lee, B and Kaiser, JC and Cheever, M and Uldrick, TS and Kwok, LL and Wright, A and Fling, SP and Wang, CJ}, title = {Phase I study of efineptakin alfa (NT-I7) for the treatment of Kaposi sarcoma.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {2}, pages = {}, pmid = {39915263}, issn = {2051-1426}, support = {UM1 CA154967/CA/NCI NIH HHS/United States ; ZIA BC011954/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Male ; *Sarcoma, Kaposi/drug therapy/immunology ; Middle Aged ; Female ; Adult ; *Interleukin-7/therapeutic use/pharmacology/administration & dosage/adverse effects ; Aged ; Maximum Tolerated Dose ; HIV Infections/complications ; }, abstract = {BACKGROUND: CD4[+] T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4[+] T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes.
METHODS: In this multicenter phase I study with a 3+3 dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480 µg/kg, DL2: 960 µg/kg and DL3: 1200 µg/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4[+] and CD8[+] T-cells.
RESULTS: Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had
CONCLUSIONS: Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS.
TRIAL REGISTRATION NUMBER: NCT04893018.}, }
@article {pmid39914257, year = {2025}, author = {Carter, JJ and Smith, RA and Scherer, EM and Skibinski, DAG and Sankaranarayanan, S and Luxembourg, A and Kollmann, T and Marty, KD and Sadarangani, M and Dobson, S and Galloway, DA}, title = {Term immune memory responses to human papillomavirus (HPV) vaccination following 2 versus 3 doses of HPV vaccine.}, journal = {Vaccine}, volume = {50}, number = {}, pages = {126817}, doi = {10.1016/j.vaccine.2025.126817}, pmid = {39914257}, issn = {1873-2518}, mesh = {Humans ; Female ; *Immunologic Memory ; Adolescent ; Antibodies, Viral/blood ; Child ; *Papillomavirus Infections/prevention & control/immunology ; *Papillomavirus Vaccines/administration & dosage/immunology ; Young Adult ; Adult ; Immunization Schedule ; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18/administration & dosage/immunology ; Vaccination/methods ; Immunization, Secondary ; Male ; Human Papillomavirus Viruses ; }, abstract = {Human papillomavirus (HPV) vaccines provide excellent protection from infection and disease. The minimum number of doses needed for long-term protection and the potential need for boosters are areas of continuing interest. Studies on the durability of vaccines have focused on antibodies, fewer have analyzed memory immune cells that could provide protection even when antibody levels are low. In this study, subjects who had participated in one of two trials comparing two and three doses (2D, 3D), were given an additional vaccine dose (Gardasil®9, 9vHPV) several years after the initial vaccine doses, and the magnitude of immune responses were compared. Both trials had 2D children who received doses at 0 and 6 months (G1a), 3D children 9-13 (08-001) or 9-14 (V503-010) years old at enrollment in the original trial (G2) and 3D women (age 16-26) (G3). Trial V503-010 had a second 2D group of children vaccinated at 0 and 12 months (G1b). Changes in numbers of HPV specific memory B cells (Bmem) (N = 6 per group, both studies) at 1 month and plasmablasts (PB) (08-001: N = 6 per group, V503-010: G1a N = 12, G1b N = 8, G2 N = 6, G3 N = 28) at 1 week, relative to baseline at the additional dose, were compared among groups. Changes in the geometric mean titers (GMTs) of HPV specific antibodies relative to baseline were compared (N = same as PB). Statistically significant (p < 0.05) increases in the numbers of PB, Bmem and antibody levels (GMT) were seen among subjects receiving an extra vaccine dose relative to baseline. Increases in the number of PB and Bmem were not significantly different among subjects receiving two or three doses. Thus, robust immune responses were observed and did not differ significantly among subjects vaccinated with two or three doses.}, }
@article {pmid39913928, year = {2025}, author = {Venditti, A and Palmieri, R and Maurillo, L and Röllig, C and Wierzbowska, A and de Leeuw, D and Efficace, F and Curti, A and Ngai, LL and Tettero, J and Adès, L and Almeida, A and Bullinger, L and Dennis, M and Esteve, J and Ferrara, F and Heuser, M and Huls, G and Lübbert, M and Mehta, P and Montesinos, P and Pabst, T and Récher, C and Rossi, G and Russell, N and Sierra, J and Stauder, R and Vey, N and Walter, RB and Wang, E and Nier, S and Martins, CG and Ossenkoppele, G}, title = {Fitness assessment in acute myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.}, journal = {Blood advances}, volume = {9}, number = {9}, pages = {2207-2220}, pmid = {39913928}, issn = {2473-9537}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/diagnosis ; Quality of Life ; *Physical Fitness ; Europe ; }, abstract = {Fitness assessment in patients with acute myeloid leukemia (AML) is critical to deliver the right therapy to the right patient. Although several scoring systems are available to aid in determining fitness, the absence of validation studies has resulted in the lack of universally accepted assessment procedures. This limitation, combined with the increasing availability of novel agents expanding the spectrum of less-intensive options, has introduced additional complexity to the fitness assessment process. In this evolving context, fitness should reflect eligibility for a specific treatment among the several available, rather than a generic binary classification of eligibility for intensive chemotherapy. Moreover, the growing emphasis on patient-centered care, further highlights the importance of integrating quality of life, patient preferences, patient self-reported physical and social functioning status, social support, and early integration of palliative care into the assessment framework. A modern interpretation of fitness assessment should incorporate a comprehensive evaluation that extends beyond traditional clinical and biological disease characteristics. Thus, fitness assessment in patients with AML represents only 1 piece of a larger puzzle, encompassing the patient's overall capacity to sustain and benefit from a specific therapeutic program.}, }
@article {pmid39913208, year = {2025}, author = {Pitzen, SP and Rudenick, AN and Qiu, Y and Zhang, W and Munro, SA and McCluskey, BM and Forster, C and Bergom, HE and Ali, A and Boytim, E and Lafin, JT and Linder, S and Ismail, M and Devlies, W and Sessions, CJ and Claessens, F and Joniau, S and Attard, G and Zwart, W and Nelson, PS and Corey, E and Wang, Y and Lang, JM and Beltran, H and Strand, D and Antonarakis, ES and Hwang, J and Murugan, P and Huang, RS and Dehm, SM}, title = {Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {6}, pages = {e2415308122}, pmid = {39913208}, issn = {1091-6490}, support = {R01CA276269//HHS | NIH | National Cancer Institute (NCI)/ ; R01 CA270539/CA/NCI NIH HHS/United States ; R01 CA276269/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; R01CA174777//HHS | NIH | National Cancer Institute (NCI)/ ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01CA270539//HHS | NIH | National Cancer Institute (NCI)/ ; R01 CA174777/CA/NCI NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/metabolism ; *Epithelial Cells/metabolism/pathology ; Kruppel-Like Transcription Factors/genetics/metabolism ; Receptors, Androgen/metabolism/genetics ; *Transcriptome ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Receptors, Retinoic Acid/metabolism/genetics ; Gene Expression Profiling ; Prostate/pathology/metabolism ; }, abstract = {Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.}, }
@article {pmid39912912, year = {2025}, author = {Sharifi, MN and Sperger, JM and Taylor, AK and Tippins, KE and Reese, SR and Carreno, V and Kaufmann, KR and Chang, AH and Nunamaker, LA and Linebarger, C and Mora-Rodriguez, L and Schehr, JL and Krause, HM and Helzer, KT and Bootsma, ML and Blitzer, GC and Floberg, JM and Kyriakopoulos, CE and Emamekhoo, H and Heath, EI and Wells, M and Tagawa, ST and Sjöström, M and Choudhury, AD and Yu, M and Armstrong, AJ and Rathkopf, DE and Beltran, H and Nelson, PS and Feng, FY and Dehm, SM and Kosoff, D and Wei, XX and McKay, RR and Zhao, SG and Lang, JM}, title = {High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-1509}, pmid = {39912912}, issn = {2159-8290}, abstract = {The development of treatment resistance remains universal for patients with metastatic prostate cancer, driven by AR alterations and lineage state transitions. Identifying the evolution of lineage transitions in treatment resistance has been limited by the challenges of collecting serial tissue biopsies on treatment, which can be overcome using blood-based liquid biopsies. Utilizing a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. 146 samples from 70 patients had tumor purity comparable to tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype defined by persistent AR signaling and high proliferation, as well as those with a neuroendocrine CTC phenotype, had significantly shorter survival than patients with luminal-A-like and low proliferation phenotypes. In a prospective substudy, pre-treatment CTC luminal-B-like phenotype was associated with early progression on 177Lu-PSMA-617.}, }
@article {pmid39912719, year = {2025}, author = {Mongiovi, JM and Townsend, MK and Vitonis, AF and Harris, HR and Doherty, JA and Babic, A and Hecht, JL and Soong, TR and Titus, L and Conejo-Garcia, JR and Fridley, BL and Tworoger, SS and Terry, KL and Sasamoto, N}, title = {Associations between Parity, History of Breastfeeding, and T-cell Profile of Ovarian Tumors.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {4}, pages = {550-559}, pmid = {39912719}, issn = {1538-7755}, support = {R03CA259659//National Institutes of Health (NIH)/ ; P01 CA087969/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; R01 CA258679/CA/NCI NIH HHS/United States ; R03 CA259659/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; //Rivkin Center for Ovarian Cancer (Rivkin Center)/ ; R01 CA168758/CA/NCI NIH HHS/United States ; W81XWH2110320//U.S. Department of Defense (DOD)/ ; }, mesh = {Humans ; Female ; *Breast Feeding/statistics & numerical data ; *Ovarian Neoplasms/immunology/pathology/epidemiology ; *Parity/immunology ; Middle Aged ; Adult ; *Lymphocytes, Tumor-Infiltrating/immunology ; Tumor Microenvironment/immunology ; Pregnancy ; *T-Lymphocytes/immunology ; Aged ; }, abstract = {BACKGROUND: Parity and breastfeeding are associated with systemic changes in maternal inflammation and reduced risk of ovarian cancer, but little is known about their impact on the ovarian tumor immune microenvironment.
METHODS: We evaluated the associations of self-reported parity and history of breastfeeding with tumor-infiltrating T cells among 1,706 ovarian carcinoma cases with tumor tissue collected across four studies. The abundance of tumor-infiltrating T cells was measured by multiplex immunofluorescence in tumor tissue microarrays. ORs and 95% confidence intervals (CI) for the positivity of tumor immune cells were calculated using beta-binomial models and stratified by histotype.
RESULTS: Compared with ovarian tumors in nulliparous women, there was no association between parity and ovarian tumor T-cell abundance among all histotypes combined but suggestion of increased cytotoxic T cells and T-cell exhaustion among parous women with clear-cell tumors. When restricted to parous women, history of breastfeeding was associated with increased odds for all T-cell types [i.e., total T, cytotoxic T, helper T (Th), regulatory T, and exhausted T cells], with ORs ranging from 1.11 to 1.42. For every 6 months of breastfeeding, we observed increased odds of activated Th-cell infiltration (CD3+CD4+CD69+; OR, 1.13, 95% CI, 0.99-1.29), with a similar association for high-grade serous tumors, but lower odds in clear-cell tumors (OR, 0.43, 95% CI, 0.21-0.87).
CONCLUSIONS: History of breastfeeding may alter the ovarian tumor immune microenvironment by modulating the abundance of tumor-infiltrating T cells.
IMPACT: Although replication is required, history of breastfeeding may play a role in the activation of the ovarian tumor immune response.}, }
@article {pmid39909144, year = {2025}, author = {Ehret, F and Bhandarkar, AR and Chisam, M and Goulenko, V and Kumar, R and Fekrmandi, F and Skalina, KA and Kresl, J and Lo, SS and Gibbs, IC and Soltys, SG and Sheehan, JP and Fürweger, C and Slotman, BJ and Shih, HA and Chao, ST}, title = {Stereotactic Radiosurgery for Vestibular Schwannoma - A Case-Based Practice Guide From the Radiosurgery Society.}, journal = {Practical radiation oncology}, volume = {15}, number = {4}, pages = {335-346}, doi = {10.1016/j.prro.2025.01.010}, pmid = {39909144}, issn = {1879-8519}, mesh = {Humans ; *Radiosurgery/methods ; *Neuroma, Acoustic/radiotherapy/surgery/pathology ; Male ; Female ; Middle Aged ; Adult ; Practice Guidelines as Topic ; }, abstract = {PURPOSE: Vestibular schwannomas (VS) are the most common benign intracranial nerve sheath tumors. Surgery and radiation therapy - particularly stereotactic radiosurgery (SRS) - are the primary treatment options. SRS is the dominant treatment for small- and medium-sized VS and selected larger tumors due to its excellent local control rates and favorable safety profile compared with surgery. However, careful treatment planning is essential, taking into account patient preferences, tumor location and size, symptoms, and anticipated treatment-related toxicity.
METHODS AND MATERIALS: Four clinical VS scenarios have been selected to illustrate the use of SRS, including a unilateral small intracanalicular VS, a large VS with cystic components, reirradiation with SRS after local tumor recurrence, and bilateral VS in the setting of neurofibromatosis type 2-related schwannomatosis.
RESULTS: SRS is an effective and safe treatment modality for the majority of VS cases, requiring careful treatment planning and a thorough understanding of potential limitations and challenges.
CONCLUSIONS: This case-based practice guide aims to provide a concise overview of the treatment of VS with SRS. We present and discuss 4 different clinical scenarios of VS to highlight the pitfalls and best practice recommendations.}, }
@article {pmid39909038, year = {2025}, author = {Hesselman, MC and Zeeb, M and Rusert, P and Pasin, C and Mamrosh, J and Kariuki, S and Pichler, I and Sickmann, M and Kaufmann, MM and Schmidt, D and Friedrich, N and Metzner, KJ and Rindler, A and Kuster, H and Adams, C and Thebus, R and Huber, M and Yerly, S and Leuzinger, K and Perreau, M and Koller, R and Dollenmaier, G and Frigerio, S and Westfall, DH and Deng, W and deCamp, AC and Juraska, M and Edupuganti, S and Mgodi, N and Murrell, H and Garrett, N and Wagh, K and Mullins, JI and Williamson, C and Moore, PL and Günthard, HF and Kouyos, RD and Trkola, A}, title = {Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development.}, journal = {Cell host & microbe}, volume = {33}, number = {2}, pages = {279-293.e6}, doi = {10.1016/j.chom.2025.01.004}, pmid = {39909038}, issn = {1934-6069}, mesh = {*HIV-1/immunology/genetics ; Humans ; *Cysteine/genetics/immunology/chemistry ; *HIV Antibodies/immunology ; HIV Infections/immunology/virology ; *Antibodies, Neutralizing/immunology ; Epitopes/immunology/genetics ; *env Gene Products, Human Immunodeficiency Virus/immunology/genetics/chemistry ; Cross Reactions ; *HIV Envelope Protein gp120/immunology/genetics/chemistry ; }, abstract = {Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens.}, }
@article {pmid39908783, year = {2025}, author = {Urselli, F and Gomez, A and Gray, MD and Cameron, CE and Taylor, JJ}, title = {Identification of antibodies induced by immunization with the syphilis vaccine candidate Tp0751.}, journal = {Vaccine}, volume = {50}, number = {}, pages = {126804}, doi = {10.1016/j.vaccine.2025.126804}, pmid = {39908783}, issn = {1873-2518}, mesh = {Animals ; Rabbits ; *Antibodies, Bacterial/blood/immunology ; *Syphilis/prevention & control/immunology ; *Treponema pallidum/immunology ; B-Lymphocytes/immunology ; *Bacterial Vaccines/immunology/administration & dosage ; *Adhesins, Bacterial/immunology ; Epitope Mapping ; Spleen/immunology ; Immunization ; Humans ; Female ; }, abstract = {The continued and increasing prevalence of syphilis worldwide highlights the need for an effective syphilis vaccine to complement public health measures. Previous work demonstrated that immunization of the rabbit animal model with vaccine candidates derived from the T. pallidum endothelial cell adhesin Tp0751 could reduce dissemination of T. pallidum to lymph nodes. In those studies, a proportion of animals exhibited complete inhibition of treponemal dissemination and others exhibited partial or no inhibition of treponemal dissemination, consistent with results expected from an outbred animal model. In the current study we further characterized the Tp0751-specific antibody response in immunized animals that showed inhibition of T. pallidum dissemination. To do this, we generated Tp0751 tetramers to identify Tp0751-specific B cells before and after immunization. Using this approach, we found a robust expansion of Tp0751-specific B cells in the blood and spleens of immunized animals compared to unimmunized control animals. Ten antibodies from Tp0751-immunized rabbits were cloned and binding to specific structural regions of the Tp0751 protein was assessed using epitope mapping assays and structural modeling. Importantly, nine out of the ten antibodies cloned from Tp0751 tetramer-binding B cells were able to significantly inhibit T. pallidum attachment to human endothelial cells in vitro, including antibodies exhibiting weaker binding to Tp0751. Combined, our results provide a proof-of-principle that Tp0751-based subunit vaccines can stimulate strong B cell responses resulting in the production of antibodies able to inhibit T. pallidum attachment to endothelial cells.}, }
@article {pmid39908568, year = {2025}, author = {Newcomb, R and Amonoo, HL and Kavanaugh, AR and Wharton, KC and Rowland, M and Fausto, J and Webb, J and Jackson, V and Greer, JA and Temel, JS and Lark, P and Rabideau, DJ and O'Brien, K and LeBlanc, TW and Lee, SJ and El-Jawahri, A}, title = {Factors associated with early quality-of-life response to palliative care during hematopoietic cell transplantation.}, journal = {Blood advances}, volume = {9}, number = {9}, pages = {2033-2043}, pmid = {39908568}, issn = {2473-9537}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Hematologic Neoplasms/therapy/psychology ; *Hematopoietic Stem Cell Transplantation/methods ; *Palliative Care/methods ; *Quality of Life ; Secondary Data Analysis ; }, abstract = {Limited data exist on factors associated with early quality-of-life (QOL) response to palliative care (PC) in patients undergoing hematopoietic cell transplantation (HCT). We conducted a secondary analysis from 2 randomized clinical trials of PC vs usual care in adults with hematologic malignancies undergoing HCT. We measured patient-reported QOL, physical and psychological symptoms, and coping (categorized as approach-oriented and avoidant) at the time of HCT admission and 2 weeks, 3 months, and 6 months after HCT. PC clinicians completed weekly surveys documenting PC domains addressed. We defined early QOL response to PC as the change in Functional Assessment of Cancer Therapy-Bone Marrow Transplant total score from HCT admission to week 2, using the median split to define "high" responders. A total of 252 participants were included in analyses. The median change in QOL from HCT admission to week 2 was -10.7 (range, -77.0 to +52.0). Minoritized race (odds ratio [OR], 3.2; P < .001), lower baseline QOL (OR, 0.97; P < .001), and higher physical (OR, 1.02; P = .004) and posttraumatic stress disorder symptoms (OR, 1.04; P = .008) were associated with being a high PC responder. High PC responders reported greater use of approach-oriented coping at week 2 (Δ = 2.5; P = .002) and 3 months (Δ = 1.7; P = .04) and 6 months after HCT (Δ = 2.6; P = .003). Based on PC clinician surveys during HCT, high responders' PC visits focused on coping, illness/HCT education, and symptom education, whereas low responders' visits focused on symptom management. These findings provide insights into factors associated with early QOL response to PC in HCT and help identify those most likely to benefit in real-world practice. These trials were registered at www.ClinicalTrials.gov as #NCT02207322 and #NCT03641378.}, }
@article {pmid39905680, year = {2025}, author = {Johnson, ACM and Zager, RA}, title = {RBT-1, a "preconditioning" agent, mitigates syndecan-1 shedding in patients undergoing "on pump" cardiac surgery and following experimental AKI.}, journal = {Physiological reports}, volume = {13}, number = {3}, pages = {e70218}, pmid = {39905680}, issn = {2051-817X}, support = {//Renibus Therapeutics/ ; }, mesh = {Aged ; Animals ; Female ; Humans ; Male ; Mice ; Middle Aged ; *Acute Kidney Injury/blood/prevention & control/metabolism/etiology ; *Cardiac Surgical Procedures/adverse effects ; Hepatitis A Virus Cellular Receptor 1/metabolism ; Interleukin-6/metabolism ; NF-E2-Related Factor 2/metabolism ; *Postoperative Complications/prevention & control/blood ; *Syndecan-1/blood/metabolism ; }, abstract = {During systemic stress, syndecan-1 (SDC-1) shedding into plasma results, implying endothelial damage. RBT-1, a "preconditioning" agent, has been shown to mitigate postoperative complications following cardiac surgeries. This study assessed whether RBT-1 preconditioning attenuated SDC-1 shedding in these patients, implying a vascular protective effect. Patients (n, 112) were randomized to receive low-dose RBT-1, high-dose RBT-1, or placebo 24-48 h prior to surgery. Plasma samples were obtained before and 2 days postsurgery and assayed for SDC-1 (ELISA). To gain further insights, male CD-1 mice were subjected to acute renal injuries, and RBT-1's impact on plasma SDC-1 increases, vascular/aortic stress responses (NGAL/KIM-1/IL-6 gene induction), and two vascular cytoprotective pathways (Nrf2; ferritin) were assessed. Baseline plasma SDC-1 levels did not differ between patient groups. The placebo group developed an approximate 50% plasma SDC-1 (ng/mL) increase (p, 0.012). Conversely, no significant SDC-1 increases were seen in the RBT-1 treatment groups. Experimental injury markedly increased plasma SDC-1 concentrations, and these were significantly blunted by RBT-1 preconditioning. RBT-1 also mitigated AKI-induced aortic NGAL/KIM-1/IL-6 mRNA increases, activated aortic Nrf2, and increased vascular ferritin levels. RBT-1 preconditioning diminishes SDC-1 release and upregulates vascular ferritin and Nrf2. Hence, RBT-1 preconditioning can confer select vasoprotective effects.}, }
@article {pmid39902315, year = {2025}, author = {Garrett, N and Tapley, A and Hudson, A and Dadabhai, S and Zhang, B and Mgodi, NM and Andriesen, J and Takalani, A and Fisher, LH and Kee, JJ and Magaret, CA and Villaran, M and Hural, J and Andersen-Nissen, E and Ferarri, G and Miner, MD and Le Roux, B and Wilkinson, E and Lessells, R and de Oliveira, T and Odhiambo, J and Shah, P and Polakowski, L and Yacovone, M and Samandari, T and Chirenje, Z and Elyanu, PJ and Makhema, J and Kamuti, E and Nuwagaba-Biribonwoha, H and Badal-Faesen, S and Brumskine, W and Coetzer, S and Dawson, R and Delany-Moretlwe, S and Diacon, AH and Fry, S and Gill, KM and Ebrahim Hoosain, ZA and Hosseinipour, MC and Inambao, M and Innes, C and Innes, S and Kalonji, D and Kasaro, M and Kassim, P and Kayange, N and Kilembe, W and Laher, F and Malahleha, M and Maluleke, VL and Mboya, G and McHarry, K and Mitha, E and Mngadi, K and Mda, P and Moloantoa, T and Mutuluuza, CK and Naicker, N and Naicker, V and Nana, A and Nanvubya, A and Nchabeleng, M and Otieno, W and Potgieter, EL and Potloane, D and Punt, Z and Said, J and Singh, Y and Tayob, MS and Vahed, Y and Wabwire, DO and McElrath, MJ and Kublin, JG and Bekker, LG and Gilbert, PB and Corey, L and Gray, GE and Huang, Y and Kotze, P and , }, title = {Hybrid versus vaccine immunity of mRNA-1273 among people living with HIV in East and Southern Africa: a prospective cohort analysis from the multicentre CoVPN 3008 (Ubuntu) study.}, journal = {EClinicalMedicine}, volume = {80}, number = {}, pages = {103054}, pmid = {39902315}, issn = {2589-5370}, support = {T32 AI007044/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: With limited access to mRNA COVID-19 vaccines in lower income countries, and people living with HIV (PLWH) largely excluded from clinical trials, Part A of the multicentre CoVPN 3008 (Ubuntu) study aimed to assess the safety of mRNA-1273, the relative effectiveness of hybrid versus vaccine immunity, and SARS-CoV-2 viral persistence among PLWH in East and Southern Africa during the omicron outbreak.
METHODS: Previously unvaccinated adults with HIV and/or other comorbidities associated with severe COVID-19 received either one (hybrid immunity) or two (vaccine immunity) 100-mcg doses of ancestral strain mRNA-1273 in the first month, depending on baseline evidence of prior SARS-CoV-2 infection. In a prospective cohort study design, we used covariate-adjusted Cox regression and counterfactual cumulative incidence methods to determine the hazard ratio and relative risk of COVID-19 and severe COVID-19 with hybrid versus vaccine immunity within six months. The ongoing Ubuntu study is registered on ClinicalTrials.gov (NCT05168813) and this work was conducted from December 2021 to March 2023.
FINDINGS: Between December 2021 and September 2022, 14,237 participants enrolled, and 14,002 (83% PLWH, 69% SARS-CoV-2 seropositive) were included in the analyses. Vaccinations were safe and well tolerated. Common adverse events were pain or tenderness at the injection site (26.7%), headache (20.4%), and malaise (20.3%). Severe adverse events were rare (0.8% of participants after the first and 1.1% after the second vaccination), and none were life-threatening or fatal. Among PLWH, the median CD4 count was 635 cells/μl and 18.5% had HIV viraemia. The six-month cumulative incidences in the hybrid immunity and vaccine immunity groups were 2.02% (95% confidence interval [CI] 1.61-2.44) and 3.40% (95% CI 2.30-4.49) for COVID-19, and 0.048% (95% CI 0.00-0.10) and 0.32% (95% CI 0.59-0.63) for severe COVID-19. Among all PLWH the hybrid immunity group had a 42% lower hazard rate of COVID-19 (hazard ratio [HR] 0.58; 95% CI 0.44-0.77; p < 0.001) and a 73% lower hazard rate of severe COVID-19 (HR 0.27; 95% CI 0.07-1.04; p = 0.056) than the vaccine immunity group, but this effect was not seen among PLWH with CD4 counts <350 cells/μl or HIV viraemia. Twenty PLWH had persistent SARS-CoV-2 virus at least 50 days.
INTERPRETATION: Hybrid immunity was associated with superior protection from COVID-19 compared to vaccine immunity with the ancestral mRNA-1273 vaccine. Persistent infections among immunocompromised PLWH may provide reservoirs for emerging variants.
FUNDING: National Institute of Allergy and Infectious Diseases.}, }
@article {pmid39901049, year = {2025}, author = {Kachuri, L and Hoffmann, TJ and Jiang, Y and Berndt, SI and Shelley, JP and Schaffer, KR and Machiela, MJ and Freedman, ND and Huang, WY and Li, SA and Easterlin, R and Goodman, PJ and Till, C and Thompson, I and Lilja, H and Van Den Eeden, SK and Chanock, SJ and Haiman, CA and Conti, DV and Klein, RJ and Mosley, JD and Graff, RE and Witte, JS}, title = {Author Correction: Genetically adjusted PSA levels for prostate cancer screening.}, journal = {Nature medicine}, volume = {31}, number = {2}, pages = {697}, doi = {10.1038/s41591-025-03539-4}, pmid = {39901049}, issn = {1546-170X}, }
@article {pmid39900920, year = {2025}, author = {Musalgaonkar, S and Yelland, JN and Chitale, R and Rao, S and Ozadam, H and Taylor, DW and Cenik, C and Johnson, AW}, title = {The assembly factor Reh1 is released from the ribosome during its initial round of translation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1278}, pmid = {39900920}, issn = {2041-1723}, support = {R35 GM127127/GM/NIGMS NIH HHS/United States ; R35 GM138348/GM/NIGMS NIH HHS/United States ; R35 GM150667/GM/NIGMS NIH HHS/United States ; R35GM138348//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Protein Biosynthesis ; Cryoelectron Microscopy ; *Ribosomes/metabolism/ultrastructure ; Ribosome Subunits, Large, Eukaryotic/metabolism ; *Ribosomal Proteins/metabolism/genetics ; RNA, Transfer/metabolism ; Peptide Initiation Factors/metabolism ; Ribosome Subunits, Small, Eukaryotic/metabolism ; RNA-Binding Proteins/metabolism ; Eukaryotic Translation Initiation Factor 5A ; Open Reading Frames ; RNA, Transfer, Amino Acyl/metabolism ; Peptide Chain Elongation, Translational ; Protein Binding ; }, abstract = {Assembly of functional ribosomal subunits and successfully delivering them to the translating pool is a prerequisite for protein synthesis and cell growth. In S. cerevisiae, the ribosome assembly factor Reh1 binds to pre-60S subunits at a late stage during their cytoplasmic maturation. Previous work shows that the C-terminus of Reh1 inserts into the polypeptide exit tunnel of the pre-60S subunit. Here, we show that Reh1-bound nascent 60S subunits associate with 40S subunits to form actively translating ribosomes. Using selective ribosome profiling, we found that Reh1-bound ribosomes populate open reading frames near start codons. Reh1-bound ribosomes are also strongly enriched for initiator tRNA, indicating they are associated with early elongation. Using cryo-electron microscopy to image Reh1-bound 80S ribosomes, we found they contain A site peptidyl tRNA, P site tRNA and eIF5A, indicating that Reh1 does not dissociate from 60S until translation elongation. We propose that Reh1 is displaced by the elongating peptide chain, making it the last assembly factor released from the nascent 60S subunit during its initial round of translation.}, }
@article {pmid39900903, year = {2025}, author = {Zeng, Z and Zhang, T and Zhang, J and Li, S and Connor, S and Zhang, B and Zhao, Y and Wilson, J and Singh, D and Kulikauskas, R and Church, CD and Pulliam, TH and Jani, S and Nghiem, P and Topalian, SL and Forde, PM and Pardoll, DM and Ji, H and Smith, KN}, title = {A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1070}, pmid = {39900903}, issn = {2041-1723}, support = {R01 HG009518/HG/NHGRI NIH HHS/United States ; R01 HG013409/HG/NHGRI NIH HHS/United States ; R01HG013409//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; T32CA080416//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R37 CA251447/CA/NCI NIH HHS/United States ; R37CA251447//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA225517/CA/NCI NIH HHS/United States ; P01CA255517//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HG010889//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 HG010889/HG/NHGRI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P30CA006973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 CA006973/CA/NCI NIH HHS/United States ; R01HG009518//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; CRI4946//Cancer Research Institute (CRI)/ ; }, mesh = {Humans ; *Antigens, Neoplasm/immunology/genetics ; *Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; CD8-Positive T-Lymphocytes/immunology/metabolism ; *Lung Neoplasms/immunology/genetics ; *Neoplasms/immunology/genetics ; Melanoma/immunology/genetics ; Algorithms ; Gene Expression Regulation, Neoplastic ; Mutation ; Immunotherapy ; Single-Cell Analysis ; }, abstract = {Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.}, }
@article {pmid39899881, year = {2025}, author = {Zaiken, MC and Jin, S and McDonald-Hyman, CS and Hartigan, CR and Sage, PT and Hippen, KL and Koehn, BH and Panoskaltsis-Mortari, A and Riddle, MJ and Eide, CR and Tolar, J and Hill, GR and Luznik, L and Cutler, CS and Ritz, JR and Kean, LS and Tsagaratou, A and Rao, A and Blazar, BR}, title = {Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.}, journal = {Blood}, volume = {145}, number = {24}, pages = {2813-2827}, pmid = {39899881}, issn = {1528-0020}, mesh = {Animals ; *Graft vs Host Disease/immunology/genetics/pathology ; *Dioxygenases/genetics ; Mice ; *Immunoglobulin Class Switching ; Chronic Disease ; *Proto-Oncogene Proteins/genetics ; *DNA Demethylation ; *T Follicular Helper Cells/immunology/metabolism ; *DNA-Binding Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; *T-Lymphocytes, Helper-Inducer/immunology ; *Immunoglobulin G/immunology/genetics ; }, abstract = {Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and nonrelapse-associated mortality after allogeneic hematopoietic cell transplantation. Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. In this study, we sought to investigate the DNA demethylase ten-eleven translocase (Tet) methylcytosine dioxygenases 2 (Tet2) and 3 (Tet3) in T follicular helper cell (TFH)-dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2-deleted donor T cells did not have improved pulmonary function tests in contrast with the markedly improved pulmonary function in Tet3-deleted donor T cells. Tet3 deleted donor T cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency led to elevated GATA3 (GATA-binding protein 3) expression in and interleukin-4 production by TFHs. TET3-deficient TFHs supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c, thereby enabling mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH-driven immunoglobulin class switching and suggest a new approach to mitigate cGVHD.}, }
@article {pmid39898809, year = {2025}, author = {Salerno, S and Miao, J and Afiaz, A and Hoffman, K and Neufeld, A and Lu, Q and McCormick, TH and Leek, JT}, title = {ipd: an R package for conducting inference on predicted data.}, journal = {Bioinformatics (Oxford, England)}, volume = {41}, number = {2}, pages = {}, pmid = {39898809}, issn = {1367-4811}, support = {P2C HD042828/HD/NICHD NIH HHS/United States ; R35 GM144128/GM/NIGMS NIH HHS/United States ; U01 HG012039/HG/NHGRI NIH HHS/United States ; DP2 MH122405/MH/NIMH NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {*Software ; Algorithms ; Machine Learning ; *Computational Biology/methods ; Artificial Intelligence ; }, abstract = {SUMMARY: ipd is an open-source R software package for the downstream modeling of an outcome and its associated features where a potentially sizable portion of the outcome data has been imputed by an artificial intelligence or machine learning prediction algorithm. The package implements several recent proposed methods for inference on predicted data with a single, user-friendly wrapper function, ipd. The package also provides custom print, summary, tidy, glance, and augment methods to facilitate easy model inspection. This document introduces the ipd software package and provides a demonstration of its basic usage.
AVAILABILITY: ipd is freely available on CRAN or as a developer version at our GitHub page: github.com/ipd-tools/ipd. Full documentation, including detailed instructions and a usage 'vignette' are available at github.com/ipd-tools/ipd.}, }
@article {pmid39898780, year = {2025}, author = {Chalitsios, CV and Markozannes, G and Papagiannopoulos, C and Aglago, EK and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Dimou, N and Drew, DA and French, AJ and Georgeson, P and Giannakis, M and Gruber, SB and Gunter, MJ and Harrison, TA and Hoffmeister, M and Hsu, L and Huang, WY and Hullar, MAJ and Huyghe, JR and Lynch, BM and Moreno, V and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Qu, C and Schmit, SL and Steinfelder, RS and Sun, W and Thomas, CE and Toland, AE and Trinh, QM and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Murphy, N and Peters, U and Phipps, AI and Tsilidis, KK}, title = {Waist Circumference, a Body Shape Index, and Molecular Subtypes of Colorectal Cancer: A Pooled Analysis of Four Cohort Studies.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {4}, pages = {568-577}, pmid = {39898780}, issn = {1538-7755}, support = {R35 CA197735/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; R01 CA297681/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; PPRCPJT\100005//Cancer Research UK (CRUK)/ ; UM1 CA167552/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; 509348//National Health and Medical Research Council (NHMRC)/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; //American Cancer Society (ACS)/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology/pathology ; Male ; Female ; *Waist Circumference ; Middle Aged ; Risk Factors ; Aged ; Cohort Studies ; Case-Control Studies ; Proto-Oncogene Proteins B-raf/genetics ; Microsatellite Instability ; }, abstract = {BACKGROUND: Waist circumference (WC) and its allometric counterpart, "a body shape index" (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease.
METHODS: Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively.
RESULTS: Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04-1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00-1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis.
CONCLUSIONS: Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention.
IMPACT: The proposed results have potential utility in colorectal cancer prevention.}, }
@article {pmid39896663, year = {2025}, author = {Dadonaite, B and Burrell, AR and Logue, J and Chu, HY and Payne, DC and Haslam, DB and Staat, MA and Bloom, JD}, title = {SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39896663}, issn = {2692-8205}, support = {U01 AI144673/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; UL1 TR001425/TR/NCATS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, abstract = {The immune response to viral infection is shaped by past exposures to related virus strains, a phenomenon known as imprinting. For SARS-CoV-2, much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by a XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), serum neutralizing activity of infants only infected with XBB* mostly targets the spike N-terminal domain (NTD). In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity towards the RBD, although the specific RBD sites targeted are different than for imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.}, }
@article {pmid39894975, year = {2025}, author = {Yay Donderici, E and Forbes, SP and Zhang, NJ and Schafer, G and Raymond, VM and Das, AK and Eagle, C and Talasaz, A and Grady, WM}, title = {Cost-effectiveness of blood-based colorectal cancer screening - a simulation model incorporating real-world longitudinal adherence.}, journal = {Expert review of pharmacoeconomics & outcomes research}, volume = {25}, number = {5}, pages = {671-677}, doi = {10.1080/14737167.2025.2458044}, pmid = {39894975}, issn = {1744-8379}, mesh = {Humans ; Cost-Benefit Analysis ; *Colorectal Neoplasms/diagnosis/economics ; *Early Detection of Cancer/methods/economics ; Quality-Adjusted Life Years ; *Patient Compliance ; Computer Simulation ; *Mass Screening/economics/methods ; Middle Aged ; Aged ; Male ; Female ; Occult Blood ; Models, Economic ; }, abstract = {OBJECTIVES: Although U.S. Preventive Services Task Force (USPSTF) recommended CRC screenings are effective; patient reluctance reduces adherence. Most cost-effectiveness models assume perfect adherence, yet one-third of eligible individuals aren't current with CRC screening. Our study assesses the cost-effectiveness of Shield, an FDA-approved blood-based CRC screening test, using real-world adherence.
METHODS: The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, a validated discrete-event simulation, evaluated clinical and economic outcomes of CRC screening under real-world adherence scenarios. We compared the Shield blood-based test administered every 3 years to no screening, considering it cost-effective if the incremental cost-effectiveness ratio (ICER) was under $100,000 per quality-adjusted life-year (QALY) gained.
RESULTS: Shield increased QALYs by 154 and raised costs by $7.5 million per 1,000 individuals, with an ICER of $48,662 per QALY, meeting the $100,000/QALY threshold. Shield remained cost-effective up to a unit cost of $3,241 (at $100,000/QALY) and $4,942 (at $150,000/QALY). Sensitivity analyses confirmed cost-effectiveness with lower adherence to diagnostic colonoscopy (56.1%) and annual screenings.
CONCLUSION: The CAN-SCREEN model shows that Shield is cost-effective compared to no screening. Including real-world adherence improves accuracy in assessing screening strategies. Shield's noninvasive approach offers a promising, cost-effective way to increase adherence and reduce CRC mortality.}, }
@article {pmid39892391, year = {2025}, author = {Lemarquis, AL and Kousa, AI and Argyropoulos, KV and Jahn, L and Gipson, B and Pierce, J and Serrano-Marin, L and Victor, K and Kanno, Y and Girotra, NN and Andrlova, H and Tsai, J and Velardi, E and Sharma, R and Grassmann, S and Ekwall, O and Goldstone, AB and Dudakov, JA and DeWolf, S and van den Brink, MRM}, title = {Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage.}, journal = {Immunity}, volume = {58}, number = {2}, pages = {397-411.e6}, pmid = {39892391}, issn = {1097-4180}, support = {R01 HL164902/HL/NHLBI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; R35 CA284024/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; }, mesh = {*Amphiregulin/metabolism/genetics/immunology ; *T-Lymphocytes, Regulatory/immunology/metabolism ; *Thymus Gland/immunology/physiology/injuries ; Animals ; Humans ; Mice ; *Regeneration/immunology ; Mice, Inbred C57BL ; Mice, Knockout ; Adoptive Transfer ; }, abstract = {Thymic injury associated with disease or cancer treatment reduces T cell production and makes patients more vulnerable to infections and cancers. Here, we examined the role of regulatory T (Treg) cells on thymic regeneration. Treg cell frequencies increased in the thymus in various acute injury models. Depletion of Treg cells impaired thymic regeneration, impacting both the thymocyte compartment and the stromal cell compartment; adoptive transfer of Treg cells enhanced regeneration. Expansion of circulating Treg cells, as opposed to that of tissue resident or recent thymic emigrants, explained this increase, as seen using parabiotic and adoptive transfer models. Single-cell analyses of recirculating Treg cells revealed expression of various regenerative factors, including the cytokine amphiregulin. Deletion of amphiregulin in these Treg cells impaired regeneration in the injured thymus. We identified an analogous population of CD39[+]ICOS[+] Treg cells in the human thymus. Our findings point to potential therapeutic avenues to address aging- and treatment-induced immunosuppression.}, }
@article {pmid39892390, year = {2025}, author = {Zhang, Y and Luo, K and Peters, BA and Mossavar-Rahmani, Y and Moon, JY and Wang, Y and Daviglus, ML and Van Horn, L and McClain, AC and Cordero, C and Floyd, JS and Yu, B and Walker, RW and Burk, RD and Kaplan, RC and Qi, Q}, title = {Sugar-sweetened beverage intake, gut microbiota, circulating metabolites, and diabetes risk in Hispanic Community Health Study/Study of Latinos.}, journal = {Cell metabolism}, volume = {37}, number = {3}, pages = {578-591.e4}, pmid = {39892390}, issn = {1932-7420}, support = {R01 DK119268/DK/NIDDK NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; U01 DK140761/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Diabetes Mellitus/metabolism/epidemiology ; *Gastrointestinal Microbiome ; *Hispanic or Latino ; Risk Factors ; *Sugar-Sweetened Beverages/adverse effects ; }, abstract = {No population-based studies examined gut microbiota and related metabolites associated with sugar-sweetened beverage (SSB) intake among US adults. In this cohort of US Hispanic/Latino adults, higher SSB intake was associated with nine gut bacterial species, including lower abundances of several short-chain-fatty-acid producers, previously shown to be altered by fructose and glucose in animal studies, and higher abundances of fructose- and glucose-utilizing Clostridium bolteae and Anaerostipes caccae. Fifty-six serum metabolites were correlated with SSB intake and a gut microbiota score based on these SSB-related species in consistent directions. These metabolites were clustered into several modules, including a glycerophospholipid module, two modules comprising branched-chain amino acid (BCAA) and aromatic amino acid (AAA) derivatives from microbial metabolism, etc. Higher glycerophospholipid and BCAA derivative levels and lower AAA derivative levels were associated with higher incident diabetes risk during follow-up. These findings suggest a potential role of gut microbiota in the association between SSB intake and diabetes.}, }
@article {pmid39890673, year = {2025}, author = {Ergas, IJ and Cheng, RK and Roh, JM and Kresovich, JK and Iribarren, C and Nguyen-Huynh, M and Rana, JS and Rillamas-Sun, E and Laurent, CA and Lee, VS and Quesenberry, CP and Bhatt, A and Yao, S and Kushi, LH and Greenlee, H and Kwan, ML}, title = {Diet quality and cardiometabolic health in breast cancer survivors: the Pathways Study.}, journal = {Breast cancer research and treatment}, volume = {211}, number = {1}, pages = {139-150}, pmid = {39890673}, issn = {1573-7217}, support = {U01 CA195565/CA/NCI NIH HHS/United States ; R01CA214057/CA/NCI NIH HHS/United States ; R01 CA105274/CA/NCI NIH HHS/United States ; R01CA105274/CA/NCI NIH HHS/United States ; R01 CA214057/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/complications ; Middle Aged ; *Cancer Survivors/statistics & numerical data ; Aged ; Adult ; Prospective Studies ; *Diet, Healthy ; Dyslipidemias/epidemiology ; *Hypertension/epidemiology ; Diabetes Mellitus/epidemiology ; Incidence ; }, abstract = {PURPOSE: Breast cancer (BC) survivors experience higher rates of cardiometabolic conditions, partly due to treatment. While healthy eating decreases the risk of these conditions in the general population, its association in BC survivors is unclear.
METHODS: We included 3415 participants from the Pathways Study, a prospective cohort of women diagnosed with invasive BC between 2005 and 2013 and followed through 2021. Concordance of food intakes from food frequency questionnaires was estimated for five healthy eating patterns at BC diagnosis: Dietary Approaches to Stop Hypertension (DASH), healthy Plant-based Dietary Index (hPDI), 2020 Healthy Eating Index (HEI), American Cancer Society nutrition guidelines (ACS), and the alternate Mediterranean Diet Index (aMED). Incident hypertension, diabetes, and dyslipidemia were identified through electronic health records. Cumulative incidence rates (CIRs) were estimated accounting for the competing risk of death. Covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Fine and Gray regression models, stratified by BC treatment status.
RESULTS: Over an average 11.5 years (range = 0.3-16.3) of follow-up, 554 (16.2%) participants developed hypertension, 362 (10.6%) developed diabetes, and 652 (19.1%) developed dyslipidemia. CIRs for any cardiometabolic condition 15 years after BC diagnosis were 39.2% for women in the highest HEI quartile compared to 49.3% in the lowest. After adjustment, women in the highest HEI quartile had lower risks of any cardiometabolic condition (HR = 0.70, 95% CI 0.54-0.91, Ptrend = 0.006), including hypertension (HR = 0.71, 95% CI 0.54-0.94, Ptrend = 0.007), diabetes (HR = 0.57, 95% CI 0.41-0.79, Ptrend < 0.001), and dyslipidemia (HR = 0.77, 95% CI 0.59-0.99, Ptrend = 0.04). Similar associations were observed for DASH, hPDI, and ACS with diabetes incidence.
CONCLUSION: Healthier diets at BC diagnosis, particularly those aligned with the HEI, were associated with lower cardiometabolic risks.}, }
@article {pmid39890520, year = {2025}, author = {Baker, SG and Etzioni, R}, title = {Letter to the editor regarding "Early detection of pancreatic cancer: Study design and analytical considerations in biomarker discovery and early phase validation studies".}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {25}, number = {2}, pages = {284-285}, doi = {10.1016/j.pan.2025.01.009}, pmid = {39890520}, issn = {1424-3911}, }
@article {pmid39890296, year = {2025}, author = {Cheng, GS and Ramirez, JA and Staitieh, BS and Evans, SE}, title = {Challenges of Managing Pulmonary Disease in the Immunocompromised Host.}, journal = {Clinics in chest medicine}, volume = {46}, number = {1}, pages = {xiii-xvii}, doi = {10.1016/j.ccm.2024.12.001}, pmid = {39890296}, issn = {1557-8216}, }
@article {pmid39889280, year = {2025}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Cupertino, AP and Salloum, RG and Triplette, M and Zvolensky, MJ and Bricker, JB}, title = {Evaluating the Impact of Pharmacotherapy in Augmenting Quit Rates Among Hispanic Adults in an App-Delivered Smoking Cessation Intervention: Secondary Analysis of a Randomized Controlled Trial.}, journal = {JMIR formative research}, volume = {9}, number = {}, pages = {e69311}, pmid = {39889280}, issn = {2561-326X}, support = {R01 CA192849/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/ethnology ; *Hispanic or Latino/statistics & numerical data/psychology ; Female ; Male ; *Mobile Applications/statistics & numerical data ; Adult ; Middle Aged ; Tobacco Use Cessation Devices/statistics & numerical data ; *Smoking Cessation Agents/therapeutic use ; Bupropion/therapeutic use ; Varenicline/therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: Hispanic adults receive less advice to quit smoking and use fewer evidence-based smoking cessation treatments compared to their non-Hispanic counterparts. Digital smoking cessation interventions, such as those delivered via smartphone apps, provide a feasible and within-reach treatment option for Hispanic adults who smoke and want to quit smoking. While the combination of pharmacotherapy and behavioral interventions are considered best practices for smoking cessation, its efficacy among Hispanic adults, especially alongside smartphone app-based interventions, is uncertain.
OBJECTIVE: This secondary analysis used data from a randomized controlled trial that compared the efficacy of 2 smoking cessation apps, iCanQuit (based on acceptance and commitment therapy) and QuitGuide (following US clinical practice guidelines), to explore the association between pharmacotherapy use and smoking cessation outcomes among the subsample of 173 Hispanic participants who reported on pharmacotherapy use. Given the randomized design, we first tested the potential interaction of pharmacotherapy use and intervention arm on 12-month cigarette smoking abstinence. We then examined whether the use of any pharmacotherapy (ie, nicotine replacement therapy [NRT], varenicline, or bupropion) and NRT alone augmented each app-based intervention efficacy.
METHODS: Participants reported using pharmacotherapy on their own during the 3-month follow-up and cigarette smoking abstinence at the 12-month follow-up via web-based surveys. These data were used (1) to test the interaction effect of using pharmacotherapy to aid smoking cessation and intervention arm (iCanQuit vs QuitGuide) on smoking cessation at 12 months and (2) to test whether the use of pharmacotherapy to aid smoking cessation augmented the efficacy of each intervention arm to help participants successfully quit smoking.
RESULTS: The subsample of Hispanic participants was recruited from 30 US states. They were on average 34.5 (SD 9.3) years of age, 50.9% (88/173) were female, and 56.1% (97/173) reported smoking at least 10 cigarettes daily. Approximately 22% (38/173) of participants reported using pharmacotherapy to aid smoking cessation at the 3-month follow-up, including NRT, varenicline, or bupropion, with no difference between intervention arms. There was an interaction between pharmacotherapy use and intervention arm that marginally influenced 12-month quit rates at 12 months (P for interaction=.053). In the iCanQuit arm, 12-month missing-as-smoking quit rates were 43.8% (7/16) for pharmacotherapy users versus 28.8% (19/16) for nonusers (odds ratio 2.21, 95% CI 0.66-7.48; P=.20). In the QuitGuide arm, quit rates were 9.1% (2/22) for pharmacotherapy users versus 21.7% (15/69) for nonusers (odds ratio 0.36, 95% CI 0.07-1.72; P=.20). Results were similar for the use of NRT only.
CONCLUSIONS: Combining pharmacotherapy to aid smoking cessation with a smartphone app-based behavioral intervention that teaches acceptance of cravings to smoke (iCanQuit) shows promise in improving quit rates among Hispanic adults. However, this combined approach was not effective with the US clinical guideline-based app (QuitGuide).
TRIAL REGISTRATION: ClinicalTrials.gov NCT02724462; https://clinicaltrials.gov/study/NCT02724462.
RR2-10.1001/jamainternmed.2020.4055.}, }
@article {pmid39889250, year = {2025}, author = {Bhatia, S and Topalian, SL and Sharfman, W and Meyer, T and Steven, N and Lao, CD and Fariñas-Madrid, L and Devriese, LA and Moore, K and Ferris, RL and Honma, Y and Elias, I and Srirangam, A and Garnett-Benson, C and Lee, M and Nghiem, P}, title = {Nivolumab With or Without Ipilimumab in Patients With Recurrent or Metastatic Merkel Cell Carcinoma: A Nonrandomized, Open-Label, International, Multicenter Phase I/II Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {9}, pages = {1137-1147}, pmid = {39889250}, issn = {1527-7755}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/pathology/mortality/secondary ; Male ; Female ; Aged ; *Nivolumab/administration & dosage/adverse effects/therapeutic use ; *Ipilimumab/administration & dosage/adverse effects/therapeutic use ; Middle Aged ; *Skin Neoplasms/drug therapy/pathology/mortality ; Aged, 80 and over ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Neoplasm Recurrence, Local/drug therapy/pathology ; Progression-Free Survival ; Adult ; Immune Checkpoint Inhibitors/adverse effects ; }, abstract = {PURPOSE: Approximately 50% of patients with advanced Merkel cell carcinoma (MCC) have primary or acquired resistance to PD-(L)1 blockade, which may be overcome using combination immune checkpoint inhibition (ICI) with anti-cytotoxic T lymphocyte antigen-4 antibody. We present results from the recurrent/metastatic MCC cohort in CheckMate 358, a nonrandomized, multicohort, phase I/II study of nivolumab (NIVO) with or without ipilimumab (IPI) in virus-associated cancers (ClinicalTrials.gov identifier: NCT02488759).
METHODS: ICI-naïve patients with recurrent/metastatic MCC and 0-2 previous systemic therapies were administered NIVO monotherapy at 240 mg once every 2 weeks or combination therapy with NIVO 3 mg/kg once every 2 weeks + IPI 1 mg/kg once every 6 weeks. The primary end point was objective response. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
RESULTS: Sixty-eight patients received NIVO (n = 25) or NIVO + IPI (n = 43). The objective response rate (95% CI) and median DOR (95% CI), respectively, were 60% (38.7 to 78.9) and 60.6 months (16.7 to not applicable [NA]) with NIVO and 58% (42.1 to 73) and 25.9 months (10.4 to NA) with NIVO + IPI. The median PFS (95% CI) and OS (95% CI), respectively, were 21.3 (9.2 to 62.5) and 80.7 (23.3 to NA) months with NIVO and 8.4 (3.7 to 24.3) and 29.8 (8.5 to 48.3) months with NIVO + IPI. The incidence of grade 3/4 treatment-related adverse events was 28% with NIVO and 47% with the combination.
CONCLUSION: This nonrandomized study showed frequent and durable responses with both NIVO and NIVO + IPI in patients with ICI-naïve advanced MCC. However, it did not show improvement in efficacy with the combination, thus contradicting previous study reports that had suggested clinical benefit with combination ICI. A randomized trial of NIVO + IPI versus NIVO monotherapy is warranted.}, }
@article {pmid39888950, year = {2025}, author = {Montaño, MA and Sindelo, S and Fata, A and Rousseau, E and Bekker, LG and Katz, IT and Drain, PK}, title = {Urine tenofovir adherence testing: Perspectives of recently diagnosed South African adolescents and young adults with HIV accessing care via mobile HIV clinics.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0318308}, pmid = {39888950}, issn = {1932-6203}, support = {R34 MH114897/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Tenofovir/urine/therapeutic use ; Adolescent ; *HIV Infections/drug therapy/urine ; Male ; South Africa ; Female ; Young Adult ; *Anti-HIV Agents/therapeutic use/urine ; *Medication Adherence ; Adult ; Focus Groups ; Point-of-Care Testing ; }, abstract = {BACKGROUND: Adolescents and young adults (AYA) living with HIV face several challenges to engaging in HIV care, which can impact adherence to antiretroviral therapy (ART). Point-of-care (POC) diagnostics that detect tenofovir in urine may be a useful tool to support ART adherence, but perspectives from AYA in South Africa have not been explored.
METHODS: We conducted in-depth interviews (IDIs) among young people (age 18-24) newly diagnosed with HIV in Cape Town, and a focus group discussion (FGD) with HIV care providers to understand their perspectives regarding the use of POC urine tenofovir testing to support ART adherence. Transcripts were analyzed using Dedoose, with an iterative thematic approach.
RESULTS: Transcripts from 8 IDI participants and 8 FGD participants were included in the analysis. Major themes identified during analysis related to beliefs about POC urine adherence testing and recommendations for future clinical implementation. Most IDI participants indicated they would want to use the tests if clinically available, and both IDI and FGD participants believed the tests would be helpful to clinicians. Participants believed the tests could motivate people to take their ART regularly, either by reassuring them ART was present in their bodies, or to avoid the negative consequences of being found to be non-adherent. Drawbacks of POC adherence testing identified by respondents included not wanting to be caught skipping ART doses, concerns about privacy, how the test results would be explained, and adding to the amount of testing required for HIV clinical care.
CONCLUSIONS: AYA living with HIV in South Africa had favorable views toward POC tenofovir adherence testing and felt utilizing these tests in HIV clinical care would motivate people to remain adherent to ART.}, }
@article {pmid39887373, year = {2025}, author = {Byrd, DA and Damerell, V and Gomez Morales, MF and Hogue, SR and Lin, T and Ose, J and Himbert, C and Ilozumba, MN and Kahlert, C and Shibata, D and Toriola, AT and Li, CI and Figueiredo, J and Stephens, WZ and Warby, CA and Hardikar, S and Siegel, EM and Round, J and Ulrich, CM and Gigic, B}, title = {The gut microbiome is associated with disease-free survival in stage I-III colorectal cancer patients.}, journal = {International journal of cancer}, volume = {157}, number = {1}, pages = {64-73}, doi = {10.1002/ijc.35342}, pmid = {39887373}, issn = {1097-0215}, support = {01KD2101D//German Federal Ministry of Education and Research/ ; R01 AG083580/AG/NIA NIH HHS/United States ; //Stiftung LebensBlicke/ ; //ERA-NET on Translational Cancer Research (TRANSCAN)/ ; //Rahel Goitein-Straus-Program/ ; 01KT1503//German Federal Ministry of Education and Research/ ; //Matthias-Lackas Foundations/ ; U01 CA206110/NH/NIH HHS/United States ; //Heidelberger Stiftung Chirurgie, Heidelberg University Hospital/ ; R01 CA189184/NH/NIH HHS/United States ; //Medizinische Fakultät Heidelberg, Universität Heidelberg/ ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA189184/NH/NIH HHS/United States ; U01 CA206110/NH/NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome/genetics ; *Colorectal Neoplasms/microbiology/pathology/mortality ; Female ; Male ; Middle Aged ; Aged ; Feces/microbiology ; Disease-Free Survival ; RNA, Ribosomal, 16S/genetics ; Prospective Studies ; Neoplasm Staging ; Bacteria/genetics/classification/isolation & purification ; }, abstract = {Colorectal cancer (CRC) is the second overall leading cause of cancer death in the United States, with recurrence being a frequent cause of mortality. Approaches to improve disease-free survival (DFS) are urgently needed. The gut microbiome, reflected in fecal samples, is likely mechanistically linked to CRC progression and may serve as a non-invasive biomarker. Accordingly, we leveraged baseline fecal samples from N = 166 stage I-III CRC patients in the ColoCare Study, a prospective cohort of newly diagnosed CRC patients. We sequenced the V3 and V4 regions of the 16S rRNA gene to characterize fecal bacteria. We calculated estimates of alpha diversity, beta diversity, and a priori- and exploratory-selected bacterial presence/absence and relative abundance. Associations of microbial metrics with DFS were estimated using multivariable Cox proportional hazards models. We found that alpha diversity was strongly associated with improved DFS, most strongly among rectal cancer patients (Shannon HRrectum = 0.40 95% CI = 0.19, 0.87; p = .02). Overall microbiome composition differences (beta diversity), as characterized by principal coordinate axes, were statistically significantly associated with DFS. Peptostreptococcus was statistically significantly associated with worse DFS (HR = 1.62, 95% CI = 1.13, 2.31; p = .01 per 1-SD) and Order Clostridiales was associated with improved DFS (HR = 0.62, 95% CI = 0.43-0.88; p = .01 per 1-SD). In exploratory analyses, Coprococcus and Roseburia were strongly associated with improved DFS. Overall, higher bacterial diversity and multiple bacteria were strongly associated with DFS. Metagenomic sequencing to elucidate species, gene, and functional level details among larger, diverse patient populations are critically needed to support the microbiome as a biomarker of CRC outcomes.}, }
@article {pmid39885116, year = {2025}, author = {Edwards, ER and Geraci, JC and Gildea, SM and Houtsma, C and Holdcraft, JA and Kennedy, CJ and King, AJ and Luedtke, A and Marx, BP and Naifeh, JA and Sampson, NA and Stein, MB and Ursano, RJ and Kessler, RC}, title = {Improving explainability of post-separation suicide attempt prediction models for transitioning service members: insights from the Army Study to Assess Risk and Resilience in Servicemembers - Longitudinal Study.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {37}, pmid = {39885116}, issn = {2158-3188}, support = {HU0001-15-2-0004//U.S. Department of Defense (United States Department of Defense)/ ; Project SPR-002-24F//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; }, mesh = {Humans ; *Military Personnel/psychology/statistics & numerical data ; *Suicide, Attempted/psychology/statistics & numerical data ; Male ; Longitudinal Studies ; Adult ; *Resilience, Psychological ; Female ; Young Adult ; Risk Assessment ; *Machine Learning ; Risk Factors ; United States ; Life Change Events ; }, abstract = {Risk of U.S. Army soldier suicide-related behaviors increases substantially after separation from service. As universal prevention programs have been unable to resolve this problem, a previously reported machine learning model was developed using pre-separation predictors to target high-risk transitioning service members (TSMs) for more intensive interventions. This model is currently being used in a demonstration project. The model is limited, though, in two ways. First, the model was developed and trained in a relatively small cross-validation sample (n = 4044) and would likely be improved if a larger sample was available. Second, the model provides no guidance on subtyping high-risk TSMs. This report presents results of an attempt to refine the model to address these limitations by re-estimating the model in a larger sample (n = 5909) and attempting to develop embedded models for differential risk of post-separation stressful life events (SLEs) known to mediate the association of model predictions with post-separation nonfatal suicide attempts (SAs; n = 4957). Analysis used data from the Army STARRS Longitudinal Surveys. The revised model improved prediction of post-separation SAs in the first year (AUC = 0.85) and second-third years (AUC = 0.77) after separation, but embedded models could not predict post-separation SLEs with enough accuracy to support intervention targeting.}, }
@article {pmid39885052, year = {2025}, author = {Grady, WM}, title = {Are Non-invasive Multi-cancer Early Cancer Detection Tests the Future?.}, journal = {Digestive diseases and sciences}, volume = {70}, number = {5}, pages = {1694-1702}, pmid = {39885052}, issn = {1573-2568}, support = {U2CCA271902/CA/NCI NIH HHS/United States ; U2CCA271902/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods/trends ; *Neoplasms/diagnosis/genetics ; *Biomarkers, Tumor/genetics/blood ; }, abstract = {Current cancer screening methods are effective for detecting early stage cancers and even preventing some cancers, but their effectiveness has only been demonstrated for a handful of cancers, and for many cancers, there are no screening tests clinically available. In addition, the majority of the screening methods are not ideal, resulting in suboptimal compliance and the occurrence of preventable cancers. A screening test that is convenient, safe, accurate and that can screen for multiple cancers is an ideal screening test that would address many of the shortcomings of the current tests. Multi-cancer detection tests (MCD) have the potential to meet these challenges and have engendered substantial enthusiasm in light of this. Using advances in DNA sequencing technology, cancer epigenetics and artificial intelligence, they are able to detect a large number of cancers predominantly via the patterns of methylated DNA alterations, DNA sequence alterations, and DNA fragment patterns of cell free DNA in the plasma and can accurately distinguish the cancer site of origin. Of note, some of the tests also combine circulating free DNA (cfDNA) with protein-based markers. However, for the majority of early stage cancers, the sensitivity is modest and below that of most of the current standard of care cancer screening tests. Furthermore, the clinical utility of screening for many of the cancers detectable by MCD tests remains to be proven. Here we describe the features of MCD tests, review the current data supporting their potential to be used in the clinic for cancer screening, and discuss the knowledge gaps surrounding understanding their clinical utility, with a focus on GI cancer screening.}, }
@article {pmid39884302, year = {2025}, author = {Deming, ME and Brown, ER and McArthur, MA and Schrag, SJ and Arvay, M and Humphrys, M and Ravel, J and Adelglass, J and Essink, B and Musante, DB and Maguire, R and Gorman, R and Formentini, E and Mason, R and Robb, ML and Neuzil, KM and Rapaka, RR and Wolff, P and Kotloff, KL and , }, title = {Vaccine efficacy of NVX-CoV2373 against SARS-CoV-2 infection in adolescents in the USA: an ancillary study to a phase 3, observer-blinded, randomised, placebo-controlled trial.}, journal = {The Lancet. Microbe}, volume = {6}, number = {4}, pages = {100984}, doi = {10.1016/j.lanmic.2024.100984}, pmid = {39884302}, issn = {2666-5247}, mesh = {Adolescent ; Child ; Female ; Humans ; Male ; Antibodies, Viral/blood ; *COVID-19/immunology/prevention & control/virology ; *COVID-19 Vaccines/immunology/administration & dosage ; *SARS-CoV-2/immunology ; United States ; *Vaccine Efficacy ; Clinical Trials, Phase III as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Although existing COVID-19 vaccines are known to be highly effective against severe disease and death, data are needed to assess their ability to reduce SARS-CoV-2 infection. We aimed to estimate the efficacy of the NVX-CoV2373 protein subunit vaccine against SARS-CoV-2 infection, regardless of symptoms, among adolescents.
METHODS: We performed an ancillary observational study (SNIFF) to the phase 3, observer-blinded, randomised, placebo-controlled PREVENT-19 trial that assessed vaccine efficacy against symptomatic COVID-19 in the USA. Participants in the PREVENT-19 trial included healthy adolescents aged 12-17 years and with no history of laboratory-confirmed SARS-CoV-2 infection. They were randomly assigned (2:1) to receive either the NVX-CoV2373 (Novavax, Gaithersburg, MD, USA) vaccine (immediate NVX-CoV2373 group) or placebo (delayed NVX-CoV2373 group) on days 0 and 21 (initial series). After 2 months, in a crossover series, participants received two doses, 21 days apart, of the intervention that they did not receive in their initial series. Participants at 47 of the PREVENT-19 sites were invited to participate in the SNIFF study and self-collect nasal swabs at home twice weekly for SARS-CoV-2 testing to assess vaccine efficacy against SARS-CoV-2 infection. This primary outcome was defined as the first identification of SARS-CoV-2 detected by RT-PCR, regardless of symptoms, with onset within 4 weeks after the second dose of the initial vaccination series until the second dose of the crossover series. Secondary outcomes were vaccine efficacy against asymptomatic and minimally symptomatic SARS-CoV-2 infection, durability of vaccine efficacy against SARS-CoV-2 infection, and durability of vaccine efficacy against asymptomatic and minimally symptomatic infections. Outcomes were analysed in the modified intention-to-treat population, which included all participants without previous SARS-CoV-2 infection and was restricted to participants enrolled within 4 weeks of the second dose of the primary (primary analysis population) or crossover (post-crossover analysis population) series. This study is registered with ClinicalTrials.gov (NCT04611802).
FINDINGS: Between June 1 and Dec 17, 2021, 1196 (53·2%) of the 2247 adolescent participants recruited in the PREVENT-19 trial enrolled in the SNIFF study. The primary analysis population included 471 participants in the immediate NVX-CoV2373 group and 220 in the delayed NVX-CoV2373 group. Incidence of SARS-CoV-2 infection was 14·9 cases per 100 person-years (95% CI 7·9-25·5) in the immediate group and 54·2 cases per 100 person-years (33·6-82·9) in the delayed group; vaccine efficacy was 73·5% (95% CI 47·1-86·7; p=0·0002). Incidence of minimally symptomatic or asymptomatic SARS-CoV-2 infection was 10·3 cases per 100 person-years (95% CI 4·7-19·6) in the immediate group and 36·1 cases per 100 person-years (19·8-60·7) in the delayed group; vaccine efficacy was 72·8% (95% CI 37·1-88·2; p=0·0023). After the second crossover dose, incidence of SARS-CoV-2 was 14·6 cases per 100 person-years (95% CI 8·6-23·0) in the immediate group (receiving placebo at crossover) and 9·1 cases per 100 person-years (3·0-21·3) in the delayed group, with a durability ratio of 160·3 (95% CI 59·5-431·6; p=0·35). Almost all infections after crossover were minimally symptomatic or asymptomatic, with a durability ratio of 151·4 (55·9-410·4; p=0·41).
INTERPRETATION: Among adolescents participating in the PREVENT-19 trial during the delta (B.1.617.2) variant wave of the COVID-19 pandemic, the NVX-CoV2373 vaccine was highly efficacious against SARS-CoV-2 infection regardless of symptoms, indicating its potential to reduce the reservoir of infections that contribute to community transmission.
FUNDING: US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.}, }
@article {pmid39883890, year = {2025}, author = {Bellmunt, J and Russell, BM and Szabados, B and Valderrama, BP and Nadal, R}, title = {Current and Future Role of Circulating DNA in the Diagnosis and Management of Urothelial Carcinoma.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {2}, pages = {e471912}, doi = {10.1200/EDBK-25-471912}, pmid = {39883890}, issn = {1548-8756}, mesh = {Humans ; *Circulating Tumor DNA/blood/genetics ; *Biomarkers, Tumor/blood/genetics ; Liquid Biopsy ; *Urinary Bladder Neoplasms/diagnosis/genetics/blood/therapy ; Disease Management ; Prognosis ; *Carcinoma, Transitional Cell/diagnosis/genetics/therapy/blood ; }, abstract = {The growing sophistication of tumor molecular profiling has helped to slowly transition oncologic care toward a more personalized approach in different tumor types, including in bladder cancer. The National Comprehensive Cancer Network recommends that all patients with stage IVA and stage IVB urothelial carcinoma have molecular analysis that integrates at least FGFR3 testing to help facilitate the selection of future therapeutic options. Sequencing of tumor-derived tissue is the mainstay to obtain this genomic testing, but as in other cancers, there has been extensive research into the integration of liquid biopsies in longitudinal management. Liquid biopsies broadly refer to the isolation of both cellular and noncellular tumor components including proteins and nucleic acids such as mRNA and circulating free DNA within a liquid sample. Although protein-based testing and testing of circulating tumor cells are options, the bulk of promising research in bladder cancer is investigating the role of plasma-based circulating tumor DNA (ctDNA). Currently, a universal consensus on optimal preanalytic and analytic approaches has not been fully defined, and the exact role that liquid biopsies should have in screening, diagnosis, prognostication, treatment selection, and monitoring is not yet known. Still, it can be expected that ctDNA testing will be a part of appropriate management of muscle-invasive bladder cancer and metastatic bladder cancer in the near future. In this review, the goal is to provide a practical overview of the current and future role of ctDNA in bladder cancer including ongoing trials.}, }
@article {pmid39883451, year = {2025}, author = {Hunter, N and Hurvitz, S}, title = {Where Did the Passion Go?-Rethinking Adjuvant Immune Therapy for Triple-Negative Breast Cancer.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.26811}, pmid = {39883451}, issn = {1538-3598}, }
@article {pmid39883059, year = {2025}, author = {Phipps, W and Bhinder, B and Towlerton, A and Mooka, P and Kafeero, J and Fitzgibbon, M and Elemento, O and Cesarman, E}, title = {Exome Sequencing Reveals a Sparse Genomic Landscape in Kaposi Sarcoma.}, journal = {Molecular cancer research : MCR}, volume = {23}, number = {5}, pages = {438-449}, pmid = {39883059}, issn = {1557-3125}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA239287/CA/NCI NIH HHS/United States ; K23 CA150931/CA/NCI NIH HHS/United States ; UM1 CA121947/CA/NCI NIH HHS/United States ; R21 CA206851/CA/NCI NIH HHS/United States ; R01 CA217138/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Sarcoma, Kaposi/genetics/pathology/virology ; *Exome Sequencing/methods ; Female ; Male ; Middle Aged ; Adult ; Mutation ; *Exome ; Aged ; Genomics/methods ; }, abstract = {Kaposi sarcoma is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus. People with immunodeficiencies, including human immunodeficiency virus (HIV), are at increased risk for developing Kaposi sarcoma, but our understanding of the contributions of the cellular genome to Kaposi sarcoma pathogenesis remains limited. To determine if there are cellular genetic alterations in Kaposi sarcoma that might provide biological or therapeutic insights, we performed whole-exome sequencing on 78 Kaposi sarcoma tumors and matched normal control skin from 59 adults with Kaposi sarcoma (46 with HIV-associated Kaposi sarcoma and 13 with HIV-negative Kaposi sarcoma) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median = 11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas. No recurrent mutations were seen, and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome was higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remains low compared with other cancers. Implications: Our findings indicate that the pathogenesis of Kaposi sarcoma differs from other malignancies and that the primary driver of carcinogenesis is Kaposi sarcoma-associated herpesvirus infection and expression of viral oncogenes, rather than clonal oncogenic transformation.}, }
@article {pmid39882642, year = {2025}, author = {Özcan, M and Cassaday, RD and Zarzycka, E and Vandendries, E and Zhang, F and Chen, Y and Nieto, A and Demirkan, F and Montesinos, P and Altuntas, F}, title = {Efficacy and safety of currently approved and lower starting doses of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukemia: a phase IV study.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.286091}, pmid = {39882642}, issn = {1592-8721}, abstract = {Inotuzumab ozogamicin (InO) is approved for treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Previous studies reported higher rates of post- hematopoietic stem cell transplant (HSCT) hepatic sinusoidal obstruction syndrome (SOS) in patients receiving InO versus chemotherapy prior to HSCT. It is unknown if a lower InO dose would reduce risk of post-HSCT SOS or if it would impact efficacy. This study evaluated efficacy and safety of the currently approved InO starting dose and a lower dose in adults with R/R ALL who were eligible for HSCT and were identified as being at higher risk of post- HSCT SOS. This open-label, phase 4 study (NCT03677596) had 2 phases: in the run-in phase patients received InO at 1.2 mg/m2/cycle (n=22); in the randomized phase patients received InO starting at dose levels of 1.8 mg/m2/cycle (n=38) or 1.2 mg/m2/cycle (n=42). Primary endpoints were rate of SOS and rate of hematologic remission. Overall, SOS was reported in 10 patients (9.8%); all were post-HSCT SOS. In patients who proceeded to HSCT, post-HSCT SOS rates were 20%, 28.6%, 25.8%, and 16.7% in 1.2 mg/m2/cycle (run-in), 1.2 mg/m2/cycle (randomized), 1.2 mg/m2/cycle (run-in and randomized), and 1.8 mg/m2/cycle (randomized), respectively. The CR/CRi rates were 50.0%, 83.3%, 71.9%, and 68.4% in the respective subgroups. The study found that a starting dose of 1.2mg/m2/cycle demonstrated consistent efficacy and safety to the recommended 1.8 mg/m2/cycle dose in adults with R/R ALL who were eligible for HSCT and had a higher risk of post-HSCT SOS.}, }
@article {pmid39881206, year = {2025}, author = {Vo, PT and Sandmaier, BM and Othus, M and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Davis, C and Basom, RS and Storb, R and Walter, RB}, title = {Relationship between age, conditioning intensity, and outcome after allografting in adults age ≥60 years with AML.}, journal = {Bone marrow transplantation}, volume = {60}, number = {4}, pages = {482-490}, pmid = {39881206}, issn = {1476-5365}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Middle Aged ; Male ; Female ; Aged ; *Leukemia, Myeloid, Acute/therapy/mortality ; *Transplantation Conditioning/methods ; Retrospective Studies ; Age Factors ; Treatment Outcome ; *Hematopoietic Stem Cell Transplantation/methods ; Disease-Free Survival ; }, abstract = {Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥70 (n = 122) allografted for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥70 years had higher non-relapse mortality (NRM) than those aged ≥60-64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Relative to age 60-64, age ≥70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no such associations were found with nonmyeloablative (NMA) conditioning. Underlying, patients aged 60-64 and 65-69, but not those aged ≥70, had a significantly lower relapse risk with RIC relative to NMA conditioning, whereas NRM risks increased across all age cohorts. Our findings support allografting for adults ≥70 with AML in remission, especially with NMA conditioning.}, }
@article {pmid39881190, year = {2025}, author = {Toghani, D and Gupte, S and Zeng, S and Mahammadov, E and Crosse, EI and Seyedhassantehrani, N and Burns, C and Gravano, D and Radtke, S and Kiem, HP and Rodriguez, S and Carlesso, N and Pradeep, A and Georgiades, A and Lucas, F and Wilson, NK and Kinston, SJ and Göttgens, B and Zong, L and Beerman, I and Park, B and Janssens, DH and Jones, D and Toghani, A and Nerlov, C and Pietras, EM and Mesnieres, M and Maes, C and Kumanogoh, A and Worzfeld, T and Cheong, JG and Josefowicz, SZ and Kharchenko, P and Scadden, DT and Scialdone, A and Spencer, JA and Silberstein, L}, title = {Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.}, journal = {Nature aging}, volume = {5}, number = {4}, pages = {558-575}, pmid = {39881190}, issn = {2662-8465}, support = {P01 HL131477/HL/NHLBI NIH HHS/United States ; R01 HL148189/HL/NHLBI NIH HHS/United States ; HL148189//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Animals ; *Hematopoietic Stem Cells/metabolism/cytology ; *Semaphorins/metabolism/genetics ; Mice ; *Myeloid Cells/metabolism/cytology ; *Stem Cell Niche ; Aging ; Neutrophils/metabolism ; Inflammation/metabolism ; Mice, Inbred C57BL ; Male ; }, abstract = {Somatic stem cell pools comprise diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased hematopoietic stem cells (myHSCs) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but, at the same time, become irreversibly damaged during inflammation and aging. Here we identify an extrinsic factor, Semaphorin 4A (Sema4A), which non-cell-autonomously confers myHSC resilience to inflammatory stress. We show that, in the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor, Plexin D1, and safeguards the myHSC epigenetic state. Our study shows that, by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.}, }
@article {pmid39875703, year = {2025}, author = {Harris, HR and Lind, K and Fest, S and Thomson, CA and Saquib, N and Shadyab, AH and Schnatz, PF and Robles-Morales, R and Qi, L and Strickler, HD and Roe, DJ and Farland, LV}, title = {Infertility and Risk of Ovarian Cancer in the Women's Health Initiative.}, journal = {Cancer causes & control : CCC}, volume = {36}, number = {6}, pages = {617-624}, pmid = {39875703}, issn = {1573-7225}, support = {R03 HD102403/HD/NICHD NIH HHS/United States ; R03 HD102403/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/epidemiology/etiology/pathology ; Middle Aged ; Risk Factors ; Women's Health ; Follow-Up Studies ; *Infertility, Female/complications/epidemiology ; Aged ; Postmenopause ; Proportional Hazards Models ; *Infertility/complications ; }, abstract = {PURPOSE: There is a consistent relationship with greater ovulation frequency and increased risk of ovarian cancer. However, prior research on infertility, which may be associated with ovulation frequency through multiple mechanisms, and ovarian cancer has yielded conflicting results, possibly due to prior research conflating fertility treatment with infertility and restricting follow-up to premenopausal cases. Our objective was to determine the association between infertility and risk of postmenopausal ovarian cancer, overall and by histotype, in a population that had not received treatment with IVF.
METHODS: We utilized data from the Women's Health Initiative (n = 112,925 postmenopausal participants) with over 25 years of follow-up. At baseline, participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant and whether a reason was found. Cox proportional hazards models were used to calculate hazard ratios (HRs) of incident adjudicated ovarian cancer comparing participants with a history of infertility to fertile participants overall and by histotype.
RESULTS: 17% of participants reported a history of infertility at baseline and 1,109 ovarian cancer cases were diagnosed during follow-up. No statistically significant association was observed between infertility and risk of any ovarian cancer (HR: 1.09, 95% CI 0.92-1.29), but those reporting infertility had a 90% higher risk of endometrioid and clear cell ovarian cancers (HR: 1.90 95% CI 1.09-3.34) compared to fertile participants. The reported reason(s) for infertility had no discernable impact on these associations.
CONCLUSIONS: Infertility may be associated with clear cell and endometrioid ovarian cancer but not other ovarian tumor histotypes.}, }
@article {pmid39874304, year = {2025}, author = {Sabo, MC and Mustafa, S and Saha, A and Oyaro, B and Fiedler, TL and Krueger, M and Fuchs, E and Mureithi, M and Mandaliya, K and Jaoko, W and Richardson, BA and Gharib, SA and Fredricks, DN and Shah, JA and McClelland, RS}, title = {Bacterial vaginosis is associated with transcriptomic changes but not higher concentrations of cervical leukocytes in a study of women at high risk for HIV acquisition.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf049}, pmid = {39874304}, issn = {1537-6613}, support = {K23 HD100221/HD/NICHD NIH HHS/United States ; }, abstract = {BACKGROUND: The association between bacterial vaginosis (BV) and increased HIV acquisition risk may be related to concentrations of HIV-susceptible immune cells in the cervix.
METHODS: Participants (31 with BV and 30 with normal microbiota) underwent cervical biopsy at a single visit. Immune cells were quantified and sorted using flow cytometry (N=55), localization assessed by immunofluorescence (N=16), and function determined by bulk RNA sequencing (RNA-seq) of live CD45+ cells (N=21).
RESULTS: Linear regression analyses demonstrated no differences in mean log2 [cells/mg tissue] between women with BV vs normal microbiota for antigen presenting cell (APC) subtypes linked to HIV risk (including CD1a+HLA-DR+ Langerhans cells, CD11c+CD14+ dendritic cells [DCs], and CD11c+HLA-DR+ DCs) and CD4+ T cells. Women with BV had a higher median proportion of CD11c+HLA-DR+ APCs (out of total cells) in cervical epithelium (0.1% vs 0.0%; p=0.03 using Mann-Whitney testing). RNA-seq identified 1,032 differentially expressed genes (adjusted p-value <0.05) in CD45+ cells between women with BV vs normal microbiota. Women with BV demonstrated downregulation of pathways linked to translation, metabolism, cell stress, and immune signaling.
CONCLUSIONS: BV alters immune cell localization and function; future studies are needed to address how these changes may mediate HIV acquisition risk.}, }
@article {pmid39873851, year = {2025}, author = {Javid, SH and Kazerouni, AS and Hippe, DS and Hirano, M and Schnuck-Olapo, J and Biswas, D and Bryant, ML and Li, I and Xiao, J and Kim, AG and Guo, A and Dontchos, B and Kilgore, M and Kim, J and Partridge, SC and Rahbar, H}, title = {Preoperative MRI to Predict Upstaging of DCIS to Invasive Cancer at Surgery.}, journal = {Annals of surgical oncology}, volume = {32}, number = {5}, pages = {3234-3243}, pmid = {39873851}, issn = {1534-4681}, support = {ROI CA203883 (Rahbar)/GF/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/surgery/pathology/diagnostic imaging ; *Carcinoma, Intraductal, Noninfiltrating/surgery/pathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Prospective Studies ; Middle Aged ; Neoplasm Invasiveness ; Aged ; Prognosis ; Follow-Up Studies ; *Carcinoma, Ductal, Breast/surgery/pathology/diagnostic imaging ; Neoplasm Staging ; Adult ; Preoperative Care ; Contrast Media ; Biopsy, Large-Core Needle ; ROC Curve ; Mammography ; }, abstract = {BACKGROUND: Ductal carcinoma in situ (DCIS) is overtreated, in part because of inability to predict which DCIS cases diagnosed at core needle biopsy (CNB) will be upstaged at excision. This study aimed to determine whether quantitative magnetic resonance imaging (MRI) features can identify DCIS at risk of upstaging to invasive cancer.
METHODS: This prospective observational clinical trial analyzed women with a diagnosis of DCIS on CNB. All the participants underwent preoperative 3T MRI. Quantitative MRI features from routine dynamic contrast-enhanced (DCE) MR images (e.g., peak percent enhancement [PE]) and from advanced high temporal-resolution DCE MR images (e.g., Ktrans) were measured. Clinical, pathologic, and mammographic features were reviewed. Associations with upstaging were summarized using the area under the receiver operating characteristic curve (AUC).
RESULTS: Of 58 DCIS lesions at CNB, 15 (26%) were upstaged to invasive cancer at surgery. Of the 58 lesions, 46 (79%) enhanced on MRI, although enhancement alone was not significantly associated with upstaging (p = 0.71). Among the DCIS lesions that enhanced, higher PE was most strongly associated with upstaging (AUC, 0.81; adjusted p = 0.009) and outperformed MRI features acquired via high temporal resolution DCE-MRI (AUC, 0.50-0.73). Lesion span on MRI was not significantly associated with upstaging risk (AUC, 0.55; adjusted p = 0.61), nor were any clinical, pathologic, or mammographic features (p > 0.24).
CONCLUSIONS: Quantitative features acquired from routine clinical breast MRI and advanced DCE-MRI demonstrated good performance in identifying which DCIS lesions were upstaged to invasive cancer at excision. These features may prove valuable for appropriate selection of active surveillance in future DCIS de-escalation trials.}, }
@article {pmid39873699, year = {2025}, author = {Huang, Y and Kwan, ML and Heckbert, SR and Smith, NL and Othus, M and Laurent, CA and Roh, JM and Rillamas-Sun, E and Lee, VS and Kolevska, T and Cheng, RK and Irribarren, C and Nguyen-Huynh, M and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Duration of aromatase inhibitor use and long-term cardiovascular risk in breast cancer survivors.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {1}, pages = {}, pmid = {39873699}, issn = {2515-5091}, support = {R01 CA214057/CA/NCI NIH HHS/United States ; U01 CA195565/CA/NCI NIH HHS/United States ; //MPIs: M.L.K./H.G./ ; //PI: L.H.K./ ; //MPIs: L.H.K./Ambrosone/ ; }, mesh = {Humans ; Female ; *Aromatase Inhibitors/administration & dosage/adverse effects ; *Breast Neoplasms/drug therapy/chemistry/mortality ; Middle Aged ; *Cardiovascular Diseases/mortality/epidemiology/chemically induced ; Postmenopause ; Aged ; *Cancer Survivors/statistics & numerical data ; Anastrozole/administration & dosage/adverse effects ; Time Factors ; Proportional Hazards Models ; Stroke/epidemiology ; Heart Disease Risk Factors ; }, abstract = {BACKGROUND: There are limited data on duration of aromatase inhibitor (AI) and cardiovascular disease (CVD) risk in breast cancer (BC) survivors. We examined the risk of CVD and mortality associated with the duration of AI use in postmenopausal women with early stage hormone receptor-positive BC.
METHODS: Postmenopausal women diagnosed with hormone receptor-positive BC (n = 5853) who used an AI were included. Cause-specific hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between AI use duration (short term: >0 and <2 years; intermediate term: ≥2 and <5 years; long term: ≥5 years) and CVD and mortality outcomes. The landmark method was used to avoid immortal time bias; the selected landmark was 6 years after BC diagnosis.
RESULTS: Anastrozole was the AI predominantly prescribed (95.4%). Over a median follow-up of 3 years for women who survived 6 years after BC diagnosis, a lower risk of stroke was observed in intermediate-term AI users (HR = 0.60, 95% CI = 0.37 to 0.96) and long-term AI users (HR = 0.51, 95% CI = 0.30 to 0.85), than in short-term AI users. The longer duration of AI use was also associated with lower risk of all-cause mortality and non-CVD-related mortality. In addition, long-term AI users were at 37% lower risk of CVD-related mortality than short-term AI users. No statistically significant differences were observed in risks of major adverse cardiovascular events, ischemic heart disease, and heart failure across the 3 groups.
CONCLUSION: Among postmenopausal women with early stage hormone receptor-positive BC who survived 6 years after BC diagnosis, longer duration of AI use was not associated with elevated CVD risk.}, }
@article {pmid39871186, year = {2025}, author = {Pinto-Santini, D and Jalil, EM and Fernandes, GT and Hilaire, G and Kolevic, L and Cabello, R and Grinsztejn, B and Pape, W and Deschamps, MM and House, MG and Brofsky, E and Sahasrabuddhe, VV and Dasgupta, S and Pasalar, S and Madeleine, MM and Carter, J and Prabhu, PR and Galloway, D and Duerr, A}, title = {ULACNet-301, OPTIMO protocol: optimizing HPV vaccination regimen for cancer prevention in children and adolescents living with HIV.}, journal = {BMC cancer}, volume = {25}, number = {1}, pages = {151}, pmid = {39871186}, issn = {1471-2407}, support = {U54 CA242977/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Child ; Adolescent ; *HIV Infections/immunology/complications/virology ; *Papillomavirus Infections/prevention & control/immunology/complications/virology ; Female ; *Papillomavirus Vaccines/administration & dosage/immunology ; Male ; Vaccination/methods ; Immunization Schedule ; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18/administration & dosage ; *Uterine Cervical Neoplasms/prevention & control/virology ; }, abstract = {BACKGROUND: Persistent infection with human papillomavirus (HPV) is associated with most cervical and anal cancer cases and a large fraction of other anogenital and oropharyngeal cancers. The prophylactic HPV vaccines are known to prevent HPV infections and HPV-associated disease, although there is evidence of reduced response to the HPV vaccination among individuals living with HIV. Prior studies among individuals without HIV suggest that a single HPV vaccine dose induces humoral immune responses that, while lower than those induced by two or three doses, still confer protection against HPV infection. Current recommendations for HPV vaccine include a single-dose schedule for children 9-14-years-olds without HIV. Although two to three doses are recommended for children living with HIV (CLWH), there is very limited data comparing responses to one vs. 2-3 doses in CLWH.
METHODS: The OPTIMO study will compare immune responses to HPV vaccination in CLWH by measuring antibody and memory B cell (Bmem) responses after 1, 2, or 3 doses of the 9-valent HPV (9vHPV) vaccine, Gardasil-9. A comparison group of children without HIV will receive one dose of the vaccine. The durability of the response will be assessed at 24 months after the last dose of a given regimen. The OPTIMO trial will take place among CLWH from low and middle-income country (LMIC) settings in Peru, Brazil, and Haiti.
DISCUSSION: Previous studies of single-dose regimens in individuals without HIV raise questions about whether one dose would suffice for CLWH and, if not, whether two or three doses are needed to provide protection against HPV-related cancers. These questions have operational consequences in LMICs given the barriers to delivering multiple doses, uneven availability, and intermittent shortages of HPV vaccines. In addition, information on HIV status for children and adolescents is rarely available during vaccination campaigns based in schools or public health clinics, so CLWH may receive a single dose despite policy recommendations that they receive two or three. This study will provide evidence on the optimal number of doses needed for CLWH that can inform HPV vaccination campaigns in LMICs, especially those with a higher burden of HIV infection and higher incidence of HPV-related cancers.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04265950.}, }
@article {pmid39870767, year = {2025}, author = {Costa, LJ and Banerjee, R and Mian, H and Weisel, K and Bal, S and Derman, BA and Htut, MM and Nagarajan, C and Rodriguez, C and Richter, J and Frigault, MJ and Ye, JC and van de Donk, NWCJ and Voorhees, PM and Puliafito, B and Bahlis, N and Popat, R and Chng, WJ and Ho, PJ and Kaur, G and Kapoor, P and Du, J and Schjesvold, F and Berdeja, J and Einsele, H and Cohen, AD and Mikhael, J and Biru, Y and Rajkumar, SV and Lin, Y and Martin, TG and Chari, A}, title = {International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma.}, journal = {Leukemia}, volume = {39}, number = {3}, pages = {543-554}, pmid = {39870767}, issn = {1476-5551}, mesh = {Humans ; *Multiple Myeloma/therapy/immunology ; *Immunotherapy/methods ; *Practice Guidelines as Topic/standards ; Immunotherapy, Adoptive/methods ; }, abstract = {T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.}, }
@article {pmid39870766, year = {2025}, author = {Othus, M and Garcia-Manero, G and Appelbaum, FR and Erba, HP and Dietrich, E and Raychaudhuri, S and Appelbaum, J and Estey, E and Percival, ME}, title = {Probability of remission with reinduction with 7+3 versus high-dose cytarabine: analysis of SWOG trial S1203.}, journal = {Leukemia}, volume = {39}, number = {3}, pages = {752-754}, pmid = {39870766}, issn = {1476-5551}, support = {CA180819//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid39869930, year = {2025}, author = {Cardle, II and Scherer, DR and Jensen, MC and Pun, SH and Sellers, DL}, title = {In Situ Bioconjugation of Synthetic Peptides onto Universal Chimeric Antigen Receptor T Cells for Targeted Cancer Immunotherapies.}, journal = {ACS nano}, volume = {19}, number = {5}, pages = {5750-5768}, doi = {10.1021/acsnano.4c16824}, pmid = {39869930}, issn = {1936-086X}, support = {R01 AG063845/AG/NIA NIH HHS/United States ; R01 NS118247/NS/NINDS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {*Receptors, Chimeric Antigen/immunology/chemistry ; Animals ; Humans ; Mice ; *Peptides/chemistry/immunology ; *Immunotherapy/methods ; *Immunotherapy, Adoptive ; Cell Line, Tumor ; *T-Lymphocytes/immunology ; *Neoplasms/therapy/immunology ; *Receptors, Antigen, T-Cell/immunology ; }, abstract = {The recent development of modular universal chimeric antigen receptor (CAR) T-cell platforms that use bifunctional adaptor intermediates to redirect engineered T-cell effector function has greatly expanded the capabilities of adoptive T-cell therapy, enabling safer and more comprehensive cancer treatment. However, universal CAR receptor systems rely on unstable transient recognition of tag-coupled intermediates for T-cell activation, and the array of targeting intermediates has been limited to antibodies and small molecules. Addressing these shortcomings, we engineered universal CAR T-cell receptors that can be covalently modified with synthetic biomaterials in vivo by accelerated SpyCatcher003-SpyTag003 chemistry for cancer-cell targeting. SpyCatcher003-modified CARs, nicknamed DB5 CARs, displayed fast, low-nanomolar reaction kinetics with a synthetic αvβ6-binding peptide that incorporates a SpyTag003 peptide via branched peptide synthesis to comprise a bifunctional intermediate. Prearming DB5 CAR T cells or prelabeling target cells with the bifunctional peptide produced selective CD4[+] and CD8[+] CAR T-cell responses against αvβ6[+] cancer cells in vitro. Furthermore, the synthetic targeting intermediate showed robust DB5 CAR T-cell arming in vivo and selectively reduced αvβ6[+] tumor progression in a dual flank xenograft model. We demonstrate the versatility and therapeutic potential of "Cyborg" CAR T-cell therapies that utilize synthetic biomaterials to direct CAR T-cell activity via highly selective bioconjugation that occurs in vivo.}, }
@article {pmid39869835, year = {2025}, author = {Mascarenhas, L and DuBois, SG and Albert, CM and Bielack, S and Orbach, D and Federman, N and Geoerger, B and Nagasubramanian, R and Zhang, Y and Chisholm, J and Gallego Melcon, S and Goto, H and Morgenstern, DA and Owens, C and Pappo, AS and Perreault, S and Schulte, JH and Shukla, N and Zwaan, CM and Neu, N and Bernard-Gauthier, V and De La Cuesta, E and van Tilburg, CM and Laetsch, TW}, title = {Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {10}, pages = {1180-1187}, pmid = {39869835}, issn = {1527-7755}, mesh = {Humans ; Child ; *Pyrazoles/administration & dosage/adverse effects/therapeutic use ; Male ; Female ; *Pyrimidines/administration & dosage/adverse effects/therapeutic use ; Adolescent ; *Sarcoma/drug therapy/genetics/pathology ; Child, Preschool ; *Oncogene Proteins, Fusion/genetics ; *Receptor, trkA/genetics/antagonists & inhibitors ; Infant ; *Protein Kinase Inhibitors/adverse effects/administration & dosage ; *Soft Tissue Neoplasms/drug therapy/genetics ; }, abstract = {Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.}, }
@article {pmid39869680, year = {2025}, author = {Lum, MA and Jonas, KA and Parmar, S and Black, AR and O'Connor, CM and Dobersch, S and Yamamoto, N and Robertson, TM and Schutter, A and Giambi, M and Avelar, RA and DiFeo, A and Woods, NT and Kugel, S and Narla, G and Black, JD}, title = {Small-molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {4}, pages = {}, pmid = {39869680}, issn = {1558-8238}, support = {P20 GM121316/GM/NIGMS NIH HHS/United States ; R21 CA273979/CA/NCI NIH HHS/United States ; R01 CA054807/CA/NCI NIH HHS/United States ; P30 CA036727/CA/NCI NIH HHS/United States ; R01 CA240993/CA/NCI NIH HHS/United States ; T32 CA009476/CA/NCI NIH HHS/United States ; }, mesh = {*Protein Phosphatase 2/metabolism/genetics ; Humans ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mice ; Animals ; Cell Cycle Proteins ; Cell Line, Tumor ; *Eukaryotic Initiation Factor-4E/metabolism/genetics ; *Protein Biosynthesis/drug effects ; *Phosphoproteins/metabolism/genetics ; *Neoplasms/genetics/drug therapy/metabolism/pathology ; *Eukaryotic Initiation Factors/metabolism/genetics ; Activating Transcription Factor 4/metabolism/genetics ; Phosphorylation/drug effects ; *Small Molecule Libraries/pharmacology ; *Neoplasm Proteins/metabolism/genetics ; }, abstract = {Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E-binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small-molecule activators of PP2A (SMAPs) to explore the role of B56-PP2A(s) in 4E-BP regulation and the potential of B56-PP2A activation for restoring translational control in tumors. SMAP treatment promoted PP2A-dependent hypophosphorylation of 4E-BP1/2, supporting a role for B56-PP2As (e.g., B56α-PP2A) as 4E-BP phosphatases. Unexpectedly, SMAPs induced transcriptional upregulation of 4E-BP1 through a B56-PP2A→TFE3/TFEB→ATF4 axis. Cap-binding and coimmunoprecipitation assays showed that B56-PP2A(s) activation blocks assembly of the eIF4F translation initiation complex, and cap-dependent translation assays confirmed the translation-inhibitory effects of SMAPs. Thus, B56-PP2A(s) orchestrate a translation-repressive program involving transcriptional induction and activation of 4E-BP1. Notably, SMAPs promoted 4E-BP1-dependent apoptosis in tumor cells and potentiated 4E-BP1 function in the presence of ERK or mTOR inhibitors, agents that rely on inhibition of eIF4E-dependent translation for antitumor activity. These findings, combined with the ability of SMAPs to regulate 4E-BP1 in vivo, highlight the potential of PP2A activators for cancer therapy and overcoming therapy resistance.}, }
@article {pmid39869261, year = {2025}, author = {Stearns, V and Chen, R and Blackford, AL and Saylor, E and Mull, J and Folmer, A and Jelinek, J and Hodgdon, C and Bacon, J and Engle, J and Shah, M and Sheinberg, R and Pedraza-Cardozo, S and Wilkinson, M and Alvendia, M and Snyder, C and Smith, KL}, title = {The Johns Hopkins Hope at Hopkins Clinic: supporting the comprehensive needs of individuals with metastatic breast cancer.}, journal = {Breast cancer research and treatment}, volume = {210}, number = {3}, pages = {551-562}, pmid = {39869261}, issn = {1573-7217}, support = {5 NU58DP006673//Centers for Disease Control and Prevention Foundation/ ; P30CA006973//Johns Hopkins Cancer Center Support Grant/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/therapy/psychology/pathology/epidemiology ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; Patient Reported Outcome Measures ; Neoplasm Metastasis ; Quality of Life ; }, abstract = {PURPOSE: Individuals with metastatic breast cancer (MBC) may live with their disease for many years. We initiated the Johns Hopkins Hope at Hopkins Clinic to assess the needs and optimize the care of these patients.
PATIENTS AND METHODS: Patients with MBC who agreed to participate in the Clinic in addition to usual care completed patient-reported outcome (PRO) surveys. They met with a navigator and underwent core consults (cancer rehabilitation, integrative medicine, supportive and palliative care, social work, and nutrition), clinical trial eligibility assessment, and optional services based on PRO responses and selection from a Clinic Menu. A medical oncologist provided a Care Plan during a final consult. Participants were asked to complete 3- and 6-month follow-up PRO surveys. We report on initial Clinic implementation, participant characteristics, and baseline PROs.
RESULTS: From 11/2020 to 6/2022, 45 patients completed baseline surveys and participated in the Clinic. Median age was 58 (32-86); the majority (71%) were white and had estrogen receptor-positive (84%) tumors. Baseline physical and mental health were not good for ≥ 14 days of the past month for 22 and 10%, respectively. PROMIS measure scores were > 1 standard deviation worse than average for 32% for Physical Health, 16% for Mental Health, and 23% for Physical Function. PHQ-8 and GAD-7 scores suggested depression and anxiety for 22 and 7%, respectively. More than 80% of participants received specific recommendations from the core consultants. Only 20% of participants completed follow-up surveys.
CONCLUSION: Patients living with MBC have multiple needs. We used our results to implement routine PRO assessments and to expand services for patients with MBC. Our experience can serve as a model for coordinated care in other systems.}, }
@article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Brain/immunology ; Immunotherapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, }
@article {pmid39868296, year = {2025}, author = {Guccione, C and Sfiligoi, I and Gonzalez, A and Shaffer, JP and Kazachkova, M and Weng, Y and McDonald, D and Shah, SC and Minot, SS and Paulson, T and Grady, WM and Alexandrov, LB and Knight, R and Curtius, K}, title = {Community assembly modeling of microbial evolution within Barrett's esophagus and esophageal adenocarcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868296}, issn = {2692-8205}, support = {K12 GM068524/GM/NIGMS NIH HHS/United States ; R01 CA241728/CA/NCI NIH HHS/United States ; P30 DK120515/DK/NIDDK NIH HHS/United States ; R01 CA140657/CA/NCI NIH HHS/United States ; IK2 CX002027/CX/CSRD VA/United States ; T32 GM007198/GM/NIGMS NIH HHS/United States ; R21 CA259687/CA/NCI NIH HHS/United States ; R01 CA270235/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; U24 CA248454/CA/NCI NIH HHS/United States ; }, abstract = {Mathematical modeling of somatic evolution, a process impacting both host cells and microbial communities in the human body, can capture important dynamics driving carcinogenesis. Here we considered models for esophageal adenocarcinoma (EAC), a cancer that has dramatically increased in incidence over the past few decades in Western populations, with high case fatality rates due to late-stage diagnoses. Despite advancements in genomic analyses of the precursor Barrett's esophagus (BE), prevention of late-stage EAC remains a significant clinical challenge. Previous microbiome studies in BE and EAC have focused on quantifying static microbial abundance differences rather than evolutionary dynamics. Using whole genome sequencing data from esophageal tissues, we first applied a robust bioinformatics pipeline to extract non-host DNA reads, mapped these putative reads to microbial taxa, and retained those taxa with high genomic coverage. When applying mathematical models of microbial evolution to sequential stages of progression to EAC, we observed evidence of neutral dynamics in community assembly within normal esophageal tissue and BE, but not EAC. In a case-control study of BE patients who progressed to EAC cancer outcomes (CO) versus those who had non-cancer outcomes (NCO) during follow-up (mean=10.5 years), we found that Helicobacter pylori deviated significantly from the neutral expectation in BE NCO, suggesting that factors related to H. pylori or H. pylori infection itself may influence EAC risk. Additionally, simulations incorporating selection recapitulated non-neutral behaviors observed in the datasets. Formally modeling dynamics during progression holds promise in clinical applications by offering a deeper understanding of microbial involvement in cancer development.}, }
@article {pmid39868184, year = {2025}, author = {Gen, R and Addetia, A and Asarnow, D and Park, YJ and Quispe, J and Chan, MC and Brown, JT and Lee, J and Campbell, MG and Lapointe, CP and Veesler, D}, title = {SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868184}, issn = {2692-8205}, support = {75N93022C00036/AI/NIAID NIH HHS/United States ; DP1 AI158186/AI/NIAID NIH HHS/United States ; }, abstract = {SARS-CoV-2 nonstructural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats which are natural reservoirs of sarbecoviruses and possess a markedly different innate immune system than humans. Here, we reveal that SARS-CoV-2 nsp1 potently inhibits translation in bat cells from Rhinolophus lepidus, belonging to the same genus as known sarbecovirus reservoirs hosts. We determined a cryo-electron microscopy structure of SARS-CoV-2 nsp1 bound to the Rhinolophus lepidus 40S ribosome and show that it blocks the mRNA entry channel via targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cell lines from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity (including bats), providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillovers.}, }
@article {pmid39868116, year = {2025}, author = {Gupta, A and Morella, N and Sutormin, D and Li, N and Gaisser, K and Robertson, A and Ispolatov, Y and Seelig, G and Dey, N and Kuchina, A}, title = {Combinatorial phenotypic landscape enables bacterial resistance to phage infection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868116}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R21 DE032890/DE/NIDCR NIH HHS/United States ; R35 GM150994/GM/NIGMS NIH HHS/United States ; }, abstract = {Success of phage therapies is limited by bacterial defenses against phages. While a large variety of anti-phage defense mechanisms has been characterized, how expression of these systems is distributed across individual cells and how their combined activities translate into protection from phages has not been studied. Using bacterial single-cell RNA sequencing, we profiled the transcriptomes of ~50,000 cells from cultures of a human pathobiont, Bacteroides fragilis, infected with a lytic bacteriophage. We quantified the asynchronous progression of phage infection in single bacterial cells and reconstructed the infection timeline, characterizing both host and phage transcriptomic changes as infection unfolded. We discovered a subpopulation of bacteria that remained uninfected and determined the heterogeneously expressed host factors associated with protection. Each cell's vulnerability to phage infection was defined by combinatorial phase-variable expression of multiple genetic loci, including capsular polysaccharide (CPS) biosynthesis pathways, restriction-modification systems (RM), and a previously uncharacterized operon likely encoding fimbrial genes. By acting together, these heterogeneously expressed phase-variable systems and anti-phage defense mechanisms create a phenotypic landscape where distinct protective combinations enable the survival and re-growth of bacteria expressing these phenotypes without acquiring additional mutations. The emerging model of complementary action of multiple protective mechanisms heterogeneously expressed across an isogenic bacterial population showcases the potent role of phase variation and stochasticity in bacterial anti-phage defenses.}, }
@article {pmid39866881, year = {2025}, author = {Vo, P and Ng, K and Schoch, HG and Cooper, J and Vupalanchi, A and Flowers, M and Sandmaier, B and Gooley, T and Storb, R}, title = {Subsequent Cancers following Non-myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39866881}, issn = {2693-5015}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {We examined the risk of subsequent malignant neoplasms (SMNs) in 1720 patients with hematologic cancers given allogeneic hematopoietic grafts from 03/1998 to 08/2023 after nonmyeloablative conditioning regimens. With a median follow-up of 12 years, the cumulative incidence of SMNs was 17% (95% CI, [15%, 19%]). Most SMNs (n = 543) were non-melanoma skin cancers seen in 208 patients; unfortunately, information on these cancers was not available in the Surveillance, Epidemiology, and End Results (SEER) database for comparison with such tumors in the general population. However, developing non-melanoma skin cancers was statistically significantly associated with chronic GVHD and, thus, unlikely to be conditioning regimen related. Eighty-six patients (5%) developed 93 other SMNs. This number (93 SNMs) significantly exceeded the expected 73.4 cases in the comparison group (p = 0.03). This increase was driven exclusively by increases in uterine adenocarcinoma (n = 2), squamous lip cancer (n = 5), and squamous penile cancer (n = 2); the latter two cancers were, again, associated with chronic GVHD. Apart from these three tumor types, there were no observed increases in the risk of other tumors compared to those in the general population.}, }
@article {pmid39866245, year = {2025}, author = {Knäusl, B and Vestergaard, A and Schwarz, M and Muren, LP}, title = {New guidelines and recommendations to advance treatment planning in proton therapy.}, journal = {Physics and imaging in radiation oncology}, volume = {33}, number = {}, pages = {100695}, pmid = {39866245}, issn = {2405-6316}, }
@article {pmid39866161, year = {2025}, author = {Goldberg, SR and Ko, LK and Hsu, L and Yin, H and Kooperberg, C and Peters, U and Burnett-Hartman, AN}, title = {Patient Perspectives on Personalized Risk Communication Using Polygenic Risk Scores to Inform Colorectal Cancer Screening Decisions.}, journal = {AJPM focus}, volume = {4}, number = {1}, pages = {100308}, pmid = {39866161}, issn = {2773-0654}, support = {R01 CA244588/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Colorectal cancer is increasingly diagnosed in people aged <50 years. New U.S. guidelines recommend screening initiation at age 45 years. Providing personalized risk for colorectal cancer using polygenic risk scores may be an opportunity to engage this younger population in colorectal cancer screening. There is limited research on patient understanding of polygenic risk scores results and use of polygenic risk scores to inform colorectal cancer screening decisions.
METHODS: From May 2022 to June 2023, 20 Kaiser Permanente Colorado members aged 46-51 years who had been offered colorectal cancer screening but had never completed it signed consent to provide a saliva sample for colorectal cancer polygenic risk score analysis. After receiving personalized polygenic risk scores for colorectal cancer, participants completed a semistructured interview regarding the understanding of their polygenic risk scores, perceived colorectal cancer risk, and intention to screen. Thematic analysis was conducted using Atlas.ti, Version 8.
RESULTS: Of the 19 participants who successfully completed polygenic risk score-related testing and a semistructured interview, 13 were female, 14 never smoked cigarettes, 6 were Hispanic, and 13 were non-Hispanic White. One participant had high risk for colorectal cancer on the basis of polygenic risk score results. Qualitative interviews showed participants' understanding of their results, trust in polygenic risk scores, perception of risk for colorectal cancer, plans to complete colorectal cancer screening, intent to share polygenic risk scores with healthcare providers, and concerns about genetic results impacting health care.
CONCLUSIONS: Qualitative analyses suggest that participants were interested in and understood their polygenic risk score results. Further study is needed to develop guidelines, effective calls to action, provider engagement, and health education materials on use of polygenic risk scores for health decision making.}, }
@article {pmid39866156, year = {2025}, author = {Marcotte, LM and Khor, S and Wong, ES and Akinsoto, N and Lee, ES and Onstad, S and Issaka, RB}, title = {A Pilot Analysis of Patient Portal Use and Breast Cancer Screening Among Black Patients in a Large Academic Health System.}, journal = {AJPM focus}, volume = {4}, number = {1}, pages = {100305}, pmid = {39866156}, issn = {2773-0654}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; K12 HS026369/HS/AHRQ HHS/United States ; }, abstract = {INTRODUCTION: Patient portals may facilitate breast cancer screening and could be an important factor to address inequities; however, this association is not well characterized. The authors sought to examine this association in a large academic health system to inform interventions to address breast cancer screening inequities.
METHODS: The authors conducted a cross-sectional study among Black patients in a large academic health system using logistic regression to examine the association between breast cancer screening and portal use, adjusting for multilevel covariates and interactions. The authors estimated average marginal effects to examine the additive probability of breast cancer screening completion given portal use in the prior 12 months.
RESULTS: In the unadjusted model, portal use was associated with an estimated mean 24.8 percentage points (95% CI=20.7, 29.0) increased likelihood of completing breast cancer screening. In the adjusted model, portal use was associated with an estimated mean 16.2 percentage points (95% CI=11.2, 21.3) increased likelihood for completing breast cancer screening.
CONCLUSIONS: Improving portal access and use among racialized groups who face both portal and breast cancer screening inequities could be one strategy to address inequities. These pilot data will inform subsequent community-engaged research to better understand this association and develop and test a portal intervention to facilitate breast cancer screening access among Black patients eligible for screening.}, }
@article {pmid39866001, year = {2025}, author = {Karvonen, KA and Doody, DR and Barry, D and Bona, K and Winestone, LE and Rosenberg, AR and Mendoza, JA and Schwartz, SM and Chow, EJ}, title = {Historical redlining and survival among children, adolescents, and young adults with cancer diagnosed between 2000-2019 in Seattle and Tacoma, Washington.}, journal = {Cancer}, volume = {131}, number = {3}, pages = {e35677}, doi = {10.1002/cncr.35677}, pmid = {39866001}, issn = {1097-0142}, support = {2023YIA-6719883013//Conquer Cancer Foundation/ ; N01-PC-35142//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; HE-FY24-MS-07-Karvonen//Mentored Scholars Grant by Seattle Children's Hospital Center for Diversity and Health/ ; N01-PC-2010-00029//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; N01-CN-67009//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; T32CA009351/NH/NIH HHS/United States ; HHSN261201800004I//Cancer Surveillance System of the Fred Hutchinson Cancer Center/ ; }, mesh = {Humans ; Adolescent ; *Neoplasms/mortality/epidemiology/diagnosis ; Male ; Female ; Young Adult ; Child ; Washington/epidemiology ; Adult ; Child, Preschool ; Poverty ; Proportional Hazards Models ; Infant ; }, abstract = {BACKGROUND: Historical redlining has been associated with inferior survival in adult-onset cancers. However, its relationship with pediatric, adolescent, and young-adult-onset cancer outcomes is unknown.
METHODS: This study identified incident cancer among individuals <40 years of age living in Seattle and Tacoma between 2000-2019 via the population-based Cancer Surveillance System. The authors determined case redlining status using Home Owners' Loans Corporation data overlaid with 2000 and 2010 census tracts. Kaplan-Meier methods and multivariable Cox proportional hazards models were used to determine 5- and 10-year overall survival and hazard ratio (HR) of death according to redlined status. Cox models adjusted for patient and tumor characteristics and area-level poverty; interaction between redlining and area-level poverty was also assessed.
RESULTS: Among 4355 cases (median age at diagnosis 32 years), overall survival at 5 years was lower (85.1%; 95% confidence interval [CI], 83.5%-86.5%) among individuals residing in redlined neighborhoods compared with those in unexposed neighborhoods (90.3%; 95% CI, 89.0%-91.5%). Survival differences persisted at 10 years. The unadjusted hazard of death for redlined exposed individuals with cancer was higher than redlined unexposed (hazard ratio [HR], 1.62; 95% CI, 1.39-1.89). In the fully adjusted model, mortality remained higher for redlined cases (HR, 1.32; 95% CI, 1.12-1.56). There did not appear to be effect modification from area-level poverty in the relationship between redlining and death (p = .49).
CONCLUSIONS: Among young individuals with cancer, residence at diagnosis in previously redlined neighborhoods was associated with lower survival compared with those residing in nonredlined neighborhoods, supporting the hypothesis that structural racism exerts persistent effects on contemporary health outcomes.}, }
@article {pmid39865921, year = {2025}, author = {Yanes, R and Saridogan, T and Gorantla, V and Overacre, A and Hsieh, RW and Celebrezze, J and Magge, T and Singhi, M and Saeed, A and Zureikat, AH and Dasari, AN and Sahin, IH}, title = {Shedding Light on the Prognostic and Predictive Value of Circulating Tumor DNA for Management of Patients with Early-Stage Colon Cancer.}, journal = {Technology in cancer research & treatment}, volume = {24}, number = {}, pages = {15330338251317094}, pmid = {39865921}, issn = {1533-0338}, mesh = {Humans ; *Circulating Tumor DNA/blood/genetics ; *Colonic Neoplasms/genetics/blood/diagnosis/therapy/pathology ; Prognosis ; *Biomarkers, Tumor/blood ; Neoplasm Staging ; Disease Management ; }, abstract = {The management of early-stage colon cancer involves surgical resection of the primary tumor with or without chemotherapy, depending on pathological staging. The benefit of adjuvant chemotherapy for stage II and III colon cancer is approximately 5% and 15%, indicating the need for optimization for risk stratification and patient selection. Several studies have revealed that current clinicopathological factors lack precision. Circulating tumor DNA (ctDNA) is cell-free DNA originating from cancer cells and can be detected even in the absence of radiologically detectable disease among patients with colon cancer. Recent cohort studies revealed that ctDNA is one of the most significant prognostic factors for patients with early-stage colon cancer, surpassing pathological and clinical risk factors. Prospective cohort studies also suggest there may be a predictive role for ctDNA on the decision for consideration of adjuvant therapy. Currently, randomized clinical trials are enrolling to better define this role. In this review article, we review recent literature on ctDNA and its role in patients with colon cancer. We also elaborate on the future clinical utility of ctDNA in clinical practice and the unmet need for research to optimize currently available ctDNA assays.}, }
@article {pmid39863610, year = {2025}, author = {Reddi, S and Senyshyn, L and Ebadi, M and Podlesny, D and Minot, SS and Gooley, T and Kabage, AJ and Hill, GR and Lee, SJ and Khoruts, A and Rashidi, A}, title = {Fecal microbiota transplantation to prevent acute graft-versus-host disease: pre-planned interim analysis of donor effect.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1034}, pmid = {39863610}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; ACT9016-24//Leukemia and Lymphoma Society (Leukemia & Lymphoma Society)/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Acute Disease ; Double-Blind Method ; *Fecal Microbiota Transplantation/methods ; Feces/microbiology ; *Gastrointestinal Microbiome ; *Graft vs Host Disease/prevention & control/microbiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Tissue Donors ; Transplantation, Homologous/adverse effects ; Treatment Outcome ; }, abstract = {Gut microbiota disruptions after allogeneic hematopoietic cell transplantation (alloHCT) are associated with increased risk of acute graft-versus-host disease (aGVHD). We designed a randomized, double-blind placebo-controlled trial to test whether healthy-donor fecal microbiota transplantation (FMT) early after alloHCT reduces the incidence of severe aGVHD. Here, we report the results from the single-arm run-in phase which identified the best of 3 stool donors for the randomized phase. The primary and key secondary endpoints were microbiota engraftment and severe aGVHD, respectively. Three cohorts of patients (20 total) received FMT, each from a different donor. FMT was safe and effective in restoring microbiota diversity and commensal species. Microbiota engraftment, determined from shotgun sequencing data, correlated with larger microbiota compositional shifts toward donor and better clinical outcomes. Donor 3 yielded a median engraftment rate of 66%, higher than donors 1 (P = 0.02) and 2 (P = 0.03) in multivariable analysis. Three patients developed severe aGVHD; all 3 had received FMT from donor 1. Donor 3 was selected as the sole donor for the randomized phase. Our findings suggest a clinically relevant donor effect and demonstrate feasibility of evidence-based donor selection. FMT is a holistic microbiota restoration approach that can be performed as a precision therapeutic. ClinicalTrials.gov identifier NCT06026371.}, }
@article {pmid39862925, year = {2025}, author = {Nguyen, TK and Louie, AV and Kotecha, R and Saxena, A and Zhang, Y and Guckenberger, M and Kim, MS and Scorsetti, M and Slotman, BJ and Lo, SS and Sahgal, A and Tree, AC}, title = {Stereotactic body radiotherapy for non-spine bone metastases: A meta-analysis and international stereotactic radiosurgery society (ISRS) clinical practice guidelines.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {205}, number = {}, pages = {110717}, doi = {10.1016/j.radonc.2025.110717}, pmid = {39862925}, issn = {1879-0887}, mesh = {Humans ; *Radiosurgery/methods ; *Bone Neoplasms/secondary/radiotherapy/mortality ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: While SBRT to NSBM has become common, particularly in the oligometastatic population, the approach to treating non-spine bone metastases (NSBM) with stereotactic body radiotherapy (SBRT) varies widely across institutions and clinical trial protocols. We present a comprehensive systematic review of the literatures to inform practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).
METHODS: A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with at least 10 patients receiving SBRT for NSBM were identified and meta-analyses were completed to estimate pooled local control and overall survival rates. Published guidelines on NSBM SBRT were reviewed and consolidated.
RESULTS: There were 25 studies included for qualitative analysis and 18 studies for quantitative analysis consisting of 13 retrospective studies, 2 non-randomized prospective studies, 1 randomized phase 2/3 trial, and a subgroup analysis of a phase I trial. The pooled local control rates at 1 and 2 years were 95 % (95 % CI: 89 %-98 %) and 94 % (95 % CI: 86 %-98 %), respectively. Pooled overall survival rates at 1 year and 2 years were 84 % (95 % CI: 73 %-91 %) and 81 % (95 % CI: 45 %-95 %), respectively. Consensus was reached on recommendations to inform treatment simulation, target delineation, dose fractionation, and anatomic site-specific recommendations.
CONCLUSION: We present ISRS-endorsed consensus recommendations to inform best practice of SBRT to NSBM, which we found to be efficacious and associated with low rates of adverse events.}, }
@article {pmid39862490, year = {2025}, author = {Nickel, B and Ayre, J and Marinovich, ML and Smith, DP and Chiam, K and Lee, CI and Wilt, TJ and Taba, M and McCaffery, K and Houssami, N}, title = {Are AI chatbots concordant with evidence-based cancer screening recommendations?.}, journal = {Patient education and counseling}, volume = {134}, number = {}, pages = {108677}, doi = {10.1016/j.pec.2025.108677}, pmid = {39862490}, issn = {1873-5134}, mesh = {Humans ; Male ; *Early Detection of Cancer ; Female ; *Breast Neoplasms/diagnosis ; *Prostatic Neoplasms/diagnosis ; Middle Aged ; Aged ; *Mass Screening ; Adult ; United States ; Practice Guidelines as Topic ; Evidence-Based Medicine ; Generative Artificial Intelligence ; }, abstract = {OBJECTIVE: This study aimed to assess whether information from AI chatbots on benefits and harms of breast and prostate cancer screening were concordant with evidence-based cancer screening recommendations.
METHODS: Seven unique prompts (four breast cancer; three prostate cancer) were presented to ChatGPT in March 2024. A total of 60 criteria (30 breast; 30 prostate) were used to assess the concordance of information. Concordance was scored between 0 and 2 against the United States Preventive Services Task Force (USPSTF) breast and prostate cancer screening recommendations independently by international cancer screening experts.
RESULTS: 43 of 60 (71.7 %) criteria were completely concordant, 3 (5 %) were moderately concordant and 14 (23.3 %) were not concordant or not present, with most of the non-concordant criteria (9 of 14, 64.3 %) being from prompts for the oldest age groups. ChatGPT hallucinations (i.e., completely made up, non-sensical or irrelevant information) were found in 9 of 60 criteria (15 %).
CONCLUSIONS: ChatGPT provided information mostly concordant with USPSTF breast and prostate cancer screening recommendations, however, important gaps exist. These findings provide insights into the role of AI to communicate cancer screening benefits and harms and hold increased relevance for periods of guideline change.
PRACTICE IMPLICATIONS: AI generated information on cancer screening should be taken in conjunction with official screening recommendations and/or information from clinicians.}, }
@article {pmid39861671, year = {2024}, author = {Lee, YS and Kwon, RJ and Lee, HS and Chung, JH and Kim, YS and Jeong, HS and Park, SJ and Lee, SY and Kim, T and Yoon, SH}, title = {The Role of Pentacyclic Triterpenoids in Non-Small Cell Lung Cancer: The Mechanisms of Action and Therapeutic Potential.}, journal = {Pharmaceutics}, volume = {17}, number = {1}, pages = {}, pmid = {39861671}, issn = {1999-4923}, support = {2024 research grant//Pusan National University Yangsan Hospital/ ; }, abstract = {Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action.}, }
@article {pmid39858050, year = {2025}, author = {Hatashima, A and Shadman, M and Raghunathan, V}, title = {Chimeric Antigen Receptor-T Cells in the Modern Era of Chronic Lymphocytic Leukemia Treatment.}, journal = {Cancers}, volume = {17}, number = {2}, pages = {}, pmid = {39858050}, issn = {2072-6694}, abstract = {Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This subgroup of "double refractory" patients has limited treatment options and poor prognosis. Chimeric antigen receptor (CAR)-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. Although the earliest success of CAR-T cell therapy was in CLL, the clinical application of this modality has lagged until the recent approval of the first CAR-T cell product for CLL. In this review, we describe the current treatment options for upfront and subsequent therapies and the unmet need for novel agents highlighted by the burgeoning role and challenges of CAR-T cell therapy.}, }
@article {pmid39857099, year = {2025}, author = {Cicero, KI and Banerjee, R and Kwok, M and Dima, D and Portuguese, AJ and Chen, D and Chalian, M and Cowan, AJ}, title = {Illuminating the Shadows: Innovation in Advanced Imaging Techniques for Myeloma Precursor Conditions.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {39857099}, issn = {2075-4418}, abstract = {Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), the asymptomatic precursors to multiple myeloma, affect up to 5% of the population over the age of 40. Bone involvement, a myeloma-defining event, represents a major source of morbidity for patients. Key goals for the management of myeloma precursor conditions include (1) identifying patients at the highest risk for progression to MM with bone involvement and (2) differentiating precursor states from active myeloma requiring treatment. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT with [[18]F]fluorodeoxyglucose (FDG) have improved sensitivity for the detection of myeloma bone disease compared to traditional skeletal surveys, and such advanced imaging also provides this field with better tools for detecting early signs of progression. Herein, we review the data supporting the use of advanced imaging for both diagnostics and prognostication in myeloma precursor conditions.}, }
@article {pmid39856213, year = {2025}, author = {Patel, SP and Cano-Linson, E and Chae, YK and Schokrpur, S and Lao, CD and Powers, BC and Victor, AI and Onitilo, AA and Shin, S and Takebe, N and Threlkel, S and McLeod, CM and Chen, HX and Sharon, E and Othus, M and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {Dual anti-CTLA-4 and anti-PD-1 blockade in metastatic basal cell carcinoma.}, journal = {NPJ precision oncology}, volume = {9}, number = {1}, pages = {24}, pmid = {39856213}, issn = {2397-768X}, support = {UG1 CA233331/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; CA180888 CA180819 U10CA180820 CA180821 CA233331 CA233320 CA180828//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180828/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19-50%), and the 12-month OS, 75% (95% CI, 57-100%). Median PFS was 9.3 months (95% CI, 3.3-NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013).}, }
@article {pmid39856067, year = {2025}, author = {Pareja, F and Bhargava, R and Borges, VF and Brogi, E and Canas Marques, R and Cardoso, F and Desmedt, C and Harigopal, M and Lakhani, SR and Lee, A and Leone, JP and Linden, H and Lord, CJ and Marchio, C and Merajver, SD and Rakha, E and Reis-Filho, JS and Richardson, A and Sawyer, E and Schedin, P and Schwartz, CJ and Tutt, A and Ueno, NT and Vincent-Salomon, A and Weigelt, B and Wen, YH and Schnitt, SJ and Oesterreich, S}, title = {Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {6}, pmid = {39856067}, issn = {2374-4677}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30CA008748//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; AACR-BRCF 09-06-26BORG//Breast Cancer Research Foundation (BCRF)/ ; P50 CA24779 01//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored.}, }
@article {pmid39855565, year = {2025}, author = {Dávila Saldaña, BJ and Schultz, KR and Ramgopal, A and Boiko, JR and Beebe, K and Carpenter, PA and Chan, SS and Paczesny, S and Aguayo-Hiraldo, P and Cuvelier, GDE and Rotz, SJ and Duncan, CN and Williams, KM}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for Children with Chronic Graft-versus-Host Disease after Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {6}, pages = {347.e1-347.e17}, pmid = {39855565}, issn = {2666-6367}, support = {R13 HL172559/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Graft vs Host Disease/etiology/therapy/immunology ; Child ; Chronic Disease ; *Immune Reconstitution ; }, abstract = {While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplantation (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of, cGVHD is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, and development of new treatments and specifies aims of future research endeavors.}, }
@article {pmid39855457, year = {2025}, author = {Jenkins, MT and Chu, YE and Franceski, AM and Potts, CR and Dubin, R and Dickerson, KM and Lee, SC and Lu, R and Welner, RS and Ferrell, PB}, title = {TET2-loss enhances immediate and time-resolved interferon-γ signaling responses across myeloid differentiation.}, journal = {Experimental hematology}, volume = {144}, number = {}, pages = {104727}, doi = {10.1016/j.exphem.2025.104727}, pmid = {39855457}, issn = {1873-2399}, mesh = {Animals ; *Interferon-gamma/metabolism/pharmacology ; Dioxygenases ; *DNA-Binding Proteins/genetics/metabolism/deficiency ; Mice ; *Signal Transduction/drug effects ; Mice, Knockout ; *Proto-Oncogene Proteins/genetics/metabolism/deficiency ; *Cell Differentiation/drug effects ; STAT1 Transcription Factor/metabolism/genetics ; Hematopoietic Stem Cells/metabolism/cytology ; Janus Kinase 2/metabolism/genetics ; }, abstract = {Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter cytometry by time-of-flight (CyTOF) panel of both surface marker and phosphoprotein antigens in murine bone marrow (BM). We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells. We next investigated changes associated with BM cells from Tet2[KO] mice. High-dimensional surface marker phenotyping revealed expansion of hematopoietic stem and progenitor cells (HSPCs), committed cKIT[+]Ly6C[+] myeloid progenitors, and monocytes. Loss of TET2 function increased the magnitude of response to extracellular perturbations, including interferon (IFN)γ and H2O2. Response time courses revealed that IFNγ-mediated pSTAT1 remains elevated over time in Tet2[KO]. Further, IFNγ resulted in a more significant increase in major histocompatibility complex class II (MHCII) expression in Tet2[KO] immortalized progenitor cells than in Tet2[WT]. Inhibition of Janus kinase 1 and 2 (JAK1/2) with ruxolitinib significantly reduced STAT1 phosphorylation and MHCII expression in Tet2[KO] cells. Our results identify targetable disrupted signaling responses in Tet2[KO] cells.}, }
@article {pmid39854241, year = {2025}, author = {Langley, CA and Dietzen, PA and Emerman, M and Tenthorey, JL and Malik, HS}, title = {Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {4}, pages = {e2416811122}, pmid = {39854241}, issn = {1091-6490}, support = {Mathilde Krim Fellowship 110298-71-RKHF/110537-74-RKHF//amfAR, The Foundation for AIDS Research (amfAR)/ ; Hannay Gray Fellowship GT11096/GT16732//Howard Hughes Medical Institute (HHMI)/ ; T32 GM007270/GM/NIGMS NIH HHS/United States ; Investigator Award//Howard Hughes Medical Institute (HHMI)/ ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, mesh = {Phylogeny ; *Myxovirus Resistance Proteins/genetics/metabolism ; Animals ; *Evolution, Molecular ; *Dynamins/genetics/metabolism ; *Antiviral Agents/metabolism ; *Eukaryota/genetics/metabolism ; Humans ; }, abstract = {Mx proteins, first identified in mammals, encode potent antiviral activity against a wide range of viruses. Mx proteins arose within the Dynamin superfamily of proteins (DSP), which mediate critical cellular processes, such as endocytosis and mitochondrial, plastid, and peroxisomal dynamics. Despite their crucial role, the evolutionary origins of Mx proteins are poorly understood. Through comprehensive phylogenomic analyses with progressively expanded taxonomic sampling, we demonstrate that Mx proteins predate the interferon signaling system in vertebrates. Our analyses find an ancient monophyletic DSP lineage in eukaryotes that groups vertebrate and invertebrate Mx proteins with fungal MxF proteins, the largely uncharacterized plant and algal Dynamin 4A/4C proteins, and representatives from several other eukaryotic lineages, suggesting that Mx-like proteins date back close to the origin of Eukarya. Our phylogenetic analyses also find host-encoded and nucleocytoplasmic large DNA viruses-encoded DSPs interspersed in four distinct DSP lineages, indicating recurrent viral theft of host DSPs. Our analyses thus reveal an ancient history of viral and antiviral functions encoded by the Dynamin superfamily in eukaryotes.}, }
@article {pmid39853979, year = {2025}, author = {Li, NHY and Li, CI}, title = {Incidence Rate Trends of Breast Cancer Overall and by Molecular Subtype by Race and Ethnicity and Age.}, journal = {JAMA network open}, volume = {8}, number = {1}, pages = {e2456142}, pmid = {39853979}, issn = {2574-3805}, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Age Factors ; *Breast Neoplasms/epidemiology/ethnology ; Cohort Studies ; *Ethnicity/statistics & numerical data ; Incidence ; *Racial Groups/statistics & numerical data ; Registries ; SEER Program ; United States/epidemiology ; }, abstract = {IMPORTANCE: Black and Hispanic women in the US experience higher incidence rates of aggressive molecular subtypes of breast cancer, including triple-negative disease. However, how these rates are changing, particularly across different age groups, has not been well documented.
OBJECTIVE: To assess changes in overall and subtype-specific breast cancer incidence rates in the US by age and race and ethnicity.
This cohort study used Surveillance, Epidemiology, and End Results program cancer registry data from 22 US cancer registries on 1 123 658 females who received a diagnosis of invasive breast cancer from 2010 to 2019. Statistical analysis was conducted from August 2023 to October 2024.
EXPOSURES: Age and race and ethnicity.
MAIN OUTCOMES AND MEASURES: Age-adjusted incidence rates of invasive breast cancer overall and across the 4 major molecular subtypes by age and by race and ethnicity, as well as their associated annual percentage changes using Joinpoint Trend Analysis software.
RESULTS: Of the 1 123 658 participants in the study, 219 112 (19.5%) were younger than 50 years, 409 257 (36.4%) were aged 50 to 64 years, and 495 289 (44.1%) were 65 years or older. A total of 141 703 participants (12.6%) were Hispanic, 3253 (0.3%) were non-Hispanic American Indian or Alaska Native, 78 306 (7.0%) were non-Hispanic Asian or Pacific Islander, 124 560 (11.1%) were non-Hispanic Black, 769 043 (68.4%) were non-Hispanic White, and 6793 participants (0.6%) had an unknown race and/or ethnicity. Overall, breast cancer incidence rates increased 0.5% per year from 2010 to 2019. Variation by race and ethnicity was observed, with increases of 1.4% per year among Hispanic females, 1.9% per year among non-Hispanic American Indian or Alaska Native females, and 2.1% per year among non-Hispanic Asian or Pacific Islander females, while rates increased only 0.8% per year among non-Hispanic Black females and 0.5% per year among non-Hispanic White females. In subtype analyses, increases of the greatest magnitude in recent years were observed in the incidence rates of triple-negative breast cancer per year among participants aged 65 years or older (Hispanic females, 2.3%; non-Hispanic Asian or Pacific Islander females, 5.5%; and non-Hispanic Black females, 4.3%), while remaining unchanged among non-Hispanic White females.
CONCLUSIONS AND RELEVANCE: In this cohort study of 1 123 658 females with breast cancer over the 10-year period from 2010 to 2019, there were substantial differences in trends in the incidence rates of breast cancer overall and by subtype across different racial and ethnic groups. Further research is needed to understand the factors associated with these trends.}, }
@article {pmid39853273, year = {2025}, author = {Brown, JR and Li, J and Eichhorst, BF and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Huang, R and Shi, Y and Idoine, A and Salmi, T and Cohen, AC and Shadman, M}, title = {Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.}, journal = {Blood advances}, volume = {9}, number = {8}, pages = {1918-1926}, pmid = {39853273}, issn = {2473-9537}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Adenine/analogs & derivatives/therapeutic use/analogs & derivatives ; Agammaglobulinaemia Tyrosine Kinase/genetics/antagonists & inhibitors ; Disease Progression ; *Drug Resistance, Neoplasm/genetics ; *Leukemia, Lymphocytic, Chronic, B-Cell/genetics/drug therapy/pathology ; *Mutation ; Piperidines/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles/therapeutic use ; Pyrimidines/therapeutic use ; }, abstract = {Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE. No BTK mutations were observed at baseline; at PD, 8 patients (zanubrutinib, n = 5; ibrutinib, n = 3) acquired 17 BTK mutations, 82.4% (zanubrutinib, n = 11/14; ibrutinib, n = 3/3) at C481. Non-C481 mutations occurred in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n = 2; cancer cell fraction [CCF] = 9.58% and 17.6%; A428D: n = 1; CCF = 37.03%). At baseline, 48 of 52 patients had ≥1 driver gene mutation(s), most frequently in NOTCH1 (n = 21), TP53 (n = 19), BRAF (n = 10), SF3B1 (n = 8), and ATM (n = 8). At PD, acquired mutations occurred in 1 zanubrutinib-treated patient (TP53, XPO1) and 5 ibrutinib-treated patients (TP53, n = 1 patient; SETD2, n = 1; SF3B1, n = 1; ASXL1, n = 2). Baseline driver gene mutations were not associated with development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. The short treatment duration and a low BTK mutations incidence suggests that mechanisms other than BTK/PLCG2 mutations drive most early PD. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.}, }
@article {pmid39847539, year = {2025}, author = {Bea, JW and Ochs-Balcom, HM and Valencia, CI and Chen, Z and Blew, RM and Lind, KE and Caan, BJ and Roe, DJ and Rohan, TE and Reeves, KW and Manson, JE and Ballinger, T and Reding, KW and Follis, S and Ziller, SG and Odegaard, AO}, title = {Abdominal visceral and subcutaneous adipose tissue associations with postmenopausal breast cancer incidence.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {1}, pages = {}, pmid = {39847539}, issn = {2515-5091}, support = {75N92021D00001/HL/NHLBI NIH HHS/United States ; P30 CA023074/CA/NCI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; /NH/NIH HHS/United States ; R01CA253302/NH/NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Middle Aged ; Absorptiometry, Photon ; Black or African American/statistics & numerical data ; Body Mass Index ; *Breast Neoplasms/epidemiology/etiology ; Incidence ; *Intra-Abdominal Fat/diagnostic imaging ; Obesity/complications ; *Postmenopause ; Prospective Studies ; Risk Factors ; *Subcutaneous Fat/diagnostic imaging ; }, abstract = {BACKGROUND: Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear.
METHODS: We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27 years follow-up (N = 9950), during which all new cancers were adjudicated. Dual-energy x-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing-risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa.
RESULTS: Participants averaged 63.3 ± 7.4 years of age and a BMI of 28.20 ± 5.72 kg/m2 at baseline. The models included 738 incident BCa case patients (N = 593 invasive; N = 145 in situ). Baseline VAT and SAT area were associated with statistically significantly increased BCa risk, by 36% and 19%, respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, although not statistically significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared with Q1 was 1.49 (95% CI = 1.18 to 1.87).
CONCLUSION: Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample (Women's Health Initiative; NCT00000611; https://clinicaltrials.gov/study/NCT00000611).}, }
@article {pmid39846783, year = {2024}, author = {Lee, MA and Hatcher, CA and Hazelwood, E and Goudswaard, LJ and Tsilidis, KK and Vincent, EE and Martin, RM and Smith-Byrne, K and Brenner, H and Cheng, I and Kweon, SS and Le Marchand, L and Newcomb, PA and Schoen, RE and Peters, U and Gunter, MJ and Van Guelpen, B and Murphy, N}, title = {A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator.}, journal = {International journal of epidemiology}, volume = {54}, number = {1}, pages = {}, pmid = {39846783}, issn = {1464-3685}, support = {001/WHO_/World Health Organization/International ; 29019/CRUK_/Cancer Research UK/United Kingdom ; INCa SHSESP20//French National Cancer Institute/ ; //Wereld Kanker Onderzoek Fonds/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Adiposity/genetics ; Body Mass Index ; Mendelian Randomization Analysis ; Female ; Male ; Waist-Hip Ratio ; *Intercellular Signaling Peptides and Proteins/genetics/blood ; Risk Factors ; *Obesity/genetics ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.
METHODS: Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.
RESULTS: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated-suggestive of a potential mediating role-most strongly for the BMI-overall CRC association in women.
CONCLUSION: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.}, }
@article {pmid39845432, year = {2024}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Prochaska, JJ and Zvolensky, MJ and Bricker, JB}, title = {Can an Acceptance and Commitment Therapy-Based Smartphone App Help Individuals with Mental Health Disorders Quit Smoking?.}, journal = {Depression and anxiety}, volume = {2024}, number = {}, pages = {}, pmid = {39845432}, issn = {1520-6394}, support = {R01 CA192849/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/psychology ; Male ; *Acceptance and Commitment Therapy/methods ; Female ; Adult ; *Mobile Applications ; Middle Aged ; *Mental Disorders/psychology ; Smartphone ; United States ; }, abstract = {BACKGROUND: Individuals with mental health disorders face major barriers in accessing smoking cessation care, often due to the stigmas associated with mental disorders and addiction. Consequently, accessible population-based smoking cessation interventions are needed for this vulnerable group.
OBJECTIVE: This secondary analysis utilized data from a 12-month randomized trial to examine whether an acceptance and commitment therapy-based app (iCanQuit) demonstrated greater efficacy, engagement, and satisfaction compared to a United States (US) Clinical Practice Guidelines-based app (QuitGuide) in helping adults with mental health disorders quit smoking.
MATERIALS AND METHODS: Participants self-reported having bipolar disorder or schizophrenia, or screened positive for depression, generalized anxiety, panic disorder, posttraumatic stress disorder, or social anxiety. We compared the primary outcome of self-reported 30-day cigarette abstinence at 12 months between iCanQuit (n = 770) and QuitGuide (n = 785) using complete-case and multiple imputation analyses and compared engagement and satisfaction between arms. Mediation analyses were conducted to examine whether the intervention apps functioned by reinforcing hypothesized mechanisms of action, namely, acceptance of triggers to smoke and through app engagement.
RESULTS: Participants represented all 50 US states and had 30.2% non-White or Hispanic backgrounds. Among participants with any mental health disorder, iCanQuit demonstrated higher 30-day cigarette abstinence than QuitGuide at 12 months (complete-case: 24.4% vs. 20.4%, P = 0.04; multiple imputation: 24.6% vs. 20.4%, P = 0.04). A comparable effect size was observed in iCanQuit participants with bipolar disorder or schizophrenia compared to QuitGuide, albeit not statistically significant (multiple imputation: 27.1% vs. 20.9%; P = 0.06). iCanQuit's cessation efficacy was mediated by acceptance of emotions triggering smoking (P < 0.001) and app engagement (P < 0.001). iCanQuit was more satisfying than QuitGuide (88.5% vs. 77.2%; P < 0.001).
CONCLUSIONS: In the largest known study of ACT for smoking cessation among adults with mental health disorders, the smoking cessation, engagement, and satisfaction outcomes were all significantly greater with iCanQuit than QuitGuide. Acceptance of emotions triggering smoking and iCanQuit app engagement were important mechanisms of efficacy. This trial is registered with NCT02724462.}, }
@article {pmid39844469, year = {2025}, author = {Cooper, N and Jansen, AJG and Bird, R and Mayer, J and Sholzberg, M and Tarantino, MD and Garg, M and Ypma, PF and McDonald, V and Percy, C and Košťál, M and Goncalves, I and Bogdanov, LH and Gernsheimer, TB and Diab, R and Yao, M and Daak, A and Kuter, DJ}, title = {Efficacy and Safety Results With Rilzabrutinib, an Oral Bruton Tyrosine Kinase Inhibitor, in Patients With Immune Thrombocytopenia: Phase 2 Part B Study.}, journal = {American journal of hematology}, volume = {100}, number = {3}, pages = {439-449}, pmid = {39844469}, issn = {1096-8652}, support = {//Sanofi/ ; }, mesh = {Humans ; Middle Aged ; Female ; Male ; *Purpura, Thrombocytopenic, Idiopathic/drug therapy/blood ; Aged ; Adult ; *Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration & dosage ; *Pyrimidines/adverse effects/therapeutic use/administration & dosage ; Administration, Oral ; Platelet Count ; Treatment Outcome ; Aged, 80 and over ; Tyrosine Kinase Inhibitors ; }, abstract = {Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 10[9]/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 10[9]/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 10[9]/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 10[9]/L or ≥ 30 × 10[9]/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 10[9]/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.}, }
@article {pmid39844041, year = {2025}, author = {Crisp, AM and Halloran, ME and Hitchings, MDT and Longini, IM and Dean, NE}, title = {Analysis methods for covariate-constrained cluster randomized trials with time-to-event outcomes.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {16}, pmid = {39844041}, issn = {1471-2288}, support = {U01 AI148069/AI/NIAID NIH HHS/United States ; U01-AI148069/NH/NIH HHS/United States ; U01-AI148069//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Cluster Analysis ; Proportional Hazards Models ; Computer Simulation ; Mexico ; Child ; }, abstract = {BACKGROUND: Cluster randomized trials, which often enroll a small number of clusters, can benefit from constrained randomization, selecting a final randomization scheme from a set of known, balanced randomizations. Previous literature has addressed the suitability of adjusting the analysis for the covariates that were balanced in the design phase when the outcome is continuous or binary. Here we extended this work to time-to-event outcomes by comparing two model-based tests and a newly derived permutation test. A current cluster randomized trial of vector control for the prevention of mosquito-borne disease in children in Mexico is used as a motivating example.
METHODS: We assessed type I error rates and power between simple randomization and constrained randomization using both prognostic and non-prognostic covariates via a simulation study. We compared the performance of a semi-parametric Cox proportional hazards model with robust variance, a mixed effects Cox model, and a permutation test utilizing deviance residuals.
RESULTS: The permutation test generally maintained nominal type I error-with the exception of the unadjusted analysis for constrained randomization-and also provided power comparable to the two Cox model-based tests. The model-based tests had inflated type I error when there were very few clusters per trial arm. All three methods performed well when there were 25 clusters per trial arm, as in the case of the motivating example.
CONCLUSION: For time-to-event outcomes, covariate-constrained randomization was shown to improve power relative to simple randomization. The permutation test developed here was more robust to inflation of type I error compared to model-based tests. Gaining power by adjusting for covariates in the analysis phase was largely dependent on the number of clusters per trial arm.}, }
@article {pmid39841165, year = {2025}, author = {Peters, BA and Xue, X and Hanna, DB and Wang, Y and Wang, Z and Sharma, A and Floris-Moore, M and Konkle-Parker, D and Alcaide, ML and Sheth, AN and Topper, EF and Weber, KM and Tien, PC and Merenstein, D and Vásquez, E and Chen, Y and Mimiaga, MJ and Stosor, V and Brown, TT and Erlandson, KM and Dillon, SM and Elsayed, NS and Usyk, M and Sollecito, CC and Kaplan, RC and Burk, RD and Qi, Q}, title = {Healthy Aging and the Gut Microbiome in People With and Without HIV.}, journal = {The Journal of infectious diseases}, volume = {231}, number = {4}, pages = {981-992}, pmid = {39841165}, issn = {1537-6613}, support = {/NR/NINR NIH HHS/United States ; /AA/NIAAA NIH HHS/United States ; U01-HL146241/HL/NHLBI NIH HHS/United States ; /MH/NIMH NIH HHS/United States ; //Eunice Kennedy Shriver/ ; TL1 TR001431/TR/NCATS NIH HHS/United States ; UL1 -TR000004//Office of AIDS Research/ ; /NS/NINDS NIH HHS/United States ; /CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; /MD/NIMHD NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; /DE/NIDCR NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; U01 HL146245/HL/NHLBI NIH HHS/United States ; U01 HL146204/HL/NHLBI NIH HHS/United States ; U01 HL146202/HL/NHLBI NIH HHS/United States ; /DK/NIDDK NIH HHS/United States ; //National Institute of Child Health and Human Development/ ; /DA/NIDA NIH HHS/United States ; U01 HL146194/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Male ; Female ; *HIV Infections/microbiology/epidemiology ; Middle Aged ; RNA, Ribosomal, 16S/genetics ; Aged ; Adult ; *Healthy Aging ; Feces/microbiology ; Cohort Studies ; *Aging ; Bacteria/classification/genetics/isolation & purification ; Frailty ; }, abstract = {BACKGROUND: Aging-related comorbidities are more common in people with human immunodeficiency virus (HIV) compared to people without HIV. The gut microbiome may play a role in healthy aging; however, this relationship remains unexplored in the context of HIV.
METHODS: 16S rRNA gene sequencing was conducted on stool from 1409 women (69% with HIV; 2304 samples) and 990 men (54% with HIV; 1008 samples) in the MACS/WIHS Combined Cohort Study. Associations of age with gut microbiome diversity, uniqueness, and genus-level abundance were examined in women and men separately, followed by examining relationships of aging-related genera with frailty (Fried frailty phenotype) and mortality risk (Veterans Aging Cohort Study [VACS] index).
RESULTS: Older age was associated with greater microbiome diversity and uniqueness, greater abundance of Akkermansia and Streptococcus, and lower abundance of Prevotella and Faecalibacterium, among others; findings were generally consistent by sex and HIV status. An aging-related microbiome score, generated via combination of 18 age-related genera, significantly increased with age in both women and men independently of demographic, behavioral, and cardiometabolic factors. In general, age was more strongly related to microbiome features (eg, diversity, microbiome score) in men without compared to with HIV, but age-microbiome associations were similar in women with and without HIV. Some age-related genera associated with healthy/unhealthy aging, such as Faecalibacterium (related to reduced frailty) and Streptococcus (related to higher VACS index).
CONCLUSIONS: Age is associated with consistent changes in the gut microbiome in both women and men with or without HIV. Some aging-related microbiota are associated with aging-related declines in health.}, }
@article {pmid39838067, year = {2025}, author = {Haseli, S and Park, C and Azhideh, A and Karande, G and Chalian, M}, title = {Performance and reliability comparison: original vs. revised bone reporting and data system (Bone-RADS).}, journal = {Skeletal radiology}, volume = {54}, number = {8}, pages = {1681-1688}, pmid = {39838067}, issn = {1432-2161}, mesh = {Humans ; Male ; Reproducibility of Results ; Middle Aged ; Female ; Retrospective Studies ; *Bone Neoplasms/diagnostic imaging/pathology ; *Tomography, X-Ray Computed/methods ; Sensitivity and Specificity ; *Radiology Information Systems ; Adult ; Aged ; Biopsy ; Observer Variation ; }, abstract = {OBJECTIVE: To propose a revised bone reporting and data system (Bone-RADS) and evaluate its diagnostic performance and inter-reader reliability compared to the original Bone-RADS for solitary bone lesions on CT.
MATERIALS AND METHODS: This retrospective study included 159 adult patients (mean age: 56 ± 19 years; 88 men) who underwent bone biopsy for solitary bone lesions between March 2005 and September 2021. Two radiologists (R1/2) independently categorized the lesions twice, once using the original Bone-RADS and once using the revised version. Lesions were classified as follows: (1, benign; 2, incompletely assessed; 3, indeterminate; 4, malignancy or requiring treatment). The revised Bone-RADS excluded the original criteria for lesion related pain and history of malignancy. Diagnostic performance was assessed using histopathology as the reference standard, and inter-reader reliability was analyzed.
RESULTS: The bone lesions included 96 lucent and 63 sclerotic/mixed lesions. Sensitivity showed no significant difference between the original and revised Bone-RADS for both readers across lucent and sclerotic/mixed lesions (all P ≥ .05). However, the specificity of the revised Bone-RADS was significantly higher than that of the original (lucent: 11% vs. 50% [R1], 11% vs. 46% [R2]; sclerotic/mixed: 32% vs. 92% [R1], 32% vs. 86% [R2]). Other performance metrics, including positive/negative predictive value and accuracy, were also higher in the revised Bone-RADS. Inter-reader reliability was higher for the revised Bone-RADS compared to the original (κ = .744 vs .854).
CONCLUSION: The revised Bone-RADS significantly improved specificity while maintaining sensitivity compared to the original version.}, }
@article {pmid39834946, year = {2024}, author = {O'Halloran, K and Crotty, EE and Christodoulou, E and Leary, SE and Miller, A and Paulson, VA and Lockwood, CM and Margol, AS and Biegel, JA}, title = {Targeted detection of sequence variants in cell-free DNA from cerebrospinal fluid in pediatric central nervous system tumors.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1513073}, pmid = {39834946}, issn = {2234-943X}, abstract = {The emergence of liquid biopsy technologies holds great promise in the cancer setting, including in pediatric central nervous system (CNS) tumors. In contrast to broad lower-depth sequencing, commonly referred to as low pass whole genome sequencing (WGS), targeted platforms with a higher depth of coverage have also been established. Here, we review targeted liquid biopsy techniques with applicability to pediatric CNS tumors. These include polymerase chain reaction (PCR), both droplet digital PCR and reverse transcription-based PCR, Sanger sequencing, and next-generation sequencing approaches that incorporate amplicon- and hybrid capture-based methods. The goal of this paper is to facilitate an understanding of these targeted techniques and provide a context for clinical relevance within disease categories, as well as a discussion on optimizing real-world implementation for pediatric CNS tumors.}, }
@article {pmid39831734, year = {2025}, author = {Moussa, MJ and Tabet, GC and Siefker-Radtke, AO and Xiao, L and Wilson, NR and Gao, J and Logothetis, CJ and Grivas, P and Lee, B and Shah, AY and Msaouel, P and Li, R and Clemente, LC and Zhao, J and Tannir, NM and Kamat, AM and Hansel, DE and Guo, CC and Campbell, MT and Alhalabi, O}, title = {Histopathologic Progression and Metastatic Relapse Outcomes in Small Cell Neuroendocrine Carcinomas of the Urinary Tract.}, journal = {Cancer medicine}, volume = {14}, number = {2}, pages = {e70594}, pmid = {39831734}, issn = {2045-7634}, support = {//Ingram Family Fund/ ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; *Carcinoma, Neuroendocrine/pathology/therapy/secondary/mortality ; Aged ; *Carcinoma, Small Cell/pathology/therapy/secondary ; *Neoplasm Recurrence, Local/pathology/epidemiology ; Disease Progression ; *Urologic Neoplasms/pathology/therapy/mortality ; Prognosis ; Neoadjuvant Therapy ; Retrospective Studies ; Adult ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Small cell neuroendocrine carcinoma of the urinary tract (SCNEC-URO) has an inferior prognosis compared to conventional urothelial carcinoma (UC). Here, we evaluate the predictors and patterns of relapse after surgery.
MATERIALS AND METHODS: We identified a definitive-surgery cohort (n = 224) from an institutional database of patients with cT1-T4NxM0 SCNEC-URO treated in 1985-2021. Histopathologic review was conducted by independent pathologists. Relapse event was the time-to-event outcome, and relapse probabilities were estimated using a competing risk method with cumulative incidence functions (CIFs). Fine-Gray distribution models assessed covariate associations.
RESULTS: Most patients (161, 71.9%) received neoadjuvant chemotherapy (neoCTX). Ninety two (41%) patients had relapse with 77 (83.7%) having distant organs as first metastatic sites, including 10 (10.9%) with exclusive central nervous system (CNS) metastases, mostly (9/10) within 1 year of surgery. Patients with pathologic complete response (pCR) after neoCTx had the lowest 5-year CIF (16.5% [95% CI 9.3%-25.6%]). Patients with remaining exclusively small cell (SC) histology had the highest CIF (85.7% [95% CI 46.6-96.9]). Patients with eradicated SCNEC but remaining UC components had an intermediate-risk CIF (32.5% [95% CI 18.6-47.2]). Multivariable analysis adjusting for neoCTx, clinical stage at diagnosis (T3/4, N0/N+ vs. T1/T2, N0), and pathologic stage (pN+ vs. pN0) demonstrated that any SCNEC histology at resection (vs. pCR) was associated with relapse risk (hazard ratio = 3.69 [95% CI 1.91-7.13], p = 0.0001).
CONCLUSIONS: SCNEC-URO is a systemic disease with high risk of distant relapse including CNS. Our findings highlight unmet needs for neoadjuvant/adjuvant approaches targeting the rare SCNEC subtype and suggest adding CNS surveillance within the first year after definitive surgery to high-risk patients. PRÉCIS (CONDENSED ABSTRACT): Alongside neoadjuvant chemotherapy and cancer stage, histology at resection strongly impacts relapse risk in small cell neuroendocrine carcinomas of the urinary tract. The incidence of brain metastasis is notably higher than in "traditional" urothelial cancer within the first year after surgery, especially if small cell cancer persists, thus necessitating close neurological monitoring during this period.}, }
@article {pmid39831552, year = {2025}, author = {Lichauco, C and Foss, EJ and Gatbonton-Schwager, T and Athow, NF and Lofts, B and Acob, R and Taylor, E and Marquez, JJ and Lao, U and Miles, S and Bedalov, A}, title = {Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39831552}, issn = {2050-084X}, support = {R01 GM117446/GM/NIGMS NIH HHS/United States ; R01GM117446/NH/NIH HHS/United States ; }, mesh = {*Nucleosomes/metabolism ; *Sirtuin 2/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; *Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA, Ribosomal/metabolism/genetics ; *Transcription Factors/metabolism ; *DNA Replication Timing ; *DNA Replication ; *Minichromosome Maintenance Proteins/metabolism ; Replication Origin ; }, abstract = {The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.}, }
@article {pmid39830606, year = {2025}, author = {Adsul, P and Sanchez-Youngman, S and Dickson, E and Jacquez, B and Kuhlemeier, A and Muhammad, M and Briant, KJ and Hempstead, B and Mendoza, JA and Rosas, LG and Patel, A and Rodriguez Espinosa, P and Akintobi, T and Castro-Reyes, P and Carter-Edwards, L and Wallerstein, N}, title = {Assessing the context within academic health institutions toward improving equity-based, community and patient-engaged research.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e6}, pmid = {39830606}, issn = {2059-8661}, support = {U48 DP005042/DP/NCCDPHP CDC HHS/United States ; U48 DP006802/DP/NCCDPHP CDC HHS/United States ; }, abstract = {INTRODUCTION: The continued momentum toward equity-based, patient/community-engaged research (P/CenR) is pushing health sciences to embrace principles of community-based participatory research. Much of this progress has hinged on individual patient/community-academic partnered research projects and partnerships with minimal institutional support from their academic health institutions.
METHODS: We partnered with three academic health institutions and used mixed methods (i.e., institution-wide survey (n = 99); qualitative interviews with institutional leadership (n = 11); and focus group discussions (6 focus groups with patients and community members (n = 22); and researchers and research staff (n = 9)) to gain a deeper understanding of the institutional context.
RESULTS: Five key themes emerged that were supported by quantitative data. First, the global pandemic and national events highlighting social injustices sparked a focus on health equity in academic institutions; however, (theme 2) such a focus did not always translate to support for P/CenR nor align with institutional reputation. Only 52% of academics and 79% of community partners believed that the institution is acting on the commitment to health equity (Χ[2] = 6.466, p < 0.05). Third, institutional structures created power imbalances and community mistrust which were identified as key barriers to P/CenR. Fourth, participants reported that institutional resources and investments are necessary for recruitment and retention of community-engaged researchers. Finally, despite challenges, participants were motivated to transform current paradigms of research and noted that accountability, communication, and training were key facilitators.
CONCLUSIONS: Triangulating findings from this mixed-methods study revealed critical barriers which provide important targets for interventions to improving supportive policies and practices toward equity-based P/CenR.}, }
@article {pmid39830263, year = {2025}, author = {Esmaeili, S and Owens, K and Standing, JF and Lowe, DM and Zhang, S and Watson, JA and Schilling, WHK and Wagoner, J and Polyak, SJ and Schiffer, JT}, title = {Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39830263}, abstract = {Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 7-8 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.5 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.}, }
@article {pmid39829847, year = {2025}, author = {Haddox, HK and Angehrn, G and Sesta, L and Jennings-Shaffer, C and Temple, SD and Galloway, JG and DeWitt, WS and Bloom, JD and Matsen, FA and Neher, RA}, title = {The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829847}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {RNA viruses like SARS-CoV-2 have a high mutation rate, which contributes to their rapid evolution. The rate of mutations depends on the mutation type (e.g., A→C, A→G, etc.) and can vary between sites in the viral genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using the millions of available SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for all 12 possible nucleotide mutation types and examine how much these rates vary between sites. We find a surprisingly high level of variability and several striking patterns: the rates of four mutation types suddenly increase at one of two gene boundaries; the rates of most mutation types strongly depend on a site's local sequence context, with up to 56-fold differences between contexts; consistent with a previous study, the rates of some mutation types are lower at sites engaged in RNA secondary structure. A simple log-linear model of these features explains ~15-60% of the fold-variation of mutation rates between sites, depending on mutation type; more complex models only modestly improve predictive power out of sample. We estimate the fitness effect of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on the model. We identify several small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence that is independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.}, }
@article {pmid39829843, year = {2025}, author = {Xie, J and Chen, DG and Chour, W and Ng, RH and Zhang, R and Yuan, D and Choi, J and McKasson, M and Troisch, P and Smith, B and Jones, L and Webster, A and Rasheed, Y and Li, S and Edmark, R and Hong, S and Murray, KM and Logue, JK and Franko, NM and Lausted, CG and Piening, B and Algren, H and Wallick, J and Magis, AT and Watanabe, K and Mease, P and Greenberg, PD and Chu, H and Goldman, JD and Su, Y and Heath, JR}, title = {APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829843}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA264090/CA/NCI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; }, abstract = {Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.}, }
@article {pmid39829744, year = {2025}, author = {Tang, G and Carr, AV and Perez, C and Sarmiento, KR and Levy, L and Lampe, JW and Diener, C and Gibbons, SM}, title = {Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829744}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 DK133468/DK/NIDDK NIH HHS/United States ; }, abstract = {Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, qPCR, or spike-ins (i.e., adding cells or DNA from an organism not normally found in a sample), can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read ratios. We compare B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. We show how B:H ratios can be used to track antibiotic treatment response and recovery in both mice and humans, which showed 403-fold and 45-fold reductions in bacterial biomass during antibiotic treatment, respectively. Our results indicate that host and bacterial metagenomic DNA fractions in human stool fluctuate longitudinally around a stable mean in healthy individuals, and the average host read fraction varies across healthy individuals by < 8-9 fold. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning algorithms, enabling retrospective absolute biomass estimates from existing stool metagenomic data.}, }
@article {pmid39829743, year = {2025}, author = {Nguyen, A and Heim, JB and Cordara, G and Chan, MC and Johannesen, H and Charlesworth, C and Li, M and Azumaya, CM and Madden, B and Krengel, U and Meves, A and Campbell, MG}, title = {Structural and functional characterization of integrin α5-targeting antibodies for anti-angiogenic therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39829743}, issn = {2692-8205}, support = {R35 GM147414/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; F31 HL174166/HL/NHLBI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; K08 CA215105/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Integrins are a large family of heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1, also known as the fibronectin receptor, is a key mediator of angiogenesis and its dysregulation is associated with tumor proliferation, progression, and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful in large part due to efficacy and off-target effects. To mediate activation and signaling, integrins undergo drastic conformational changes. However, how therapeutics influence or are affected by integrin conformation remains incompletely characterized. Using cell biology, biophysics, and electron microscopy, we shed light on these relationships by characterizing two potentially therapeutic anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity and reduce angiogenesis in vitro. We demonstrate BIIG2 reduces tumor growth in two human xenograft mouse models and exhibits a strong specificity for connective tissue-resident fibroblasts and melanoma cells. Using electron microscopy, we map out the molecular interfaces mediating the integrin-antibody interactions and reveal that although both antibodies have overlapping epitopes and block fibronectin binding via steric hindrance, the effect on the conformational equilibrium is drastically different. While MINT1526A constricts α5β1's range of flexibility, BIIG2 binds without restricting the available conformational states. These mechanistic insights, coupled with the functional analysis, guide which aspects should be prioritized to avoid off-target effects or partial agonism in the design of future integrin-targeted therapeutics.}, }
@article {pmid39828431, year = {2025}, author = {Begnel, ER and Ojee, E and Adhiambo, J and Mabele, E and Wandika, B and Ogweno, V and Lim, ES and Gantt, S and Kinuthia, J and Lehman, DA and Slyker, J and Wamalwa, D}, title = {The Linda Kizazi study: a comparison of morbidity and mortality from birth to 2 years between children who are HIV-unexposed and HIV-exposed, uninfected in the era of universal antiretroviral therapy.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, pmid = {39828431}, issn = {2059-7908}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV Infections/drug therapy/epidemiology/mortality ; Infant ; Kenya/epidemiology ; Infant, Newborn ; Pregnancy ; Male ; Adult ; Child, Preschool ; Cohort Studies ; Morbidity ; Diarrhea/epidemiology ; Malaria/epidemiology ; Respiratory Tract Infections/epidemiology ; Hospitalization/statistics & numerical data ; *Anti-Retroviral Agents/therapeutic use ; Pregnancy Complications, Infectious/drug therapy ; Young Adult ; *Child Mortality ; }, abstract = {BACKGROUND: Historically, children who are HIV-exposed, uninfected (CHEU) have been found to have greater morbidity and mortality than children who are HIV-unexposed, uninfected (CHUU). To assess whether this difference persists in the era of universal antiretroviral therapy (ART), we conducted a cohort study to compare the risk of acute diarrhoea, respiratory tract infections (RTI), malaria, hospitalisation, and all-cause mortality between Kenyan CHEU and CHUU from birth to 2 years.
METHODS: From December 2018 to March 2020 at Mathare North Health Centre in Nairobi, we recruited pregnant women living with HIV on ART for ≥6 months and pregnant women without HIV from the same community. We followed the mother-infant pairs for 2 years post partum and collected data on symptoms of illness, clinical visits and diagnoses, and infant feeding every 3 months; a self-selected subset of participants also received weekly data collection for up to 1 year. We compared the risk of each outcome between CHEU versus CHUU using HRs from Andersen-Gill (recurrent morbidity outcomes) and Cox proportional hazards (mortality) regression models adjusted for maternal age, marital status and education level.
RESULTS: Among 187 mother-infant pairs with postpartum data, 86 (46%) infants were CHEU and 101 (54%) were CHUU. All initiated breastfeeding, and 88% of CHEU and 57% of CHUU were exclusively breastfed (EBF) for ≥6 months. There was no significant difference in risk of diarrhoea (HR=0.79, 95% CI 0.52 to 1.22), malaria (HR=0.44, 95% CI 0.16 to 1.21), hospitalisation (HR=1.11, 95% CI 0.30 to 4.14), or mortality (HR=1.87, 95% CI 0.17 to 20.5). However, CHEU had lower risk of any RTI (HR=0.60, 95% CI 0.44 to 0.82) and pneumonia (HR=0.29, 95% CI 0.091 to 0.89).
CONCLUSIONS: CHEU born to women on effective long-term ART experienced similar overall morbidity and mortality as CHUU. However, CHEU had substantially lower risk of pneumonia and other RTI, possibly due to longer EBF in this group.}, }
@article {pmid39827422, year = {2025}, author = {Sierra, J and de León, UA and Padilla-Longoria, P}, title = {Tumor microenvironment noise-induced polarization: the main challenge in macrophages' immunotherapy for cancer.}, journal = {Molecular and cellular biochemistry}, volume = {480}, number = {6}, pages = {3735-3747}, pmid = {39827422}, issn = {1573-4919}, mesh = {*Tumor Microenvironment/immunology ; Humans ; *Immunotherapy/methods ; *Epigenesis, Genetic ; *Neoplasms/therapy/immunology/pathology/genetics ; Animals ; *Macrophages/immunology/pathology ; *Tumor-Associated Macrophages/immunology/pathology ; }, abstract = {Disturbance of epigenetic processes can lead to altered gene function and malignant cellular transformation. In particular, changes in the epigenetic landscape are a central topic in cancer biology. The initiation and progression of cancer are now recognized to involve both epigenetic and genetic alterations. In this paper, we study the epigenetic mechanism (related to the tumor microenvironment) responsible for increasing tumor-associated macrophages that promote the occurrence and metastasis of tumor cells, support tumor angiogenesis, inhibit T-cell-mediated anti-tumor immune response, and lead to tumor progression. We show that the tumor benefits from the macrophages' high degree of plasticity and larger epigenetic basins corresponding to phenotypes that favor cancer development through a process that we call noise-induced polarization. Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt). Our results show that a combination therapy may be necessary to ensure the proper epigenetic stability of macrophages, which otherwise will contribute to cancer progression. On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages' immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington's landscape) as the backbone for our study, which encapsulates the biological information of the system.}, }
@article {pmid39826256, year = {2025}, author = {Lim, FY and Lea, HG and Dostie, AM and Kim, SY and van Neel, TL and Hassan, GW and Takezawa, MG and Starita, LM and Adams, KN and Boeckh, M and Schiffer, JT and Hyrien, O and Waghmare, A and Berthier, E and Theberge, AB}, title = {homeRNA self-blood collection enables high-frequency temporal profiling of presymptomatic host immune kinetics to respiratory viral infection: a prospective cohort study.}, journal = {EBioMedicine}, volume = {112}, number = {}, pages = {105531}, pmid = {39826256}, issn = {2352-3964}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *COVID-19/immunology/virology/blood/genetics ; Prospective Studies ; Adult ; *Respiratory Tract Infections/immunology/virology/blood ; Middle Aged ; SARS-CoV-2/immunology ; *Blood Specimen Collection/methods ; Kinetics ; }, abstract = {BACKGROUND: Early host immunity to acute respiratory infections (ARIs) is heterogenous, dynamic, and critical to an individual's infection outcome. Due to limitations in sampling frequency/timepoints, kinetics of early immune dynamics in natural human infections remain poorly understood. In this nationwide prospective cohort study, we leveraged a Tasso-SST based self-blood collection and stabilization tool (homeRNA) to profile detailed kinetics of the presymptomatic to convalescence host immunity to contemporaneous respiratory pathogens.
METHODS: We enrolled non-symptomatic adults with recent exposure to ARIs who subsequently tested negative (exposed-uninfected) or positive for respiratory pathogens. Participants self-collected blood and nasal swabs daily for seven consecutive days followed by weekly blood collection for up to seven additional weeks. Symptom burden was assessed during each collection. Nasal swabs were tested for SARS-CoV-2 and common respiratory pathogens. 92 longitudinal blood samples spanning the presymptomatic to convalescence phase of eight participants with SARS-CoV-2 infection and 40 interval-matched samples from four exposed-uninfected participants were subjected to high-frequency longitudinal profiling of 785 immune genes. Generalized additive mixed models (GAMM) were used to identify temporally dynamic genes from the longitudinal samples and linear mixed models (LMM) were used to identify baseline differences between exposed-infected (n = 8), exposed-uninfected (n = 4), and uninfected (n = 13) participant groups.
FINDINGS: Between June 2021 and April 2022, 68 participants across 26 U.S. states completed the study and self-collected a total of 691 and 466 longitudinal blood and nasal swab samples along with 688 symptom surveys. SARS-CoV-2 was detected in 17 out of 22 individuals with study-confirmed respiratory infection, of which five were still presymptomatic or pre-shedding, enabling us to profile detailed expression kinetics of the earliest blood transcriptional response to contemporaneous variants of concern. 51% of the genes assessed were found to be temporally dynamic during COVID-19 infection. During the pre-shedding phase, a robust but transient response consisting of genes involved in cell migration, stress response, and T cell activation were observed. This is followed by a rapid induction of many interferon-stimulated genes (ISGs), concurrent to onset of viral shedding and increase in nasal viral load and symptom burden. Finally, elevated baseline expression of antimicrobial peptides was observed in exposed-uninfected individuals.
INTERPRETATION: We demonstrated that unsupervised self-collection and stabilization of capillary blood can be applied to natural infection studies to characterize detailed early host immune kinetics at a temporal resolution comparable to that of human challenge studies. The remote (decentralized) study framework enables conduct of large-scale population-wide longitudinal mechanistic studies.
FUNDING: This study was funded by R35GM128648 to ABT for in-lab developments of homeRNA and data analysis, a Packard Fellowship for Science and Engineering from the David and Lucile Packard Foundation to ABT for the study execution, sample collection, and analysis, and R01AI153087 to AW for data analysis.}, }
@article {pmid39826253, year = {2025}, author = {Montaño, MA and Jatho, A and Nassolo, C and Mugisha, N and Bula, A and Chagomerana, MB and Borok, M and Mtisi, TJ and Joffe, M and Bender Ignacio, RA and Ndlovu, N}, title = {Healthcare provider perspectives on integrating HIV care into cancer centers in Malawi, South Africa, Uganda, and Zimbabwe.}, journal = {Translational oncology}, volume = {53}, number = {}, pages = {102273}, pmid = {39826253}, issn = {1936-5233}, abstract = {BACKGROUND: In East and Southern Africa, treatment of people with concomitant cancer and HIV is complicated by siloed service delivery pathways, which exacerbate barriers to care and impact clinical decision-making. Integrating HIV care into cancer treatment centers may improve service delivery and overall patient outcomes.
METHODS: We administered a questionnaire to clinicians and support staff at tertiary cancer referral centers in Malawi, Zimbabwe, Uganda, and South Africa to assess level of concern about clinical management of people with HIV (PWH) and cancer, barriers to integrating HIV service delivery into cancer treatment delivery, and beliefs related to HIV, antiretroviral therapy (ART), and integrated care.
RESULTS: Of 195 clinician and support staff participants, 165 (85 %) were direct providers of cancer-associated care. Over 50 % indicated that they held concerns about survival, treatment complications, co-morbidities, and drug-drug interactions in PWH compared to patients without HIV. Over 80 % agreed that knowing cancer patients' HIV status, ART status, and ART regimen would facilitate better care and should be considered in cancer care decision-making. Overall, respondents were optimistic that HIV-related care could be easily integrated into cancer care provision. The most-frequently endorsed barriers to integrated care were workspace limitations, disruptions to workflow, availability of staff, and cost to the hospital and to patients.
CONCLUSIONS: Cancer clinicians and support staff report overall positive attitudes toward integrating HIV and cancer service delivery. Research to elucidate service delivery pathways and contextualize system-based barriers to integrating care are critical next steps to optimize linked HIV and cancer care delivery.}, }
@article {pmid39825826, year = {2025}, author = {Mughal, TI and Mascarenhas, J and Rampal, RK and Bose, P and Lion, T and Ajufo, H and Yacoub, A and Meshinchi, S and Masarova, L and Mesa, R and Jamieson, C and Barbui, T and Saglio, G and Van Etten, RA}, title = {Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms.}, journal = {Hematological oncology}, volume = {43}, number = {1}, pages = {e70013}, doi = {10.1002/hon.70013}, pmid = {39825826}, issn = {1099-1069}, support = {//Alpine Oncology Foundation/ ; }, mesh = {Humans ; *Myeloproliferative Disorders/genetics/therapy/drug therapy/pathology/metabolism ; *Fusion Proteins, bcr-abl/genetics/metabolism/antagonists & inhibitors ; Protein Kinase Inhibitors/therapeutic use ; Translational Research, Biomedical ; *Proto-Oncogene Proteins c-bcr/genetics/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; }, abstract = {Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18[th] edition of the workshop and includes reference to some data presented or published after the workshop, including the 26[th] John Goldman CML conference.}, }
@article {pmid39825500, year = {2025}, author = {Prizment, A and Standafer, A and Qu, C and Beutel, KM and Wang, S and Huang, WY and Lindblom, A and Pearlman, R and Van Guelpen, B and Wolk, A and Buchanan, DD and Grant, RC and Schmit, SL and Platz, EA and Joshu, CE and Couper, DJ and Peters, U and Starr, TK and Scott, P and Pankratz, N}, title = {Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.}, journal = {Human molecular genetics}, volume = {34}, number = {7}, pages = {617-625}, pmid = {39825500}, issn = {1460-2083}, support = {//Whiteside Institute for Clinical Research/ ; R21CA256749/CA/NCI NIH HHS/United States ; //University of Minnesota Academic Health Center/ ; /NH/NIH HHS/United States ; R21 CA256749/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; *Colorectal Neoplasms/genetics/pathology ; *Genetic Predisposition to Disease ; Male ; *Cystic Fibrosis/genetics/complications ; Female ; Exome Sequencing ; Middle Aged ; Case-Control Studies ; Risk Factors ; Adult ; Aged ; }, abstract = {BACKGROUND: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.
METHODS: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk. For replication, we used whole exome sequencing data from UK Biobank (UKB; 5126 cases and 20 504 controls matched 4:1 based on genetic distance, age, and sex), and extended our analyses to all other heterozygous CFTR variants annotated as CF-causing.
RESULTS: In our meta-analysis of GECCO-CORECT-CCFR-ARIC, the odds ratio (OR) for CRC risk associated with Phe508del was 1.11 (P = 0.010). In our UKB replication, the OR for CRC risk associated with Phe508del was 1.28 (P = 0.002). The sequencing data from UKB also revealed an association between the presence of any other single CF-causing variant (excluding Phe508del) and CRC risk (OR = 1.33; P = 0.030). When stratifying CFTR variants by functional class, class I variants (no protein produced) had a stronger association (OR = 1.77; p = 0.002), while class II variants (misfolding and retention of the protein in the endoplasmic reticulum) other than Phe508del (OR = 1.75; p = 0.107) had similar effect size as Phe508del, and variants in classes III-VI had non-significant ORs less than 1.0 and/or were not present in cases.
CONCLUSIONS: CF-causing heterozygous variants, especially class I variants, are associated with a modest but statistically significant increased CRC risk. More research is needed to explain the biology underlying these associations.}, }
@article {pmid39825152, year = {2025}, author = {Okines, AFC and Curigliano, G and Mizuno, N and Oh, DY and Rorive, A and Soliman, H and Takahashi, S and Bekaii-Saab, T and Burkard, ME and Chung, KY and Debruyne, PR and Fox, JR and Gambardella, V and Gil-Martin, M and Hamilton, EP and Monk, BJ and Nakamura, Y and Nguyen, D and O'Malley, DM and Olawaiye, AB and Pothuri, B and Reck, M and Sudo, K and Sunakawa, Y and Van Marcke, C and Yu, EY and Ramos, J and Tan, S and Bieda, M and Stinchcombe, TE and Pohlmann, PR}, title = {Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.}, journal = {Nature medicine}, volume = {31}, number = {3}, pages = {909-916}, pmid = {39825152}, issn = {1546-170X}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Breast Neoplasms/drug therapy/genetics/pathology ; Mutation ; Neoplasm Metastasis ; *Oxazoles/administration & dosage/adverse effects/therapeutic use ; *Pyridines/administration & dosage/adverse effects ; *Quinazolines/administration & dosage/adverse effects/therapeutic use ; *Receptor, ErbB-2/genetics/antagonists & inhibitors ; *Trastuzumab/administration & dosage/adverse effects/therapeutic use ; }, abstract = {Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .}, }
@article {pmid39824819, year = {2025}, author = {Zhang, B and Fong, Y and Dang, L and Fintzi, J and Chen, S and Wang, J and Rouphael, NG and Branche, AR and Diemert, DJ and Falsey, AR and Graciaa, DS and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Kamidani, S and Walter, EB and Novak, RM and Rupp, R and Jackson, LA and Yu, C and Magaret, CA and Molitor, C and Borate, B and Busch, S and Benkeser, D and Netzl, A and Smith, DJ and Babu, TM and Kottkamp, AC and Luetkemeyer, AF and Immergluck, LC and Presti, RM and Bäcker, M and Winokur, PL and Mahgoub, SM and Goepfert, PA and Fusco, DN and Atmar, RL and Posavad, CM and Mu, J and Makowski, M and Makhene, MK and Nayak, SU and Roberts, PC and Gilbert, PB and Follmann, D and , }, title = {Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {759}, pmid = {39824819}, issn = {2041-1723}, support = {R37AI054165//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI148684//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; contract 75N910D00024, task order 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; Contract no. 75A50122C00008//U.S. Department of Health & Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; 75N93021D00021/AI/NIAID NIH HHS/United States ; C0000008/CL/CLC NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; 75A50122C00008//U.S. Department of Health & Human Services | Biomedical Advanced Research and Development Authority (BARDA)/ ; contract 75N910D00024, task order no. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75N93021C00012/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *COVID-19/prevention & control/immunology/virology ; *COVID-19 Vaccines/immunology/administration & dosage ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; Female ; Male ; Immunization, Secondary/methods ; Middle Aged ; Adult ; Spike Glycoprotein, Coronavirus/immunology/genetics ; mRNA Vaccines ; Vaccines, Synthetic/immunology ; }, abstract = {Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 ("COVID-19") and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal ("predicted-at-exposure") titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.}, }
@article {pmid39822915, year = {2025}, author = {Cooper, DJ and Karten, J and Hoffe, SE and King, DA and Weiss, M and DePeralta, DK and Coveler, AL and Hingorani, SR and Shefter, T and Meguid, C and Roberts, H and Hong, TS and Narang, A and Hacker-Prietz, A and Fisher, GA and Sandler, J and Singer, L and Korah, B and Hoos, W and Stricker, CT and Herman, JM}, title = {The power of personas: Exploring an innovative model for understanding stakeholder perspectives in an oncology learning health network.}, journal = {Learning health systems}, volume = {9}, number = {1}, pages = {e10422}, pmid = {39822915}, issn = {2379-6146}, abstract = {INTRODUCTION: Learning health networks (LHNs) improve clinical outcomes by applying core tenets of continuous quality improvements (QI) to reach community-defined outcomes, data-sharing, and empowered interdisciplinary teams including patients and caregivers. LHNs provide an ideal environment for the rapid adoption of evidence-based guidelines and translation of research and best practices at scale. When an LHN is established, it is critical to understand the needs of all stakeholders. To accomplish this, we used ethnographic methods to develop personas of different stakeholders within The Canopy Cancer Collective, the first oncology LHN.
METHODS: We partnered with a firm experienced in qualitative research and human-centered design to conduct interviews with stakeholders of The Canopy Cancer Collective, a newly developed pancreatic cancer LHN. Together with the firm, we developed a personas model approach to represent the wide range of diverse perspectives among the representative stakeholders, which included care team members, patients, and caregivers.
RESULTS: Thirty-one stakeholders from all facets of pancreatic cancer care were interviewed, including 20 care team members, 8 patients, and 3 caregivers. Interview transcripts were analyzed to construct 10 personas felt to represent the broad spectrum of stakeholders within The Cancer Canopy Collective. These personas were used as a foundation for the design and development of The Cancer Canopy Cancer Collective key drivers and aims.
CONCLUSIONS: As LHNs continue to facilitate comprehensive approaches to patient-centered care, interdisciplinary teams who understand each other's needs can improve Network unity and cohesion. We present the first model utilizing personas for LHNs, demonstrating this framework holds significant promise for further study. If validated, such an approach could be used as a dynamic foundation for understanding individual stakeholder needs in similar LHN ecosystems in the future.}, }
@article {pmid39820690, year = {2025}, author = {Nascimento de Lima, P and Matrajt, L and Coronado, G and Escaron, AL and Rutter, CM}, title = {Cost-Effectiveness of Noninvasive Colorectal Cancer Screening in Community Clinics.}, journal = {JAMA network open}, volume = {8}, number = {1}, pages = {e2454938}, pmid = {39820690}, issn = {2574-3805}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/economics ; *Cost-Benefit Analysis ; Middle Aged ; *Early Detection of Cancer/economics/methods ; Female ; Male ; Colonoscopy/economics ; California/epidemiology ; Occult Blood ; *Mass Screening/economics/methods ; Aged ; Quality-Adjusted Life Years ; }, abstract = {IMPORTANCE: Several noninvasive tests for colorectal cancer screening are available, but their effectiveness in settings with low adherence to screening and follow-up colonoscopy is not well documented.
OBJECTIVE: To assess the cost-effectiveness of and outcomes associated with noninvasive colorectal cancer screening strategies, including new blood-based tests, in a population with low adherence to screening and ongoing surveillance colonoscopy.
The validated microsimulation model used for the decision analytical modeling study projected screening outcomes from 2025 to 2124 for a simulated cohort of 10 million individuals aged 50 years in 2025 and representative of a predominantly Hispanic or Latino patient population served by a Federally Qualified Health Center in Southern California. The simulated population had low adherence to first-step noninvasive testing (45%), second-step follow-up colonoscopy after an abnormal noninvasive test result (40%), and ongoing surveillance colonoscopy among patients with high-risk findings at follow-up colonoscopy (80%).
EXPOSURES: Colorectal cancer screening strategies included no screening, an annual or biennial fecal immunochemical test, a triennial multitarget stool DNA test, and a triennial blood-based test. Using a blood-based test was assumed to increase first-step adherence by 17.5 percentage points.
MAIN OUTCOMES AND MEASURES: Outcomes included colorectal cancer incidence and mortality, life-years gained and quality-adjusted life-years gained relative to no screening, costs, and net monetary benefit assuming a willingness to pay of $100 000 per quality-adjusted life-year gained.
RESULTS: Under realistic adherence assumptions, a program of annual fecal immunochemical testing was the most effective and cost-effective strategy, yielding 121 life-years gained per 1000 screened individuals and a net monetary benefit of $5883 per person. Triennial blood testing was the least effective, yielding 23 life-years gained per 1000, and was not cost-effective, with a negative net monetary benefit. Annual fecal immunochemical testing with 45% first-step adherence and 80% adherence to follow-up and surveillance colonoscopy yielded greater benefit than triennial blood testing with perfect adherence (88 vs 77 life-years gained per 1000).
CONCLUSIONS AND RELEVANCE: This study suggests that in a federally qualified health care setting, prioritizing the convenience of blood tests over less costly and more effective existing stool-based tests could result in higher costs and worse population-level outcomes. Novel screening modalities should be carefully evaluated for performance in community settings before widespread adoption.}, }
@article {pmid39820359, year = {2025}, author = {Gauthier, J and Liang, EC and Huang, JJ and Kimble, EL and Hirayama, AV and Fiorenza, S and Voutsinas, JM and Wu, QV and Jaeger-Ruckstuhl, CA and Pender, BS and Kirchmeier, DR and Torkelson, A and Braathen, K and Basom, R and Shadman, M and Kopmar, NE and Cassaday, RD and Riddell, SR and Maloney, DG and Turtle, CJ}, title = {Phase 1 study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult patients with B-ALL.}, journal = {Blood advances}, volume = {9}, number = {8}, pages = {1861-1872}, pmid = {39820359}, issn = {2473-9537}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; K12 CA076930/CA/NCI NIH HHS/United States ; 75N92019D00018/HL/NHLBI NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Adult ; *Antigens, CD19/immunology ; Middle Aged ; *Immunotherapy, Adoptive/methods/adverse effects ; *Single-Chain Antibodies/immunology/genetics ; *Receptors, Chimeric Antigen/immunology ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/mortality ; Treatment Outcome ; Young Adult ; *T-Lymphocytes/immunology/metabolism ; Aged ; }, abstract = {CD19-directed chimeric antigen receptor-engineered (CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial, we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single-chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971). Twenty-three patients received lymphodepletion chemotherapy and JCAR021 infusion. Nineteen patients developed cytokine release syndrome (any grade, 83%; grade 2, 61%) and 12 developed neurotoxicity (52%; grade ≥3, 35%). The overall response and complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 82% and 64%, respectively. We observed measurable residual disease-negative bone marrow (BM) responses in 82% of those with BM disease and extramedullary responses by positron emission tomography-computed tomography in 79% (CR, 50%) of those with measurable fluorodeoxyglucose-avid disease. The median duration of remission (DOR) was 10 months with a 4-year DOR probability of 29%. Four patients underwent allogeneic hematopoietic cell transplantation while in CR/CRi after JCAR021. Durable remissions were observed in patients with low BM disease burden. In contrast, the DOR was limited in those with high BM burden. We observed similar outcomes in CAR-naïve adult patients with B-ALL receiving CD19 CAR T cells expressing a fully human or murine scFv-containing CAR. This trial was registered at www.ClinicalTrials.gov as #NCT03103971.}, }
@article {pmid39819674, year = {2025}, author = {Bordeaux, J and Blitzblau, R and Aasi, SZ and Alam, M and Amini, A and Bibee, K and Bolotin, D and Chen, PL and Contreras, CM and DiMaio, D and Donigan, JM and Farma, JM and Ghosh, K and Harms, K and LeBoeuf, N and Lukens, JN and Manber, S and Mark, L and Medina, T and Nehal, KS and Nghiem, P and Olino, K and Paragh, G and Park, S and Patel, T and Rich, J and Shaha, AR and Sharma, B and Sokumbi, Y and Srivastava, D and Thomas, V and Tomblinson, C and Venkat, P and Xu, YG and Yu, S and Yusuf, M and McCullough, B and Espinosa, S}, title = {Dermatofibrosarcoma Protuberans, Version 1.2025, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {1}, pages = {}, doi = {10.6004/jnccn.2025.0001}, pmid = {39819674}, issn = {1540-1413}, mesh = {Humans ; *Dermatofibrosarcoma/therapy/diagnosis/pathology ; *Skin Neoplasms/therapy/diagnosis/pathology ; *Medical Oncology/standards ; Neoplasm Recurrence, Local/epidemiology/prevention & control ; Combined Modality Therapy/standards/methods ; }, abstract = {Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma and affects an estimated 1,500 people annually in the United States. DFSP frequently exhibits extensive local infiltration. Initial treatment is through surgical excision, and care should be taken to ensure that negative margins are achieved to minimize recurrence. Although DFSP has a reported high rate of recurrence, metastasis is more uncommon. Fibrosarcomatous DFSP is an aggressive variant with an increased risk for local recurrence and metastasis. If achieving negative margins or resection is not feasible, radiation therapy or systemic treatment are options that may be considered by a multidisciplinary team. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline recommended treatment options available for DFSP.}, }
@article {pmid39819601, year = {2025}, author = {Wood, DE and Kazerooni, EA and Aberle, DR and Argento, C and Baines, J and Boer, B and Brown, LM and Donington, J and Eapen, GA and Ferguson, JS and Hou, L and Klippenstein, D and Kolansky, AS and Kumar, R and Leard, LE and Leung, ANC and Mazzone, P and Merritt, RE and Norris, K and Onaitis, M and Pipavath, S and Puri, V and Raz, D and Reddy, C and Reid, ME and Sandler, KL and Sands, J and Schabath, MB and Sears, CR and Studts, JL and Tanoue, L and Thacker, AL and Tong, BC and Travis, WD and Wei, B and Westover, K and McCullough, B and Ramakrishnan, S}, title = {NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2025.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {1}, pages = {}, doi = {10.6004/jnccn.2025.0002}, pmid = {39819601}, issn = {1540-1413}, mesh = {Humans ; *Lung Neoplasms/diagnosis/epidemiology ; *Early Detection of Cancer/standards/methods ; *Mass Screening/standards/methods ; Practice Guidelines as Topic ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.}, }
@article {pmid39818460, year = {2025}, author = {Daneshmand, S and Kamat, AM and Shore, ND and Meeks, JJ and Galsky, MD and Jacob, JM and van der Heijden, MS and Williams, SB and Powles, T and Chang, SS and Catto, JWF and Psutka, SP and Guerrero-Ramos, F and Xylinas, E and Miyake, M and Simone, G and Daniel, K and Sweiti, H and Cutie, C and Necchi, A}, title = {Development of TAR-200: A novel targeted releasing system designed to provide sustained delivery of gemcitabine for patients with bladder cancer.}, journal = {Urologic oncology}, volume = {43}, number = {5}, pages = {286-296}, doi = {10.1016/j.urolonc.2024.12.264}, pmid = {39818460}, issn = {1873-2496}, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy ; Gemcitabine ; *Deoxycytidine/analogs & derivatives/administration & dosage/therapeutic use/pharmacokinetics ; *Antimetabolites, Antineoplastic/administration & dosage/pharmacokinetics ; Administration, Intravesical ; *Drug Delivery Systems ; }, abstract = {Treatment options for recurrent high-risk non-muscle-invasive bladder cancer (HR NMIBC) and muscle-invasive bladder cancer (MIBC) are limited, highlighting a need for clinically effective, accessible, and better-tolerated alternatives. In this review we examine the clinical development program of TAR-200, a novel targeted releasing system designed to provide sustained intravesical delivery of gemcitabine to address the needs of patients with NMIBC and of those with MIBC. We describe the concept and design of TAR-200 and the clinical development of this gemcitabine intravesical system in the SunRISe portfolio of studies. This includes 3 phase I studies evaluating the safety and initial tumor activity of TAR-200 and 5 phase II/III studies assessing the efficacy and safety of TAR-200, with or without systemic cetrelimab, as a treatment option for patients with HR NMIBC (bacillus Calmette-Guérin naive [papillary and carcinoma in situ] and MIBC (neoadjuvant and patients ineligible for or refusing radical cystectomy). Pharmacokinetics demonstrate intravesical gemcitabine delivery via TAR-200 over a prolonged period without detectable plasma levels. Phase I studies showed that TAR-200 is well tolerated, with preliminary antitumor activity in intermediate-risk NMIBC and MIBC. Preliminary data from the phase IIb SunRISe-1 study demonstrate that TAR-200 monotherapy is safe and effective in patients with bacillus Calmette-Guérin-unresponsive high-risk NMIBC. TAR-200 represents an innovative approach to the local treatment of bladder cancer.}, }
@article {pmid39817910, year = {2025}, author = {Termote, M and Marques, RC and Hyllner, E and Guryleva, MV and Henskens, M and Brutscher, A and Baken, IJL and Dopico, XC and Gasull, AD and Murrell, B and Stamatatos, L and Westerberg, LS and Dosenovic, P}, title = {Antigen affinity and site of immunization dictate B cell recall responses.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115221}, doi = {10.1016/j.celrep.2024.115221}, pmid = {39817910}, issn = {2211-1247}, mesh = {Animals ; Mice ; Germinal Center/immunology ; *B-Lymphocytes/immunology ; *Memory B Cells/immunology ; Immunologic Memory ; *Immunization ; HIV-1/immunology ; *Antibody Affinity/immunology ; *Antigens/immunology ; Mice, Inbred C57BL ; Lymph Nodes/immunology ; HIV Antibodies/immunology ; }, abstract = {Protective antibodies against HIV-1 require unusually high levels of somatic mutations introduced in germinal centers (GCs). To achieve this, a sequential vaccination approach was proposed. Using HIV-1 antibody knockin mice with fate-mapping genes, we examined if antigen affinity affects the outcome of B cell recall responses. Compared to a high-affinity boost, a low-affinity boost resulted in decreased numbers of memory-derived B cells in secondary GCs but with higher average levels of somatic mutations, indicating an affinity threshold for memory B cells to enter GCs. Furthermore, upon boosting local lymph nodes (LNs), the composition of primary GCs was modified in an antigen-affinity-dependent manner to constitute less somatically mutated B cells. Our results demonstrate that antigen affinity and location of the boost affect the outcome of the B cell recall response. These results can help guide the design of vaccine immunogens aiming to selectively engage specific B cell clones for further diversification.}, }
@article {pmid39817771, year = {2025}, author = {Cohen, P and Lambson, BE and Mkhize, NN and Moodley, C and Yssel, AEJ and Moyo-Gwete, T and York, T and Gwashu-Nyangiwe, A and Ndabambi, N and Thebus, R and Juraska, M and deCamp, AC and Williamson, BD and Magaret, CA and Gilbert, PB and Westfall, D and Deng, W and Mullins, JI and Morris, L and Williamson, C and Moore, PL}, title = {Resistance mutations that distinguish HIV-1 envelopes with discordant VRC01 phenotypes from multi-lineage infections in the HVTN703/HPTN081 trial: implications for cross-resistance.}, journal = {Journal of virology}, volume = {99}, number = {2}, pages = {e0173024}, pmid = {39817771}, issn = {1098-5514}, support = {INV-036842/GATES/Gates Foundation/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; R01 AI152115/AI/NIAID NIH HHS/United States ; AI152115//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; 95803//South African Medical Research Council (SAMRC)/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV-1/genetics/immunology/drug effects ; *HIV Infections/virology/immunology/drug therapy ; *HIV Antibodies/immunology/therapeutic use ; *Drug Resistance, Viral/genetics ; *Mutation ; *env Gene Products, Human Immunodeficiency Virus/genetics/immunology ; Antibodies, Neutralizing/immunology/therapeutic use ; Phenotype ; Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/immunology ; CD4 Antigens ; }, abstract = {The Antibody Mediated Prevention (AMP) trials showed that passively infused VRC01, a broadly neutralizing antibody (bNAb) targeting the CD4 binding site (CD4bs) on the HIV-1 envelope protein (Env), protected against neutralization-sensitive viruses. We identified six individuals from the VRC01 treatment arm with multi-lineage breakthrough HIV-1 infections from HVTN703, where one variant was sensitive to VRC01 (IC50 < 25 ug/mL) but another was resistant. By comparing Env sequences of resistant and sensitive clones from each participant, we identified sites predicted to affect VRC01 neutralization and assessed the effect of their reversion in the VRC01-resistant clone on neutralization sensitivity. In four pairs, a single mutation restored partial or full sensitivity to VRC01, whereas in the fifth participant, transfer of the entire [Formula: see text]23-V5 loop was required. No VRC01 resistance mutations could be identified in the sixth participant, with the discordant clones differing by >100 amino acids. Mutations responsible for the differential neutralization phenotypes occurred at distinct sites across Env, including residues in loop D, the CD4-binding loop, and between the [Formula: see text]23 and V5 loops. Analysis of deep sequencing env data showed that VRC01 resistance was likely the property of the acquired virus, rather than occurring through post-acquisition evolution. Although VRC01-resistant parental clones generally retained sensitivity to other CD4-binding site bNAbs, they were less potently neutralized than the VRC01-sensitive clones. In conclusion, VRC01 resistance mutations occurred through multiple mutational pathways, but sensitivity to second-generation CD4bs bNAbs was retained even in VRC01-resistant transmitted viruses, confirming the potential of these bNAbs for HIV-1 prevention studies.IMPORTANCEThe Antibody Mediated Prevention (AMP) trials provided proof of principle that VRC01, a CD4-binding site (CD4bs) HIV-1 broadly neutralizing antibody (bNAb), prevented the acquisition of antibody-sensitive viruses. However, understanding common mutations that confer resistance to different bNAbs provides important insights into the genetic barrier to resistance. Here we studied six AMP trial participants with breakthrough infections mediated by multiple viral lineages with discordant VRC01 sensitivity. We identified different mutations across the CD4-binding site that conferred resistance to VRC01 and showed that these mutations were a property of the acquired virus, rather than a result of post-acquisition evolution. We found that although VRC01 resistance was associated with reduced neutralization potency of second-generation CD4-binding site bNAbs, overall neutralization sensitivity was generally retained, which is promising for future use of such bNAbs in clinical trials.}, }
@article {pmid39817189, year = {2025}, author = {Kundel, V and Devarakonda, K and Khan, S and Suarez-Farinas, M and Cohen, O and Santos-Gallego, C and Menegus, MA and Kini, A and Vengrenyuk, Y and Okamoto, N and Ueda, H and Gidwani, U and Kizer, JR and Redline, S and Kaplan, R and Shah, N}, title = {Exploring the Relationship Between Sleep Apnea, Myocardial Infarct Size, and Coronary Collaterals in Acute Myocardial Infarction: A Multidisciplinary Study.}, journal = {Nature and science of sleep}, volume = {17}, number = {}, pages = {27-42}, pmid = {39817189}, issn = {1179-1608}, support = {K23 HL125923/HL/NHLBI NIH HHS/United States ; K23 HL161324/HL/NHLBI NIH HHS/United States ; R01 HL143221/HL/NHLBI NIH HHS/United States ; R01 HL168897/HL/NHLBI NIH HHS/United States ; }, abstract = {PURPOSE: We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation.
METHODS: We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0-3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher's Exact test as appropriate, with a significance threshold set at p <0.05.
RESULTS: Among 33 adults, mean age was 54.4±11.5 and mean BMI was 28.4±5.9. 8 patients (24%) had no SA, and 25 (76%) had SA (mild n=10, moderate n=8, severe n=7). 66% (n=22) underwent CMR, and all patients had Rentrop scores. Median infarct size in the no-SA group was 22% versus 28% in the SA group (p=0.79). While we did not find statistically significant differences, moderate SA had a trend toward a smaller infarct size (median 15.5%; IQR 9.23) compared to the other groups (no SA [22.0%; 16.8,31.8], mild SA [27%; 23.8,32.5], and severe SA [34%; 31.53], p=0.12). A higher proportion of moderate SA patients had a Rentrop grade >0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08).
CONCLUSION: Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.}, }
@article {pmid39817081, year = {2024}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Hyde, J and Martínez, J and Ahmed, CA and Briceno, G and Patel, H and Pena, J and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kattan, MW and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Electrical Heterogeneity in Hispanic Background Subpopulations: The HCHS/SOL.}, journal = {JACC. Advances}, volume = {3}, number = {12}, pages = {101225}, pmid = {39817081}, issn = {2772-963X}, support = {R01 HL118277/HL/NHLBI NIH HHS/United States ; R56 HL118277/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: The Hispanic/Latino population is not uniform. Prevalence and clinical outcomes of cardiac arrhythmias in ethnic background subgroups are variable, but the reasons for differences are unclear. Vectorcardiographic Global Electrical Heterogeneity (GEH) has been shown to be associated with adverse cardiovascular outcomes.
OBJECTIVES: The purpose of this study was to compare GEH in Hispanic/Latino background subpopulations. We hypothesized that ethnicity category moderates an association of prevalent cardiovascular disease (CVD) with GEH.
METHODS: Cross-sectional analysis of the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) included 15,684 participants (mean age 41 years; 38% Mexican, 20% Cuban, 16% Puerto Rican, 10% Dominican, 7% Central American, 5% South American, 4% mixed Hispanic/Latino background). Acculturation and socioeconomic data were collected. GEH was measured as spatial QRS-T angle, spatial ventricular gradient (SVG) azimuth, SVG elevation, SVG magnitude, and sum absolute QRST integral. Linear regression models included interaction terms of ethnic background category by CVD and were adjusted for age, sex, education attainment, hypertension, diabetes, smoking, dyslipidemia, obesity, chronic kidney disease, physical activity, diet quality, heart rate, and rhythm.
RESULTS: The adjusted spatial QRS-T angle was significantly (P < 0.0001) narrower in Dominican background (-3.4°[95% CI -5.0° to -1.7°]) as compared to a total mean. SVG azimuth pointed farther posteriorly in Dominican (+2.9 [95% CI: 1.6-4.2]) and Puerto Rican (+3.8 [2.4-5.2]), but farther anteriorly in South American (-2.9 [95% CI: -4.4 to -1.4]) and Mexican (-3.5 [95% CI: -4.3 to -2.6]) vs total mean. An association of coronary heart disease with GEH was especially strong in Cuban background subpopulation.
CONCLUSIONS: In CVD-free Hispanic/Latino subpopulations, cardiovascular risk factors do not fully explain GEH differences across ethnic background categories, which likely reflect unmeasured health disparities.}, }
@article {pmid39817038, year = {2025}, author = {Bradley, J and Floyd, S and Piwowar-Manning, E and Laeyendecker, O and Baker, OR and Bell-Mandla, N and Bwalya, J and Moore, A and Eshleman, SH and Donnell, D and Bock, P and Fidler, S and Ayles, H and Hayes, RJ}, title = {Strong Association Between HIV Incidence and Herpes Simplex Virus Type 2 in Zambia and South Africa: Prospective Data From the HPTN 071 (PopART) Trial.}, journal = {Open forum infectious diseases}, volume = {12}, number = {1}, pages = {ofae721}, pmid = {39817038}, issn = {2328-8957}, abstract = {BACKGROUND: Herpes simplex virus type 2 (HSV2) is an important cofactor for HIV acquisition and transmission. Associations between the infections are reexamined in longitudinal data from an HIV prevention trial.
METHODS: The HPTN 071 (PopART) trial evaluated a combination prevention intervention in 21 urban communities in Zambia and South Africa. HIV incidence was measured in a cohort of approximately 2000 adults (age, 18-44 years) selected randomly from each community and followed up for 36 months. Incidence of HSV2 infection was estimated, and the effects of risk factors were examined. The association between HIV incidence and HSV2 infection was examined at individual and community levels.
RESULTS: An overall 10 539 participants were HSV2 negative at baseline and retested after 36 months. Estimated HSV2 incidence was 5.4 per 100 person-years (95% CI, 5.0-5.7) for women and 2.9 per 100 person-years (95% CI, 2.6-3.2) for men. When compared with those remaining HSV2 negative, HIV incidence was higher in those who were HSV2 positive at baseline (women: adjusted rate ratio [aRR], 3.24 [95% CI, 2.50-4.20]; men: aRR, 2.57 [95% CI, 1.60-4.11]) and even higher in those who seroconverted to HSV2 during follow-up (women: aRR, 5.94 [95% CI, 4.42-7.98]; men: aRR, 8.37 [95% CI, 5.18-13.52]). At the community level, strong associations were seen between HIV incidence and HSV2 prevalence (R [2] = 0.48, P < .001) and incidence (R [2] = 0.36, P = .004).
CONCLUSIONS: There were strong associations between HIV incidence and HSV2 prevalence and incidence at individual and community levels. HSV2 control could contribute to HIV prevention.}, }
@article {pmid39815807, year = {2025}, author = {Lim, SYT and Cole, FM and Laszlo, GS and Lunn-Halbert, MC and Huo, J and Li, J and Kehret, AR and Walter, RB}, title = {Targeting the membrane-proximal domain of CD33 to maximize the efficacy of natural killer cell-based immunotherapies.}, journal = {Haematologica}, volume = {110}, number = {5}, pages = {1197-1201}, pmid = {39815807}, issn = {1592-8721}, support = {R21 CA259779/CA/NCI NIH HHS/United States ; R50 CA274319/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, }
@article {pmid39815460, year = {2025}, author = {Moseley, A and LeBlanc, M and Freidlin, B and Shallis, RM and Zeidan, AM and Sallman, DA and Erba, HP and Little, RF and Othus, M}, title = {Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials.}, journal = {Clinical trials (London, England)}, volume = {22}, number = {3}, pages = {361-366}, pmid = {39815460}, issn = {1740-7753}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Clinical Trials, Phase II as Topic/methods ; *Randomized Controlled Trials as Topic/methods ; Sample Size ; *Research Design ; Data Interpretation, Statistical ; Computer Simulation ; }, abstract = {Background/aimsRandomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a "stratified analysis," in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power. The impact on power and type-1 error of stratification in the setting of smaller sample sizes as in randomized phase 2 trials has not been well characterized.MethodsWe performed computational studies to characterize the power and cross-arm balance of modestly sized clinical trials (less than 170 patients) with varying numbers of stratification factors (0-6), sample sizes, randomization ratios (1:1 vs 2:1), and randomization methods (dynamic balancing vs stratified block).ResultsWe found that the power of unstratified analyses was minimally impacted by the number of stratification factors used in randomization. Analyses stratified by 1-3 factors maintained power over 80%, while power dropped below 80% when four or more stratification factors were used. These trends held regardless of sample size, randomization ratio, and randomization method. For a given randomization ratio and sample size, increasing the number of factors used in randomization had an adverse impact on cross-arm balance. Stratified block randomization performed worse than dynamic balancing with respect to cross-arm balance when three or more stratification factors were used.ConclusionStratified analyses can decrease power in the setting of phase 2 trials when the number of patients in a stratification subgroup is small.}, }
@article {pmid39815416, year = {2025}, author = {Powles, T and Park, SH and Gurney, H and Loriot, Y and Sridhar, SS and Bellmunt, J and di Pietro, A and Grivas, P}, title = {Avelumab maintenance treatment for advanced urothelial cancer: plain language summary of long-term results from the JAVELIN Bladder 100 study.}, journal = {Future oncology (London, England)}, volume = {21}, number = {4}, pages = {381-391}, doi = {10.1080/14796694.2024.2435208}, pmid = {39815416}, issn = {1744-8301}, }
@article {pmid39814501, year = {2025}, author = {Karvonen, KA}, title = {Challenging the Status Quo: Multi-level Solutions for Equitable Hematopoietic Cell Transplantation Clinical Trial Representation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {1}, pages = {7-9}, doi = {10.1016/j.jtct.2024.12.014}, pmid = {39814501}, issn = {2666-6367}, }
@article {pmid39814200, year = {2025}, author = {Rangelova, E and Stoop, TF and van Ramshorst, TME and Ali, M and van Bodegraven, EA and Javed, AA and Hashimoto, D and Steyerberg, E and Banerjee, A and Jain, A and Sauvanet, A and Serrablo, A and Giani, A and Giardino, A and Zerbi, A and Arshad, A and Wijma, AG and Coratti, A and Zironda, A and Socratous, A and Rojas, A and Halimi, A and Ejaz, A and Oba, A and Patel, BY and Björnsson, B and Reames, BN and Tingstedt, B and Goh, BKP and Payá-Llorente, C and Del Pozo, CD and González-Abós, C and Medin, C and van Eijck, CHJ and de Ponthaud, C and Takishita, C and Schwabl, C and Månsson, C and Ricci, C and Thiels, CA and Douchi, D and Hughes, DL and Kilburn, D and Flanking, D and Kleive, D and Silva, DS and Edil, BH and Pando, E and Moltzer, E and Kauffman, EF and Warren, E and Bozkurt, E and Sparrelid, E and Thoma, E and Verkolf, E and Ausania, F and Giannone, F and Hüttner, FJ and Burdio, F and Souche, FR and Berrevoet, F and Daams, F and Motoi, F and Saliba, G and Kazemier, G and Roeyen, G and Nappo, G and Butturini, G and Ferrari, G and Kito Fusai, G and Honda, G and Sergeant, G and Karteszi, H and Takami, H and Suto, H and Matsumoto, I and Mora-Oliver, I and Frigerio, I and Fabre, JM and Chen, J and Sham, JG and Davide, J and Urdzik, J and de Martino, J and Nielsen, K and Okano, K and Kamei, K and Okada, K and Tanaka, K and Labori, KJ and Goodsell, KE and Alberici, L and Webber, L and Kirkov, L and de Franco, L and Miyashita, M and Maglione, M and Gramellini, M and Ramera, M and Amaral, MJ and Ramaekers, M and Truty, MJ and van Dam, MA and Stommel, MWJ and Petrikowski, M and Imamura, M and Hayashi, M and D'Hondt, M and Brunner, M and Hogg, ME and Zhang, C and Suárez-Muñoz, MÁ and Luyer, MD and Unno, M and Mizuma, M and Janot, M and Sahakyan, MA and Jamieson, NB and Busch, OR and Bilge, O and Belyaev, O and Franklin, O and Sánchez-Velázquez, P and Pessaux, P and Holka, PS and Ghorbani, P and Casadei, R and Sartoris, R and Schulick, RD and Grützmann, R and Sutcliffe, R and Mata, R and Patel, RB and Takahashi, R and Rodriguez Franco, S and Cabús, SS and Hirano, S and Gaujoux, S and Festen, S and Kozono, S and Maithel, SK and Chai, SM and Yamaki, S and van Laarhoven, S and Mieog, JSD and Murakami, T and Codjia, T and Sumiyoshi, T and Karsten, TM and Nakamura, T and Sugawara, T and Boggi, U and Hartman, V and de Meijer, VE and Bartholomä, W and Kwon, W and Koh, YX and Cho, Y and Takeyama, Y and Inoue, Y and Nagakawa, Y and Kawamoto, Y and Ome, Y and Soonawalla, Z and Uemura, K and Wolfgang, CL and Jang, JY and Padbury, R and Satoi, S and Messersmith, W and Wilmink, JW and Abu Hilal, M and Besselink, MG and Del Chiaro, M and , and , }, title = {The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {5}, pages = {529-542}, doi = {10.1016/j.annonc.2024.12.015}, pmid = {39814200}, issn = {1569-8041}, mesh = {Humans ; *Pancreatic Neoplasms/pathology/mortality/drug therapy/therapy/surgery ; *Neoadjuvant Therapy/mortality/methods ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Pancreatectomy/mortality ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Gemcitabine ; Deoxycytidine/analogs & derivatives/administration & dosage ; Irinotecan/therapeutic use/administration & dosage ; Survival Rate ; Oxaliplatin/administration & dosage/therapeutic use ; Fluorouracil/therapeutic use/administration & dosage ; Leucovorin/therapeutic use/administration & dosage ; Adult ; Chemotherapy, Adjuvant ; Paclitaxel/administration & dosage ; Albumins ; }, abstract = {BACKGROUND: Left-sided pancreatic cancer is associated with worse overall survival (OS) compared with right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with resectable pancreatic cancer (RPC), current randomized trials included mostly patients with right-sided RPC. The purpose of this study was to assess the association between neoadjuvant therapy and OS in patients with left-sided RPC compared with upfront surgery.
PATIENTS AND METHODS: This was an international multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). The primary endpoint was OS from diagnosis. Time-dependent Cox regression analysis was carried out to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at the time of diagnosis. Adjusted OS probabilities were calculated.
RESULTS: Overall, 2282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared with upfront surgery (adjusted hazard ratio 0.69, 95% confidence interval 0.58-0.83) with an adjusted median OS of 53 versus 37 months (P = 0.0003) and adjusted 5-year OS rates of 47% versus 35% (P = 0.0001) compared with upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction = 0.003) and higher serum carbohydrate antigen 19-9 (CA19-9; Pinteraction = 0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction = 0.43), splenic vein (Pinteraction = 0.30), retroperitoneal (Pinteraction = 0.84), and multivisceral (Pinteraction = 0.96) involvement.
CONCLUSIONS: Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared with upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.}, }
@article {pmid39813621, year = {2025}, author = {Gore, S and Blyth, E and Bleakley, M and Lee, K and Micklethwaite, K and Gowrishankar, K}, title = {Current developments in T-cell receptor therapy for acute myeloid leukemia.}, journal = {Blood advances}, volume = {9}, number = {12}, pages = {3069-3089}, pmid = {39813621}, issn = {2473-9537}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/immunology ; *Receptors, Antigen, T-Cell/metabolism/immunology ; *Immunotherapy, Adoptive/methods/adverse effects ; *Receptors, Chimeric Antigen/immunology ; T-Lymphocytes/immunology/metabolism ; Animals ; Antigens, Neoplasm/immunology ; }, abstract = {T-cell receptor (TCR) therapies are a promising modality for the treatment of cancers, with significant efforts being directed toward acute myeloid leukemia (AML), a particularly challenging disease. Chimeric antigen receptor (CAR) T cells targeting single surface antigens have shown remarkable efficacy for B-cell lymphoblastic leukemia, lymphomas, and multiple myeloma. However, AML presents formidable obstacles to the effectiveness of CAR T cells because of the widespread expression of heterogenous leukemia immunophenotypes and surface antigen targets additionally present on normal myeloid cells. TCR therapies are an evolving field of cell therapies that allow targeting intracellular antigenic peptides presented via HLA molecules. The development of TCR therapy for AML is progressing rapidly through preclinical research and successful clinical trials. This review specifically explores the antigens targeted in AML, the diverse methodologies and strategies used in TCR identification, and preclinical TCR T-cell development. The review also discusses innovative molecular designs to improve functional efficacy, mitigate safety concerns, and overcome HLA restrictions. Specific outcomes of early clinical trials targeting important antigens Wilms tumor gene 1, preferentially expressed antigen in melanoma, and minor histocompatibility antigen HA-1 are also highlighted. Ultimately, this review underscores why TCR therapy is poised to become an indispensable component of AML immunotherapy.}, }
@article {pmid39812506, year = {2025}, author = {Little, A and Zhao, N and Mikhaylova, A and Zhang, A and Ling, W and Thibord, F and Johnson, AD and Raffield, LM and Curran, JE and Blangero, J and O'Connell, JR and Xu, H and Rotter, JI and Rich, SS and Rice, KM and Chen, MH and Reiner, A and Kooperberg, C and Vu, T and Hou, L and Fornage, M and Loos, RJF and Kenny, E and Mathias, R and Becker, L and Smith, AV and Boerwinkle, E and Yu, B and Thornton, T and Wu, MC}, title = {General Kernel Machine Methods for Multi-Omics Integration and Genome-Wide Association Testing With Related Individuals.}, journal = {Genetic epidemiology}, volume = {49}, number = {1}, pages = {e22610}, doi = {10.1002/gepi.22610}, pmid = {39812506}, issn = {1098-2272}, support = {//U.S. Department of Health and Human Services, National Institute on Minority Health and Health Disparities, National Institutes of Health, National Human Genome Research Institute, National Center for Research Resources, COPD Foundation, National Heart, Lung, and Blood Institute, National Science Foundation, National Institute on Aging, and National Institute of Neurological Disorders and Stroke./ ; }, mesh = {Humans ; *Genome-Wide Association Study/methods ; *Genomics/methods ; Phenotype ; Models, Genetic ; Genotype ; Polymorphism, Single Nucleotide ; Machine Learning ; Quantitative Trait Loci ; Regression Analysis ; Algorithms ; Multiomics ; }, abstract = {Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.g. genotypes and gene expression levels) on a phenotype, particularly while accommodating routine issues, such as having related subjects' data in analyses. In this paper, we extend an existing composite kernel machine regression model to integrate two multi-omics data types, while accommodating for general correlation structures amongst outcomes. Due to the kernel machine regression framework, our methods allow for the integration of high-dimensional omics data with small, nonlinear, and interactive effects, and accommodation of general study designs. Here, we focus on scientific questions that aim to assess the association between a functional grouping (such as a gene or a pathway) and a quantitative trait of interest. We use a kernel machine regression to integrate the two multi-omics data types, as they may relate to the trait, and perform a global test of association. We demonstrate the advantage of this approach over single data type association tests via simulation. Finally, we apply this method to a large, multi-ethnic data set to investigate how predicted gene expression and rare genetic variation may be related to two platelet traits.}, }
@article {pmid39809874, year = {2025}, author = {Mao, JJ and Bryl, K and Gillespie, EF and Green, A and Hung, TKW and Baser, R and Panageas, K and Postow, MA and Daly, B}, title = {Randomized clinical trial of a digital integrative medicine intervention among patients undergoing active cancer treatment.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {29}, pmid = {39809874}, issn = {2398-6352}, support = {K08 CA252640/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P50 CA271357/CA/NCI NIH HHS/United States ; 1P50CA271357-01//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Exercise and mindfulness-based interventions have growing evidence for managing fatigue and comorbid symptoms; however, packaging them in a cohesive digital way for patients undergoing cancer treatment has not been evaluated. We conducted a randomized controlled trial to assess the impact of a 12 week digital integrative medicine program, Integrative Medicine at Home (IM@Home), versus enhanced usual care on fatigue severity (primary outcome), comorbid symptoms and acute healthcare utilization (secondary outcomes), in 200 patients with solid tumors experiencing fatigue during treatment. Fatigue severity decreased more in IM@Home than in the control (1.99 vs. 1.51 points; p = 0.04). IM@Home participants also had reduced symptom distress (p = 0.003), anxiety (p = 0.03), and depression (p = 0.02). Acute healthcare utilization was lower with IM@Home, with fewer emergency department visits (rate ratio 0.49; p = 0.04), hospitalizations (4% vs. 12.9%; p = 0.03), and shorter hospital stays (4.25 vs. 10 days; p < 0.001). These promising findings should be confirmed in phase III clinical trials. "Study registered at clinicaltrials.gov (NCT05053230) on 09-20-2021".}, }
@article {pmid39809842, year = {2025}, author = {Popchock, AR and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, AB and Biggins, S}, title = {Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain.}, journal = {The EMBO journal}, volume = {44}, number = {5}, pages = {1488-1511}, pmid = {39809842}, issn = {1460-2075}, support = {NIH 1DP5OD029630//HHS | National Institutes of Health (NIH)/ ; F32 GM136010/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; NIH R35GM134842//HHS | National Institutes of Health (NIH)/ ; R35 GM149357/GM/NIGMS NIH HHS/United States ; NIH R35 GM149357//HHS | National Institutes of Health (NIH)/ ; DP5 OD029630/OD/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; NIH F32GM136010//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Saccharomyces cerevisiae Proteins/metabolism/genetics/chemistry ; *Saccharomyces cerevisiae/metabolism/genetics ; *Centromere/metabolism ; *Chromosomal Proteins, Non-Histone/metabolism/genetics/chemistry ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; Kinetochores/metabolism ; Phosphorylation ; Protein Domains ; Histones/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Chromosome Segregation ; Protein Binding ; Nucleosomes/metabolism ; Aurora Kinases ; }, abstract = {Chromosome segregation relies on kinetochores that assemble on specialized centromeric chromatin containing a histone H3 variant. In budding yeast, a single centromeric nucleosome containing Cse4 assembles at a sequence-defined 125 bp centromere. Yeast centromeric sequences are poor templates for nucleosome formation in vitro, suggesting the existence of mechanisms that specifically stabilize Cse4 nucleosomes in vivo. The extended Cse4 N-terminal tail binds to the chaperone Scm3, and a short essential region called END within the N-terminal tail binds the inner kinetochore complex Okp1/Ame1. To address the roles of these interactions, we utilized single-molecule fluorescence assays to monitor Cse4 during kinetochore assembly. We found that Okp1/Ame1 and Scm3 independently stabilize Cse4 at centromeres via their END interaction. Scm3 and Cse4 stability at the centromere are enhanced by Ipl1/Aurora B phosphorylation of the Cse4 END, identifying a previously unknown role for Ipl1 in ensuring Cse4 stability. Strikingly, a phosphomimetic mutation in the Cse4 END restores Cse4 recruitment in mutants defective in Okp1/Ame1 binding. Together, these data suggest that a key function of the essential Cse4 N-terminus is to ensure Cse4 localization at centromeres.}, }
@article {pmid39808799, year = {2025}, author = {Baumrin, E and Pidala, J and Mitchell, SA and Onstad, L and Lee, SJ}, title = {Development of the Lee Symptom Scale-Skin Sclerosis for chronic GVHD-associated sclerosis.}, journal = {Blood}, volume = {145}, number = {12}, pages = {1321-1332}, pmid = {39808799}, issn = {1528-0020}, mesh = {Humans ; *Graft vs Host Disease/complications/pathology ; Female ; Male ; Middle Aged ; Adult ; Sclerosis/etiology/pathology/diagnosis ; Chronic Disease ; Aged ; *Patient Reported Outcome Measures ; *Skin Diseases/etiology/pathology/diagnosis ; Young Adult ; }, abstract = {Sclerosis is a highly morbid manifestation of chronic graft-versus-host disease (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome (PRO) measure for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults aged ≥18 years with cGVHD-associated sclerosis participated in semistructured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were used to evaluate content validity of the items, response options, recall period, and respondent instructions. Thirty-six open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (5) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n = 25). Phrasing changes were made to improve relevance and comprehension. One item was removed, and 2 items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important differences are underway in an external cohort to validate the PROs.}, }
@article {pmid39808648, year = {2025}, author = {Friedland, BA and Gundacker, H and Achilles, SL and Chen, BA and Hoesley, C and Richardson, BA and Kelly, CW and Piper, J and Johnson, S and Devlin, B and Steytler, J and Kleinbeck, K and Dangi, B and Friend, C and Song, M and Mensch, B and van der Straten, A and Jacobson, C and Hendrix, CW and Brown, J and Blithe, D and Hiller, SL and , }, title = {Acceptability of a dapivirine levonorgestrel vaginal ring in two Phase 1 trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019): Implications for multipurpose prevention technology development.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0312957}, pmid = {39808648}, issn = {1932-6203}, support = {UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; HHSN275201200002C/HD/NICHD NIH HHS/United States ; HHSN275201200002I/HD/NICHD NIH HHS/United States ; UM1 AI068633/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Adult ; *Levonorgestrel/administration & dosage ; Adolescent ; *Pyrimidines/administration & dosage ; *Contraceptive Devices, Female ; Middle Aged ; Young Adult ; *HIV Infections/prevention & control ; *Patient Acceptance of Health Care ; Contraceptive Agents, Female/administration & dosage ; Pregnancy ; }, abstract = {End-user feedback early in product development is important for optimizing multipurpose prevention technologies for HIV and pregnancy prevention. We evaluated the acceptability of the 90-day dapivirine levonorgestrel ring (DPV-LNG ring) used for 14 days compared to a dapivirine-only ring (DVR-200mg) in MTN-030/IPM 041 (n = 23), and when used for 90 days cyclically or continuously in MTN-044/IPM 053/CCN019 (n = 25). We enrolled healthy, non-pregnant, HIV-negative women aged 18-45 in Pittsburgh, PA and Birmingham, AL (MTN-030 only). Self-reports of vaginal bleeding and adherence (ring removals, expulsions) were collected via daily short message service. Acceptability data were recorded in face-to-face interviews at study exit. We assessed differences in acceptability by product characteristics and adherence; and associations between baseline characteristics/demographics, number of bleeding days, adherence, and overall acceptability. Most (21/23) women in the 14-day MTN-030 study and about half (13/25) in the 90-day MTN-044 study liked their assigned rings. In MTN-030 there were no significant associations between any variables and overall acceptability of either ring. In MTN-044, women who disliked the DPV-LNG ring had a significantly higher incidence of unanticipated vaginal bleeding, and reporting that vaginal bleeding changes were unacceptable than those who liked it. Although we found no overall association between adherence and acceptability, significantly more women who disliked (versus liked) the DPV-LNG ring reported expulsions during toileting. The DPV-LNG ring could meet the needs of women seeking simultaneous protection from HIV and unintended pregnancy. Addressing issues related to vaginal bleeding and expulsions early in product development will likely enhance acceptability of the DPV-LNG ring. Trial registration: Clinical Trial Registration: MTN-030/IPM 041: ClinicalTrials.gov NCT02855346; MTN-044/IPM 053/CCN019: ClinicalTrials.gov NCT03467347.}, }
@article {pmid39808447, year = {2025}, author = {Koyama, M}, title = {Control of antigen-independent T-cell migration after HSCT.}, journal = {Blood advances}, volume = {9}, number = {1}, pages = {207-208}, pmid = {39808447}, issn = {2473-9537}, }
@article {pmid39808161, year = {2025}, author = {Parada, H and Agalliu, I and Sotres-Alvarez, D and Olshan, AF and Evenson, KR and Rohan, TE and Kaplan, RC and Thompson, CA and Gallo, LC and Penedo, FJ and Cai, J and Wassertheil-Smoller, S and Thyagarajan, B and Thomas, SN and Garcia-Bedoya, OL and Daviglus, ML and Talavera, GA}, title = {Cancer Incidence in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-The Onco-SOL Ancillary Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {4}, pages = {491-499}, pmid = {39808161}, issn = {1538-7755}, support = {R01 CA227122/CA/NCI NIH HHS/United States ; U54 CA285117/CA/NCI NIH HHS/United States ; U54 CA285115/CA/NCI NIH HHS/United States ; U01 CA259208/CA/NCI NIH HHS/United States ; U54 MD012397/MD/NIMHD NIH HHS/United States ; N01-HC65233//National Heart, Lung, and Blood Institute (NHLBI)/ ; P30 AG059299/AG/NIA NIH HHS/United States ; BCRF-23-140//Breast Cancer Research Foundation (BCRF)/ ; K01 CA234317/CA/NCI NIH HHS/United States ; 5R01 CA227122//National Cancer Institute (NCI)/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Cohort Studies ; *Hispanic or Latino/statistics & numerical data ; Incidence ; *Neoplasms/epidemiology/ethnology ; Registries ; United States/epidemiology ; }, abstract = {BACKGROUND: Few studies have examined how cancer incidence varies by the country of origin among US Hispanic/Latino adults. In this study, we describe the incidence rates (IR) of cancer overall and for screen-detectable, tobacco-related, and obesity-related cancers among 16,415 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing population-based cohort study of Hispanic/Latino adults from diverse backgrounds.
METHODS: Cohort participant records were linked to the state cancer registries in New York, Florida, California, and Illinois to ascertain cancer incidence from baseline (2008-2011) through 2021. We estimated weighted age-adjusted IRs and age- and sex-adjusted HRs.
RESULTS: Over a mean follow-up of 10.7 (SD = 2.0) years, 715 incident invasive cancers were diagnosed including 118 female breast, 102 prostate, and 79 bronchus and lung cancers. The IR of all cancers combined was 26.2 [95% confidence interval (CI), 22.6-30.2] per 10,000 (10K) person-years (py). The IRs were lowest among persons of Mexican descent [IR, 19.0 (95% CI, 15.0-24.1) per 10K py] and highest for those of Puerto Rican [IR, 36.6 (95% CI, 28.4-47.0) per 10K py] descent. Compared with those of Mexican descent, those of Puerto Rican, Cuban, and Dominican descent had higher hazards of cancer incidence; the incidence of obesity-related (HR, 2.37; 95% CI, 1.43-3.95) and tobacco-related (HR, 3.00; 95% CI, 1.58-5.71) cancers was also the highest among Puerto Ricans.
CONCLUSIONS: Cancer IRs varied by Hispanic/Latino heritage and were masked when Hispanics/Latinos were aggregated into a single group.
IMPACT: Understanding disparities in cancer risk by Hispanic/Latino heritage may help tailor cancer prevention and control strategies.}, }
@article {pmid40241937, year = {2024}, author = {Wright, C and Meng, Q and Breshock, MR and Atta, L and Taub, MA and Jager, LR and Muschelli, J and Hicks, SC}, title = {Open Case Studies: Statistics and Data Science Education through Real-World Applications.}, journal = {Journal of statistics and data science education : an official journal of the of the American Statistical Association}, volume = {32}, number = {4}, pages = {331-344}, pmid = {40241937}, issn = {2693-9169}, support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; UE5 CA254170/CA/NCI NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {With unprecedented and growing interest in data science education, there are limited educator materials that provide meaningful opportunities for learners to practice statistical thinking, as defined by Wild and Pfannkuch, with messy data addressing real-world challenges. As a solution, Nolan and Speed advocated for bringing applications to the forefront in undergraduate statistics curriculum with the use of in-depth case studies to encourage and develop statistical thinking in the classroom. Limitations to this approach include the significant time investment required to develop a case study - namely, to select a motivating question and to create an illustrative data analysis - and the domain expertise needed. As a result, case studies based on realistic challenges, not toy examples, are scarce. To address this, we developed the Open Case Studies (opencasestudies.org) project, which offers a new statistical and data science education case study model. This educational resource provides self-contained, multimodal, peer-reviewed, and open-source guides (or case studies) from real-world examples for active experiences of complete data analyses. We developed an educator's guide describing how to most effectively use the case studies, how to modify and adapt components of the case studies in the classroom, and how to contribute new case studies (opencasestudies.org/OCS_Guide).}, }
@article {pmid39871876, year = {2024}, author = {Sokolov, D and Sullivan, LB}, title = {A metabolic signalling role for arginine in liver cancer.}, journal = {Life metabolism}, volume = {3}, number = {1}, pages = {load046}, pmid = {39871876}, issn = {2755-0230}, }
@article {pmid40575114, year = {2023}, author = {Vannier, D and Torok-Storb, B and Stromholt, S and Chowning, JT}, title = {The Pathways Undergraduate Researchers Program: Fostering Career Interests, Sense of Belonging, and Student Confidence in Pursuing Science.}, journal = {Journal of STEM outreach}, volume = {6}, number = {2}, pages = {}, pmid = {40575114}, issn = {2576-6767}, support = {R25 CA221770/CA/NCI NIH HHS/United States ; }, abstract = {The Pathways Undergraduate Researchers Program is a paid, nine-week summer internship at the Fred Hutchinson Cancer Center. It targets rising first-, second-, and third-year college students from backgrounds underrepresented in biomedical research. This paper describes how the internship impacted students' awareness of biomedical careers, scientific identification, and sense of belonging in research. Interns reported an increased awareness of biomedical careers and how to attain them. The experience also challenged interns' career ideas. Interns described a mix of feelings on sense of belonging. All felt welcomed and confident in their abilities. Nonetheless, some noted they were different from the other researchers. A number were motivated by being in the minority and ready to become leaders in diversifying the workforce. Data gathered during the COVID-19 pandemic shed a different light on the internship's impact. The interns reported becoming 'credible resources' on public health issues for their families and communities. The program supported this by building their confidence to understand and communicate science. This undergraduate program developed out of a longer running high school internship effort and many of the strategies described herein are used in both. These findings have implications for programs for underrepresented students at the high school and college level.}, }
@article {pmid40231215, year = {2023}, author = {He, B and Phipps, W and Aboulafia, DM}, title = {Engaging Resource-Constrained Countries in Research Trials of HIV and Cancer: Lessons from Sub-Saharan Africa and the AIDS Malignancy Consortium.}, journal = {International journal of cancer care and delivery}, volume = {3}, number = {2}, pages = {}, pmid = {40231215}, issn = {2770-3533}, support = {UM1 CA121947/CA/NCI NIH HHS/United States ; }, abstract = {HIV contributes significantly to the global burden of cancer. In developing countries, AIDS-defining cancers predominate due to inconsistent access to antiretroviral therapy (ART). Even though AIDS-defining cancers are now less common in developed countries, the prevalence of non-AIDS-defining cancers (NADCs) has increased due to longer life expectancy in a milieu of chronic immune activation, exposure to oncogenic viruses, lifestyle factors, and environmental variables. In resource-constrained countries with inconsistent access to ART, Kaposi sarcoma, aggressive B-cell lymphomas, and cervical cancer continue to be a large problem. Not only do people living with HIV (PLWH) face higher cancer incidence and mortality, but they also encounter persistent stigmatization and barriers to equitable access to cancer treatment. To bridge this gap, the United States National Cancer Institute (NCI) established the AIDS Malignancy Consortium (AMC) to evaluate novel treatments, preventive strategies, and clinical guidelines for PLWH by conducting both domestic and international research. The AMC also emphasizes the development of robust research infrastructure in resource-limited countries, training of researchers, and fair management of clinical trial specimens. Despite various challenges, the AMC has contributed significant insights to international cancer trials among PLWH, thereby transforming clinical practice in low-resource areas. The high global burden of HIV-associated cancer underscores the need for comprehensive research, improved healthcare access, and greater inclusion of PLWH in cancer clinical trials.}, }
@article {pmid40046543, year = {2023}, author = {Nayak, S and Waters, A and Warsi, M and Hegde, A and Chu, ES}, title = {Inpatient Physician and Nurse Experience During the COVID-19 Crisis at a Public Safety Net Hospital.}, journal = {The Brown journal of hospital medicine}, volume = {2}, number = {1}, pages = {57694}, pmid = {40046543}, issn = {2831-5553}, abstract = {BACKGROUND: The COVID-19 pandemic has been associated with front line health care provider burnout, depression, and post-traumatic stress disorder. We sought to better understand how nurses and physicians of differing genders may have been affected differently by the COVID-19 crisis.
METHODS: Between July 17, 2020, and October 31, 2020, we surveyed nurses and physicians caring for COVID-19 patients at a large, academic, public safety net hospital in the southern United States. Survey questions were adapted from validated questionnaires used to determine quality of life, assess levels of anxiety, and determine how COVID-19 may have affected our nurses' and physicians' work, home and social lives.
RESULTS: Overall, 120 (41.7%) providers responded, including 39 (50%) physicians and 81 (38.6%) nurses. 69.3% reported disruption to their home/family, 76.3% to their social lives, and 29.8% worried about financial strain. More nurses than physicians worried about being excluded from social gatherings (59.7% v 35.1%, p=0.01). Similarly, 70.1% of nurses and 46.0% of physicians expressed concern of exposing others to COVID-19 (p=0.01). Nurses also expressed greater concern about being treated differently by others when compared to physicians (64.5% v 37.8%, p= 0.01). Female physicians reported greater difficulty separating their personal lives from their professional lives than male physicians and either male or female nurses (84.6%% vs 35% vs 33.3% vs 35.9%, p <0.05). Most physicians (89.7%) and nurses (93.8%) reported some level of anxiety, with 31.5% of respondents experiencing moderate or severe anxiety.
CONCLUSION: Healthcare workers on the frontline of COVID-19 pandemic, regardless of profession, reported increased anxiety that extended beyond the hospital into their homes and social lives. Physicians and nurses, as well as men and women, reported different sources and degrees of stress and disruption to their work, home and social lives.}, }
@article {pmid39808074, year = {2024}, author = {Ho, K and Hoesley, C and Anderson, PL and Fernández-Romero, JA and Friedland, BA and Kelly, CW and Jiao, Y and Edick, S and Brand, R and Kunjara Na Ayudhya, RP and Zyhowski, A and Hartman, DJ and Reddy, NB and Al-Khouja, A and Piper, J and Bauermeister, JA and Teleshova, N and Melo, C and Cornejal, N and Barnable, P and Singh, D and Scheckter, R and McClure, T and Hillier, SL and Hendrix, CW and , }, title = {Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037).}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {97}, number = {4}, pages = {379-386}, pmid = {39808074}, issn = {1944-7884}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; U01 AI068633/AI/NIAID NIH HHS/United States ; UM1 AI068615/AI/NIAID NIH HHS/United States ; T32 GM066691/GM/NIGMS NIH HHS/United States ; P30 AI036219/AI/NIAID NIH HHS/United States ; UM1AI068633//Division of AIDS, National Institute of Allergy and Infectious Diseases/ ; UM1 AI106707/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Adult ; *Antiviral Agents/pharmacokinetics/administration & dosage/adverse effects ; Middle Aged ; *HIV Infections/prevention & control ; Male ; Administration, Rectal ; *Carrageenan/pharmacokinetics/administration & dosage/adverse effects ; Papillomavirus Infections/prevention & control ; Young Adult ; Herpesvirus 2, Human/drug effects ; *Pre-Exposure Prophylaxis/methods ; Vagina ; Pyridines ; Urea/analogs & derivatives ; }, abstract = {BACKGROUND: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005.
METHODS: HIV-uninfected adults received a series of 3 rectal PC-1005 doses-4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours.
RESULTS: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1-2 h after dosing with a median peak concentrations range of 0.07-0.23 ng/mL and median half-life range of 4.9-7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5-1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity.
CONCLUSIONS: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate.
CLINICAL TRIALS: NCT03408899.}, }
@article {pmid39807974, year = {2025}, author = {Kang, SK and Gulati, R and Moise, N and Hur, C and Elkin, EB}, title = {Multi-Cancer Early Detection Tests: State of the Art and Implications for Radiologists.}, journal = {Radiology}, volume = {314}, number = {1}, pages = {e233448}, pmid = {39807974}, issn = {1527-1315}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; R01 CA257333/CA/NCI NIH HHS/United States ; R01 CA262375/CA/NCI NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; U01 CA265729/CA/NCI NIH HHS/United States ; R01 DE030169/DE/NIDCR NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis/diagnostic imaging ; Radiologists ; Biomarkers, Tumor/blood ; }, abstract = {Multi-cancer early detection (MCED) tests are already being marketed as noninvasive, convenient opportunities to test for multiple cancer types with a single blood sample. The technology varies-involving detection of circulating tumor DNA, fragments of DNA, RNA, or proteins unique to each targeted cancer. The priorities and tradeoffs of reaching diagnostic resolution in the setting of possible false positives and negatives remain under active study. Given the well-established role of imaging in lesion detection and characterization for most cancers, radiologists have an essential role to play in selecting diagnostic pathways, determining the validity of test results, resolving false-positive MCED test results, and evaluating tradeoffs for clinical policy. Appropriate access to and use of imaging tests will also factor into clinical guidelines. Thus, all clinicians potentially involved with MCED tests for cancer screening will need to weigh the benefits and harms of MCED testing, including consideration of how the tests will be used alongside or in place of other screening options, how diagnostic confirmation tests should be selected, and what the implications are for policy and reimbursement decisions. Further, patients will need regular support to make informed decisions about screening using MCED tests in the context of their personal cancer risks, health-related values, and access to care.}, }
@article {pmid39806218, year = {2025}, author = {Bajunaid, R and Niu, C and Hambly, C and Liu, Z and Yamada, Y and Aleman-Mateo, H and Anderson, LJ and Arab, L and Baddou, I and Bandini, L and Bedu-Addo, K and Blaak, EE and Bouten, CVC and Brage, S and Buchowski, MS and Butte, NF and Camps, SGJA and Casper, R and Close, GL and Cooper, JA and Cooper, R and Das, SK and Davies, PSW and Dabare, P and Dugas, LR and Eaton, S and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and El Hamdouchi, A and Haisma, HH and Hoffman, D and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kimura, M and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Lanerolle, P and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Matsiko, E and Medin, AC and Morehen, JC and Morton, JP and Must, A and Neuhouser, ML and Nicklas, TA and Nyström, CD and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, LM and Reilly, JJ and Reynolds, R and Roberts, SB and Samaranayakem, D and Sardinha, LB and Silva, AM and Sjödin, AM and Stamatiou, M and Stice, E and Urlacher, SS and Van Etten, LM and van Mil, EGAH and Wilson, G and Yanovski, JA and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Sinha, S and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Speakman, JR}, title = {Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.}, journal = {Nature food}, volume = {6}, number = {1}, pages = {58-71}, pmid = {39806218}, issn = {2662-1355}, support = {R01 DK080763/DK/NIDDK NIH HHS/United States ; CAS 153E11KYSB20190015//Bureau of International Cooperation, Chinese Academy of Sciences/ ; BCS-1824466//National Science Foundation (NSF)/ ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Energy Intake ; Adult ; Aged ; Nutrition Surveys ; Child ; Adolescent ; *Self Report ; Young Adult ; Child, Preschool ; Aged, 80 and over ; Energy Metabolism ; Body Mass Index ; *Water ; }, abstract = {Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96 years. The resultant regression equation predicts expected TEE from easily acquired variables, such as body weight, age and sex, with 95% predictive limits that can be used to screen for misreporting by participants in dietary studies. We applied the equation to two large datasets (National Diet and Nutrition Survey and National Health and Nutrition Examination Survey) and found that the level of misreporting was >50%. The macronutrient composition from dietary reports in these studies was systematically biased as the level of misreporting increased, leading to potentially spurious associations between diet components and body mass index.}, }
@article {pmid39805421, year = {2025}, author = {Ajelli, M and Muyembe, JJ and Touré, A and Diallo, A and Litvinova, M and Merler, S and Mulangu, S and Bagayoko, A and Bah, A and Bah, I and Barry, A and Barry, F and Chérif, M and Condé, D and Diallo, AA and Diallo, F and Diakité, M and Doré, K and Mapan, KA and Koundouno, T and Onivogui, PK and Lamah, F and Maneno, H and Nomou, A and Sekouba, K and Sani, I and Soumah, A and Sy, MM and Gsell, PS and Halloran, ME and Henao-Restrepo, AM and Fall, IS and Ryan, MJ and Salama, P and Vespignani, A and Longini, IM}, title = {Vaccination strategies for Ebola in the democratic republic of Congo: the WHO-Ebola modeling collaboration.}, journal = {International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases}, volume = {153}, number = {}, pages = {107779}, doi = {10.1016/j.ijid.2025.107779}, pmid = {39805421}, issn = {1878-3511}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Adolescent ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Computer Simulation ; Democratic Republic of the Congo/epidemiology ; Disease Outbreaks/prevention & control ; *Ebola Vaccines/administration & dosage ; Ebolavirus/genetics/immunology ; *Epidemiological Models ; Health Plan Implementation ; *Hemorrhagic Fever, Ebola/epidemiology/prevention & control/transmission ; International Cooperation ; *Vaccination/methods ; Vaccines, Attenuated/administration & dosage ; Vaccines, Synthetic/administration & dosage ; World Health Organization ; Contact Tracing ; }, abstract = {OBJECTIVES: Assess the effectiveness of ring vaccination in controlling an Ebola virus outbreak in the Democratic Republic of Congo.
METHODS: This analysis focuses on two areas of the Democratic Republic of Congo, Beni and Butembo/Katwa, which were affected during the 2018-2020 Ebola outbreak. To simulate Ebola virus transmission, we used a spatially explicit agent-based model with households, health care facilities, and Ebola treatment units. Model parameters were calibrated using data collected under the ring-vaccination expanded-access protocol implemented during the outbreak. The model was used to estimate the impact of the deployed ring vaccination strategy, compared to what would have happened if there had been no ring vaccination. The impact of alternative vaccination strategies (mass vaccination, targeted geographic vaccination, and ring-plus) was evaluated as well.
RESULTS: Compared to a hypothetical scenario where vaccination was not implemented, ring vaccination was estimated to have averted 54.3% (SD, 32.5%) and 62.7% (SD, 23.2%) of potential cases in Beni and Butembo/Katwa, respectively. Under ring vaccination, the average number of averted cases per 1000 vaccine doses administered was 15.1 (SD, 16.8) and 27.8 (SD, 22.9), in Beni and Butembo/Katwa, respectively. In terms of number of averted cases per vaccine dose, ring vaccination was estimated to be more efficient than any of the other evaluated vaccination strategies.
CONCLUSION: Despite some level of social instability, ring vaccination with the rVSV-ZEBOV vaccine was highly effective during the 2018-2020 Ebola outbreak in the Democratic Republic of Congo. As compared to alternative vaccination strategies, ring vaccination was estimated to be the most efficient.}, }
@article {pmid39804957, year = {2025}, author = {Zakerzade, R and Chang, CH and Chatla, K and Krishnapura, A and Appiah, SP and Zhang, J and Unckless, RL and Blumenstiel, JP and Bachtrog, D and Wei, KH}, title = {Diversification and recurrent adaptation of the synaptonemal complex in Drosophila.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011549}, pmid = {39804957}, issn = {1553-7404}, support = {K99 GM137041/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Synaptonemal Complex/genetics ; Evolution, Molecular ; Phylogeny ; Meiosis/genetics ; *Drosophila/genetics ; Drosophila Proteins/genetics ; Chromosome Pairing/genetics ; Drosophila melanogaster/genetics ; Male ; }, abstract = {The synaptonemal complex (SC) is a protein-rich structure essential for meiotic recombination and faithful chromosome segregation. Acting like a zipper to paired homologous chromosomes during early prophase I, the complex is a symmetrical structure where central elements are connected on two sides by the transverse filaments to the chromatin-anchoring lateral elements. Despite being found in most major eukaryotic taxa implying a deeply conserved evolutionary origin, several components of the complex exhibit unusually high rates of sequence turnover. This is puzzlingly exemplified by the SC of Drosophila, where the central elements and transverse filaments display no identifiable homologs outside of the genus. Here, we exhaustively examine the evolutionary history of the SC in Drosophila taking a comparative phylogenomic approach with high species density to circumvent obscured homology due to rapid sequence evolution. Contrasting starkly against other genes involved in meiotic chromosome pairing, SC genes show significantly elevated rates of coding evolution due to a combination of relaxed constraint and recurrent, widespread positive selection. In particular, the central element cona and transverse filament c(3)G have diversified through tandem and retro-duplications, repeatedly generating paralogs with novel germline activity. In a striking case of molecular convergence, c(3)G paralogs that independently arose in distant lineages evolved under positive selection to have convergent truncations to the protein termini and elevated testes expression. Surprisingly, the expression of SC genes in the germline is prone to change suggesting recurrent regulatory evolution which, in many species, resulted in high testes expression even though Drosophila males are achiasmic. Overall, our study recapitulates the poor conservation of SC components, and further uncovers that the lack of conservation extends to other modalities including copy number, genomic locale, and germline regulation. Considering the elevated testes expression in many Drosophila species and the common ancestor, we suggest that the activity of SC genes in the male germline, while still poorly understood, may be a prime target of constant evolutionary pressures driving repeated adaptations and innovations.}, }
@article {pmid39801002, year = {2025}, author = {Schaub, SK and Simone, CB and Lo, SS and Choi, JI}, title = {The current landscape of oncologic emergencies: the role of radiotherapy.}, journal = {Annals of palliative medicine}, volume = {14}, number = {1}, pages = {1-3}, doi = {10.21037/apm-24-159}, pmid = {39801002}, issn = {2224-5839}, }
@article {pmid39800921, year = {2025}, author = {Chen, A and Baek, G and Russell, K and Shaw, C and Othus, M and Cohen, J and Palmer, S and Rasmussen, J and Bubalo, J and Tsomo, T and Schwarz, T and Namburi, S and Halpern, A}, title = {Evaluation of the Toxicity and Outcomes of the Combination of Midostaurin and CLAG-M in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML): A Multicenter Retrospective Analysis.}, journal = {The Annals of pharmacotherapy}, volume = {59}, number = {8}, pages = {703-713}, doi = {10.1177/10600280241305608}, pmid = {39800921}, issn = {1542-6270}, mesh = {Humans ; *Leukemia, Myeloid, Acute/drug therapy/genetics ; Retrospective Studies ; *Staurosporine/analogs & derivatives/administration & dosage/adverse effects ; *fms-Like Tyrosine Kinase 3/genetics ; Male ; Female ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage/therapeutic use ; Aged ; Adult ; Cytarabine/administration & dosage/adverse effects ; Mitoxantrone/administration & dosage/adverse effects ; Mutation ; Cladribine/administration & dosage/adverse effects ; Treatment Outcome ; Granulocyte Colony-Stimulating Factor/administration & dosage/adverse effects ; Young Adult ; }, abstract = {BACKGROUND: Addition of midostaurin to standard "7+3" (cytarabine and anthracycline) significantly prolongs overall and event-free survival. At University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (R/R) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated. There is limited data on the use of FLT3-inhibitors with high-dose cytarabine regimens in AML.
OBJECTIVE: This study aimed to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M versus midostaurin plus 7+3 in FLT3-mutated AML patients.
METHODS: This is a retrospective, multicenter review including FLT3-mutated AML patients undergoing (re)induction chemotherapy with either CLAG-M or 7+3 at UW/FHCC, Oregon Health & Science University, and Swedish Cancer Institute. The primary outcome was incidence of adverse events. Secondary outcomes included disease response per ELN2017 criteria and 28-day mortality. Excluded were patients on clinical trials or who started midostaurin 30 days after chemotherapy.
RESULTS: Eighty patients treated from September 2016 to December 2023 were included; 36 patients received CLAG-M, and 44 patients 7+3. Baseline characteristics were similar across all institutions. Adverse event rates were similar between the 2 cohorts, except diarrhea and bleeding which were more common in the 7+3 cohort. The rate of complete remission (CR) plus CR with incomplete blood count recovery did not significantly differ between the 2 cohorts: CLAG-M, 86% versus 7+3, 70% (P = 0.11).Conclusion & relevance:The toxicity profile of CLAG-M combined with midostaurin is comparable with the combination of 7+3 with midostaurin, and induces high remissions rates in adults with FLT3-mutated AML.}, }
@article {pmid39800670, year = {2025}, author = {Najjar, R and Wang, X and Pineda, JMB and Alessi, H and Bays, A and Bradley, RK and Jarvis, JN and Mustelin, T}, title = {Altered Protein Structures and Neoepitopes in Lupus Neutrophils From Dysregulated Splicing of Messenger RNA.}, journal = {ACR open rheumatology}, volume = {7}, number = {1}, pages = {e11770}, pmid = {39800670}, issn = {2578-5745}, support = {R01 AR074939/AR/NIAMS NIH HHS/United States ; R01 CA096949/CA/NCI NIH HHS/United States ; R01 AR081654/AR/NIAMS NIH HHS/United States ; R01 AI186337/AI/NIAID NIH HHS/United States ; R21 AR075134/AR/NIAMS NIH HHS/United States ; T32 AR007108/AR/NIAMS NIH HHS/United States ; AR075134, AR074939, and AR081654 to T.M./RG/CSR NIH HHS/United States ; AI188952/RG/CSR NIH HHS/United States ; AI-186337 and AI-183320 (to Dr Mustelin)/GF/NIH HHS/United States ; }, abstract = {OBJECTIVE: To test whether messenger RNA (mRNA) splicing is altered in neutrophils from patients with systemic lupus erythematosus (SLE) and can produce neoantigens.
METHODS: RNA sequencing of neutrophils from patients with SLE (n = 15) and healthy donors (n = 12) were analyzed for mRNA splicing using the RiboSplitter pipeline, an event-focused tool based on SplAdder with subsequent translation and protein domain annotation. RNA sequencing from SARS-CoV2-infected individuals was used as an additional comparator.
RESULTS: Neutrophils from patients with SLE contained 521 statistically significant altered mRNA splicing events compared with healthy donor neutrophils, many of them affecting important immunologic pathways, myeloid function, transcription factors, and proteins involved in mRNA splicing. A subset of splicing events were only present in SLE samples, and some of them occurred at unannotated splice acceptor or donor sites. Two patients were particularly rich in such events. Only a small number of dysregulated splicing events were more pronounced in patients with active disease or with high type I interferons but were not detected in SARS-CoV2-infected individuals, who also had high type I interferons. Besides causing a range of structural changes, 80 mRNA splice variants exclusive to SLE were predicted to translate into novel amino acid sequences. Peptides derived from these novel amino acid sequences were predicted to bind to the individual patients' class I and II major histocompatibility complex molecules with high affinity.
CONCLUSION: We conclude that aberrant mRNA splicing in SLE has the potential to affect both the function of granulocytes and to generate novel autoantigens.}, }
@article {pmid39799046, year = {2025}, author = {Ramasamy, K and Vij, R and Kuter, D and Cella, D and Durie, BGM and Abonour, R and Rifkin, RM and Ailawadhi, S and Lee, HC and Cowan, AJ and Ho, C and Dhanasiri, S and Fish, S and Yu, E and Dhamane, AD and Fang, J and Marshall, TS and Samuel, A and Liu, L and Katz, J and Gu, T and Jagannath, S}, title = {Real-World Treatment Patterns and Clinical Outcomes in Patients With Multiple Myeloma Previously Treated With Lenalidomide and an Anti-CD38 Monoclonal Antibody.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {25}, number = {5}, pages = {337-348.e2}, doi = {10.1016/j.clml.2024.12.002}, pmid = {39799046}, issn = {2152-2669}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality ; *Lenalidomide/therapeutic use/pharmacology ; Male ; Aged ; Female ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *ADP-ribosyl Cyclase 1/antagonists & inhibitors/immunology ; Aged, 80 and over ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Treatment Outcome ; }, abstract = {BACKGROUND: This analysis explored real-world characteristics, treatment patterns and clinical outcomes in patients with relapsed or refractory multiple myeloma (RRMM) previously treated with lenalidomide and an anti-CD38 monoclonal antibody (mAb) and requiring subsequent treatment.
MATERIALS AND METHODS: The PREAMBLE and Connect MM prospective registries of patients with multiple myeloma (MM), and the US nationwide Flatiron Health electronic health record-derived de-identified database were analysed. MM-specific treatment patterns (prior/index therapies) and outcomes (progression-free survival [PFS]/overall survival [OS]) were assessed.
RESULTS: This analysis included: PREAMBLE n = 215; Connect MM n = 232; Flatiron Health n = 845. Median age at index was 69.0 years, median 3 prior lines of therapy; > 50% male. The most common index regimens accounted < 15% of treatments (most common PREAMBLE, Connect MM: carfilzomib±dexamethasone; Flatiron Health: pomalidomide+daratumumab+dexamethasone); most patients received classes that they had previously; ≥ 93% were triple-class exposed (immunomodulatory drug, proteasome inhibitor, anti-CD38 mAb). In PREAMBLE, Connect MM and Flatiron Health, respectively: 80.9%, 68.1% and 77.2% were lenalidomide- and anti-CD38 mAb-refractory; 69.3%, 67.2% and 71.1% were triple-class refractory (TCR); median PFS: 5.2 (95% CI 3.7-6.7), 4.4 (3.5-5.6) and 5.3 months (4.8-6.0); median OS: 19.3 (15.8-26.1), 14.2 (11.0-16.9) and 23.1 months (19.0-28.6). PFS and OS were shorter in lenalidomide- and anti-CD38 mAb-refractory patients versus those who were not refractory to both. A similar pattern was observed for TCR patients versus non-TCR patients.
CONCLUSION: There is no uniform standard of care for patients with RRMM with prior exposure to lenalidomide and anti-CD38 mAbs. Survival outcomes are poor, with a need for effective treatments for these patients.}, }
@article {pmid39798802, year = {2025}, author = {Petersdorf, EW and McKallor, C and Malkki, M and Hsu, K and He, M and Spellman, SR and Gooley, T and Stevenson, P}, title = {The Association of HLA-E Ligand and NKG2 Receptor Variation With Relapse and Mortality After Haploidentical Related Donor Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3}, pages = {137-156}, pmid = {39798802}, issn = {2666-6367}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; U01 HL069294/HL/NHLBI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Adult ; Middle Aged ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *NK Cell Lectin-Like Receptor Subfamily C/genetics ; Haplotypes/genetics ; Recurrence ; Graft vs Host Disease/genetics/mortality/etiology ; HLA-E Antigens ; *Histocompatibility Antigens Class I/genetics/metabolism ; Adolescent ; Ligands ; Retrospective Studies ; Young Adult ; Polymorphism, Single Nucleotide ; Tissue Donors ; Child ; *Transplantation, Haploidentical ; Genotype ; Aged ; }, abstract = {BACKGROUND: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown.
OBJECTIVE: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation.
STUDY DESIGN: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, nonrelapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression.
RESULTS: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, .49 [95% CI, .26 to .89) contributing to a HR for mortality of .62 (95% CI, .38 to 1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440-rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34 to 3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11 to 1.82) and 1.43 (95% CI, 1.13 to 1.81), respectively. Hazard ratios for nonrelapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06 to 2.41) and HR 1.79 (95% CI, 1.21 to 2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotype was HR 2.52 (95% CI, 1.45 to 4.38) relative to donors with any wt-non CCC/CCC haplotype.
CONCLUSIONS: The success of haploidentical transplantation may be defined by the cumulative effects of donor NKG2 receptor and patient HLA-E ligand polymorphisms. Patient HLA-E ligand and donor NKG2C-NKG2A receptor haplotypes shed new light on their role in the control of malignancy.}, }
@article {pmid39798608, year = {2025}, author = {Marshall, A and Kassim, S and Brown-Korsah, J and Raymundo, C and Chang, C and Hippe, DS and Kim, EJ and Shinohara, MM}, title = {Black patients with Mycosis fungoides and Sézary Syndrome experience worse health-related quality of life: A cross-sectional study.}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {1100-1102}, doi = {10.1016/j.jaad.2025.01.006}, pmid = {39798608}, issn = {1097-6787}, }
@article {pmid39798390, year = {2025}, author = {Talukder, R and Bakaloudi, DR and Makrakis, D and Diamantopoulos, LN and Enright, T and Leary, JB and Raychaudhuri, R and Tripathi, N and Agarwal, N and Jindal, T and Brown, JR and Zakharia, Y and Rey-Cárdenas, M and Castellano, D and Nguyen, CB and Alva, A and Zakopoulou, R and Bamias, A and Barrera, RM and Marmolejo, D and Drakaki, A and Pinato, DJ and Korolewicz, J and Buznego, LA and Duran, I and Carballeira, CC and McKay, RR and Stewart, TF and Gupta, S and Barata, P and Yu, EY and Koshkin, VS and Khaki, AR and Grivas, P}, title = {Clinical Outcomes With Immune Checkpoint Inhibitors in Patients With FGFR2/3, MTAP or ERBB2 Genomic Alterations in Advanced Urothelial Carcinoma.}, journal = {Clinical genitourinary cancer}, volume = {23}, number = {1}, pages = {102284}, doi = {10.1016/j.clgc.2024.102284}, pmid = {39798390}, issn = {1938-0682}, mesh = {Humans ; Male ; Female ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Receptor, Fibroblast Growth Factor, Type 3/genetics ; Aged ; Receptor, Fibroblast Growth Factor, Type 2/genetics ; Middle Aged ; Receptor, ErbB-2/genetics ; *Carcinoma, Transitional Cell/drug therapy/genetics/mortality ; *Urinary Bladder Neoplasms/drug therapy/genetics ; Aged, 80 and over ; Treatment Outcome ; *Urologic Neoplasms/drug therapy/genetics ; Receptor, ErbB-3 ; }, abstract = {BACKGROUND: FGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC.
PATIENTS AND METHODS: We identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards.
RESULTS: Out of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively. and were treated with ICI in 1L or 2 + L. In patients with (vs. without) FGFR2/3 alteration, ORR with ICI was 21% vs. 32% (OR 0.54; [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR = 1.36 [95%CI 1.03-1.80]; P=0.03); OS was not significantly different (HR = 1.22 [95%CI 0.86-1.47]). In patients with (vs. without) MTAP alteration, ORR with ICI was 25% versus 40% (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were nonsignificantly different. In patients with (vs. without) ERBB2 alteration, ORR with ICI was similar (37% vs. 35%; OR 1.06; 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95); P=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively.
CONCLUSION: Our results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI.}, }
@article {pmid39796789, year = {2024}, author = {Dekker, SE and Deng, L}, title = {Correction: Dekker, S.E.; Deng, L. Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer. Cancers 2024, 16, 3885.}, journal = {Cancers}, volume = {17}, number = {1}, pages = {}, pmid = {39796789}, issn = {2072-6694}, abstract = {In the original publication [...].}, }
@article {pmid39793544, year = {2025}, author = {Wheeler, SB and Thom, B and Waters, AR and Shankaran, V}, title = {Interventions to Address Cancer-Related Financial Hardship: A Scoping Review and Call to Action.}, journal = {JCO oncology practice}, volume = {21}, number = {1}, pages = {29-40}, doi = {10.1200/OP.24.00375}, pmid = {39793544}, issn = {2688-1535}, mesh = {Humans ; *Financial Stress ; *Neoplasms/economics/therapy ; }, abstract = {PURPOSE: As oncology practices implement routine screening for financial hardship (FH) and health-related social needs, interventions that address these needs must be implemented. A growing body of literature has reported on FH interventions.
METHODS: We conducted a scoping review of the literature using PubMed, EMBASE, PsychInfo, and CINAHL to identify key studies (2000-2024) reporting on interventions to address cancer-related FH. Full-length manuscripts were included in the review if they detailed a research, quality improvement, or community-based intervention to address at least one element of FH and drew association with an outcome of interest. Studies were categorized by intervention type and qualitatively analyzed to identify critical components, outcomes, and limitations.
RESULTS: Forty-four publications reporting on 43 interventions were included in the final analysis and were categorized as research interventions (n = 20) and real-world programs (n = 20). Studies reporting on financial navigation programs (n = 17) and specialty pharmacy assistance programs (n = 11) were most common; enrolled patients received concrete assistance with direct medical costs and cost-of-living expenses (eg, transportation and food). In addition, several of these programs improved overall patient-reported financial toxicity, decreased appointment no-shows, and improved enrollment in clinical trials.
CONCLUSION: Interventions to address FH are feasible and can address all domains of FH-material, behavioral, and psychosocial. Future research should address the uptake and implementation of these interventions across diverse cancer care delivery settings. Such programs will be an essential part of cancer care delivery until broad social and policy changes can address the underlying factors that contribute to FH in Americans with cancer.}, }
@article {pmid39792043, year = {2025}, author = {Galvin, RT and Chen, Y and Yuan, Y and Cooney, T and Howell, R and Smith, S and Arnold, MA and Conces, M and Leisenring, W and Armstrong, GT and Neglia, JP and Turcotte, LM}, title = {Temporal trends of subsequent central nervous system malignancies among survivors of childhood cancer.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {5}, pages = {1036-1045}, pmid = {39792043}, issn = {1460-2105}, support = {K08 CA234232/CA/NCI NIH HHS/United States ; T32 CA099936/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; //St Jude Children's Research Hospital/ ; CA21765//Cancer Center/ ; T32 CA099936/NH/NIH HHS/United States ; U24 CA55727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Incidence ; Female ; *Central Nervous System Neoplasms/epidemiology/etiology ; Male ; Child ; Adolescent ; Child, Preschool ; Risk Factors ; *Neoplasms, Second Primary/epidemiology/etiology ; Adult ; *Cranial Irradiation/adverse effects ; Infant ; Young Adult ; United States/epidemiology ; *Survivors/statistics & numerical data ; Time Factors ; *Cancer Survivors/statistics & numerical data ; *Neoplasms/radiotherapy ; }, abstract = {BACKGROUND: It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms of the central nervous system (CNS), a frequently fatal late effect of cancer therapy.
METHODS: Five-year survivors of primary childhood cancers diagnosed between 1970 and 1999 in the Childhood Cancer Survivor Study with CNS subsequent malignant neoplasms were identified. Cumulative incidence rates and standardized incidence ratios were compared among survivors diagnosed between 1970-1979 (n = 6223), 1980-1989 (n = 9680), and 1990-1999 (n = 8999). Multivariable models assessed risk factors for CNS subsequent malignant neoplasms.
RESULTS: A total of 157 CNS subsequent malignant neoplasms (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy exposure was reduced over time (1970s, 77.0%; 1980s, 54.3%; 1990s, 33.9%), while the proportion receiving more than 35 Gy cranial radiotherapy showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence and standardized incidence ratios for CNS subsequent malignant neoplasms by treatment decade were 0.32% (95% confidence interval = 0.18% to 0.46%) and 6.6 (95% CI = 5.0 to 8.7); 0.55% (95% CI = 0.41% to 0.70%) and 8.3 (95% CI = 6.6 to 10.4); and 0.43% (95% CI = 0.31% to 0.55%) and 9.2 (95% CI = 7.0 to 12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for cranial radiotherapy dose levels more than 10 Gy and for primary diagnoses of medulloblastoma and/or primitive neuro-ectodermal tumor (hazard ratio [HR] = 18.7, 95% CI = 9.2 to 37.9) and astrocytoma (HR = 10.1, 95% CI = 5.3 to 19.5). Three-year cumulative incidence of death after CNS subsequent malignant neoplasms, by treatment decade, were 76%, 74%, and 73%, respectively.
CONCLUSION: CNS subsequent malignant neoplasm incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS subsequent malignant neoplasm remains a substantial source of mortality for affected patients.}, }
@article {pmid39790992, year = {2024}, author = {Ruiz, RA and Lehavot, K and Heffner, JL and Kava, CM and Ornelas, IJ}, title = {Coping and Social Support in Relation to Minority Stress and Cigarette Smoking Among Lesbian, Gay, and Bisexual Veterans.}, journal = {Annals of LGBTQ public and population health}, volume = {5}, number = {4}, pages = {335-352}, pmid = {39790992}, issn = {2688-4518}, support = {I01 HX002423/HX/HSRD VA/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; T32 CA193193/CA/NCI NIH HHS/United States ; }, abstract = {The intersection between a minoritized sexual orientation identity and a U.S. military Veteran status places lesbian, gay, and bisexual (LGB) Veterans at increased risk for cigarette smoking. Guided by the Minority Stress Model, this study assessed whether coping and three types of social support (general, Veteran-specific, and lesbian, gay, bisexual, and transgender [LGBT]-specific) moderated the association between minority stressors and past-year smoking among LGB Veterans. Participants were recruited online for a prospective cohort study. We conducted secondary data analysis of baseline surveys collected from September 2019 to December 2020. The study sample included cisgender LGB Veterans (N = 463). Adjusted multivariable logistic regression models estimated the odds of past-year smoking with interaction terms between minority stressors and coping/social support to test for moderation. Four statistically significant interaction terms were found. Higher versus lower levels (i.e., one-point score increase) of coping buffered the relationship between victimization and past-year smoking; Veteran-specific social support buffered the relationship between interpersonal LGB military stress and past-year smoking; and LGBT-specific social support buffered the relationship between intrapersonal LGB military stress and past-year smoking. However, general social support strengthened the relationship between social exclusion and past-year smoking. Findings provide some evidence for the minority stress model; however, regarding cigarette smoking, coping and social support may mitigate stress in some cases and exacerbate stress in others. LGB Veterans may benefit from learning positive coping skills and leveraging social support linked to LGB and Veteran identities to support smoking cessation.}, }
@article {pmid39789324, year = {2025}, author = {Du, Z and Pandey, A and Moghadas, SM and Bai, Y and Wang, L and Matrajt, L and Singer, BH and Galvani, AP}, title = {Impact of RSVpreF vaccination on reducing the burden of respiratory syncytial virus in infants and older adults.}, journal = {Nature medicine}, volume = {31}, number = {2}, pages = {647-652}, pmid = {39789324}, issn = {1546-170X}, support = {75N93021C00045/AI/NIAID NIH HHS/United States ; R01 AI151176/AI/NIAID NIH HHS/United States ; U01 IP001136/IP/NCIRD CDC HHS/United States ; }, mesh = {Humans ; *Respiratory Syncytial Virus Infections/prevention & control/epidemiology/immunology/virology/mortality ; Infant ; Aged ; Female ; *Respiratory Syncytial Virus Vaccines/immunology/therapeutic use ; *Vaccination ; *Respiratory Syncytial Virus, Human/immunology ; Hospitalization/statistics & numerical data ; Adult ; Pregnancy ; Male ; Middle Aged ; }, abstract = {Respiratory syncytial virus (RSV) causes a substantial health burden among infants and older adults. Prefusion F protein-based vaccines have shown high efficacy against RSV disease in clinical trials, offering promise for mitigating this burden through maternal and older adult immunization. Employing an individual-based model, we evaluated the impact of RSV vaccination on hospitalizations and deaths in 13 high-income countries, assuming that the vaccine does not prevent infection or transmission. Using country-specific vaccine uptake rates for seasonal influenza, we found that vaccination of older adults would prevent hospitalizations by a median of 35-64% across the countries studied here. Vaccination of pregnant women could avert infant hospitalizations by 5-50%. Reductions in RSV-related mortality mirrored those estimated for hospitalizations. While substantial hospitalization costs could be averted, the impact of vaccination depends critically on uptake rates. Enhancing uptake and accessibility is crucial for maximizing the real-world impact of vaccination on reducing RSV burden among vulnerable populations.}, }
@article {pmid39788927, year = {2025}, author = {Cardle, II and Raman, J and Nguyen, DC and Wang, T and Wu, AY and Sellers, DL and Pichon, TJ and Cheng, EL and Kacherovsky, N and Salipante, SJ and Jensen, MC and Pun, SH}, title = {DNA Aptamer-Polymer Conjugates for Selective Targeting of Integrin α4β1[+] T-Lineage Cancers.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {3}, pages = {4543-4561}, pmid = {39788927}, issn = {1944-8252}, support = {R01 EB034235/EB/NIBIB NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {*Aptamers, Nucleotide/chemistry/pharmacology ; Humans ; *Integrin alpha4beta1/metabolism ; *Polymers/chemistry ; Animals ; Cell Line, Tumor ; Mice ; Fibronectins/metabolism/chemistry ; *Leukemia, T-Cell/drug therapy/metabolism/pathology ; }, abstract = {Selective therapeutic targeting of T-cell malignancies is difficult due to the shared lineage between healthy and malignant T cells. Current front-line chemotherapy for these cancers is largely nonspecific, resulting in frequent cases of relapsed/refractory disease. The development of targeting approaches for effectively treating T-cell leukemia and lymphoma thus remains a critical goal for the oncology field. Here, we report the discovery of a DNA aptamer, named HR7A1, that displays low nanomolar affinity for the integrin α4β1 (VLA-4), a marker associated with chemoresistance and relapse in leukemia patients. After truncation of HR7A1 to a minimal binding motif, we demonstrate elevated binding of the aptamer to T-lineage cancer cells over healthy immune cells. Using cryo-EM and competition studies, we find that HR7A1 shares an overlapping binding site on α4β1 with fibronectin and VCAM-1, which has implications for sensitizing blood cancers to chemotherapy. We last characterize barriers to in vivo aptamer translation, including serum stability, temperature-sensitive binding, and short circulation half-life, and synthesize an aptamer-polymer conjugate that addresses these challenges. Future work will seek to validate in vivo targeting of α4β1[+] tumors with the conjugate, establishing an aptamer-based biomaterial that can be readily adapted for targeted treatment of T-cell malignancies.}, }
@article {pmid39788211, year = {2025}, author = {Walker, R and Joo, JE and Mahmood, K and Georgeson, P and , and Winship, IM and Buchanan, DD}, title = {DNA Mismatch Repair Gene Mosaicism Is Rare in People With Mismatch Repair-Deficient Cancers.}, journal = {Gastroenterology}, volume = {168}, number = {5}, pages = {983-986}, pmid = {39788211}, issn = {1528-0012}, support = {U01 CA167551/CA/NCI NIH HHS/United States ; }, }
@article {pmid39787437, year = {2025}, author = {Yu, EY and Rumble, RB and Agarwal, N and Cheng, HH and Eggener, SE and Bitting, RL and Beltran, H and Giri, VN and Spratt, D and Mahal, B and Lu, K and Crispino, T and Trabulsi, EJ}, title = {Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {6}, pages = {748-758}, doi = {10.1200/JCO-24-02608}, pmid = {39787437}, issn = {1527-7755}, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology ; *Genetic Testing/methods/standards ; *Germ-Line Mutation ; *Genomics/methods ; Neoplasm Metastasis ; *Biomarkers, Tumor/genetics ; Practice Guidelines as Topic ; }, abstract = {PURPOSE: To evaluate evidence on germline and somatic genomic testing for patients with metastatic prostate cancer and provide recommendations.
METHODS: A systematic review by a multidisciplinary panel with patient representation was conducted. The PubMed database was searched from January 2018 to May 2024. Articles were selected for inclusion if they reported on patients with metastatic prostate cancer who received a germline or somatic genomic test and/or made comparisons between those tests, reported detection rates, prognostic information, or treatment implications.
RESULTS: A total of 1,713 papers were identified in the literature search. After applying the eligibility criteria, 14 remained: eight systematic reviews and six clinical trials.
RECOMMENDATIONS: Patients with metastatic prostate cancer should undergo both germline and somatic DNA sequencing using panel-based assays. These tests can guide the use of poly(ADP-ribose) polymerase inhibitors, which have a survival benefit in metastatic castration-resistant prostate cancer. In addition, germline testing may have screening implications for additional cancers for patients and cascade testing implications for family members. The data supporting when to perform repeat testing and optimal tissue type to use (eg, primary tumor v metastatic biopsy versus circulating tumor DNA [ctDNA] testing) are more limited, but this panel recommends considering retesting in patients whose results were previously negative or uninformative, and to consider either a metastatic biopsy or ctDNA when a significant change in clinical status occurs. Next-generation genomic sequencing findings that are associated with prognostic only (and not predictive) value should not be used to guide treatment outside of a clinical trial.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.}, }
@article {pmid39787247, year = {2025}, author = {Welti, J and Bogdan, D and Figueiredo, I and Coleman, I and Jiménez Vacas, J and Liodaki, K and Weigl, F and Buroni, L and Zeng, W and Bernett, I and Bertan, C and Roumeliotis, TI and Bhamra, A and Rekowski, J and Gurel, B and Neeb, AJ and Ning, J and Li, D and Gil, VS and Riisnaes, R and Miranda, S and Crespo, M and Ferreira, A and Tunariu, N and Pasqua, E and Chessum, N and Cheeseman, M and Te Poele, R and Powers, M and Carreira, S and Choudhary, J and Clarke, P and Banerji, U and Swain, A and Jones, K and Yuan, W and Workman, P and Nelson, PS and de Bono, JS and Sharp, A}, title = {NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {6}, pages = {1109-1126}, pmid = {39787247}, issn = {1557-3265}, support = {Not known//Bone Cancer Research Trust (BCRT)/ ; R21 CA277368/CA/NCI NIH HHS/United States ; MR/W018217/1//Medical Research Council (MRC)/ ; C309/A11566//Cancer Research UK (CRUK)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P50CA097186//National Institute of Health Sciences (NIHS)/ ; SGCL15//Academy of Medical Sciences (The Academy of Medical Sciences)/ ; RIA18-ST2-011//Prostate Cancer UK (ProstateUK)/ ; /WT_/Wellcome Trust/United Kingdom ; Not known//CRIS Cancer Foundation (CRIS Foundation)/ ; CRUK CRM186x//Cancer Research UK (CRUK)/ ; R01 CA266452/CA/NCI NIH HHS/United States ; 219594/Z/19/Z//Wellcome Trust (WT)/ ; Not known//Chordoma Foundation (CF)/ ; N/A//NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research (BRC)/ ; 212969/Z/18/Z//Wellcome Trust (WT)/ ; R50 CA274336/CA/NCI NIH HHS/United States ; 21CHAL01//Prostate Cancer Foundation (PCF)/ ; TLD-PF19-006//Prostate Cancer UK (ProstateUK)/ ; Not known//Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)/ ; MR/M018318/1//Medical Research Council (MRC)/ ; P01 CA163227/CA/NCI NIH HHS/United States ; 18YOUN25//Prostate Cancer Foundation (PCF)/ ; R50CA274336//National Institute of Health Sciences (NIHS)/ ; }, mesh = {Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology/genetics/metabolism ; Humans ; *Receptors, Androgen/metabolism/genetics ; *Unfolded Protein Response/drug effects ; Animals ; Mice ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Heat Shock Transcription Factors ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; Cell Proliferation/drug effects ; *E2F Transcription Factors/metabolism/genetics ; Gene Expression Profiling ; }, abstract = {PURPOSE: Advanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced prostate cancer, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins (HSP) critical to AR functional activity.
EXPERIMENTAL DESIGN: We first did transcriptome analysis on multiple castration-resistant prostate cancer (CRPC) cohorts to correlate the association between the Gene Ontology cellular response to heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely, NXP800 (formerly CCT361814), in models of treatment-resistant prostate cancer. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in vivo model of CRPC.
RESULTS: We report that in multiple CRPC transcriptome cohorts, the Gene Ontology cellular response to heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models.
CONCLUSIONS: Overall, NXP800 has antitumor activity against treatment-resistant prostate cancer models, including molecular subtypes with limited treatment options, supporting its consideration for prostate cancer-specific clinical development.}, }
@article {pmid39786434, year = {2025}, author = {Lee, SJ and Zeiser, R}, title = {FDA-approved therapies for chronic GVHD.}, journal = {Blood}, volume = {145}, number = {8}, pages = {795-800}, doi = {10.1182/blood.2024026633}, pmid = {39786434}, issn = {1528-0020}, mesh = {Humans ; *Graft vs Host Disease/drug therapy/etiology ; United States Food and Drug Administration ; United States ; Chronic Disease ; *Drug Approval ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Pyrazoles/therapeutic use ; }, abstract = {Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. cGVHD can affect multiple organs and reduces quality of life, and treatment can cause serious adverse effects. In the past 10 years, the drugs ibrutinib, ruxolitinib, belumosudil, and axatilimab were approved by the US Food and Drug Administration (FDA) for cGVHD. Here, we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA approval, and future directions for clinical research.}, }
@article {pmid39786430, year = {2025}, author = {Lee, SM and Hamid, O and Jotte, R and Zakharia, Y and Medina, T and Gillespie-Twardy, A and Mehmi, I and Chandra, S and Watson, G and Ward, P and Chaney, M and Lu, H and Berndt, J and O'Connor, BP and Rathi, K and Shaikh, E and Cowey, CL}, title = {Phase II Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1-Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {5}, pages = {848-859}, pmid = {39786430}, issn = {1557-3265}, support = {//Pfizer Foundation/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Antibodies, Monoclonal, Humanized/administration & dosage ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Brentuximab Vedotin/administration & dosage ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/mortality/immunology ; *Lung Neoplasms/drug therapy/pathology/mortality/immunology ; *Melanoma/drug therapy/pathology/mortality/immunology ; Neoplasm Metastasis ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; *Skin Neoplasms/drug therapy/pathology/mortality/immunology ; }, abstract = {PURPOSE: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells that express CD30 and resensitize tumors to anti-PD-1 therapy. This study evaluated responses to BV + pembrolizumab after PD-1 therapy and explored corresponding biomarkers.
PATIENTS AND METHODS: A total of 55 patients with metastatic non-small cell lung cancer and 58 patients with metastatic cutaneous melanoma received ≥1 dose of BV + pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor.
RESULTS: For the secondary refractory metastatic non-small cell lung cancer cohort (RECIST v1.1), the ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (immune RECIST), the ORR was 24%, median PFS was 4.44 months, and median OS was 21.9 months. Overall, the median duration of OS follow-up was 17.2 months (95% confidence interval, 14.62-22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in T regulatory cells. Paired tumor biopsies from baseline and cycle 3 day 1 showed a trend of increased CD8 T-cell infiltration, especially in responding patients.
CONCLUSIONS: BV + pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.}, }
@article {pmid39786405, year = {2024}, author = {Reiner, AS and Watt, GP and Malone, KE and Lynch, CF and John, EM and Knight, JA and Woods, M and Liang, X and Tischkowitz, M and Conti, DV and Robson, ME and Mellemkjær, L and Teraoka, SN and Concannon, P and Bernstein, JL}, title = {Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer.}, journal = {JAMA network open}, volume = {7}, number = {12}, pages = {e2452158}, pmid = {39786405}, issn = {2574-3805}, support = {U01 CA261339/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Genetic Predisposition to Disease ; Case-Control Studies ; Middle Aged ; Adult ; *Breast Neoplasms/genetics/epidemiology ; Receptors, Estrogen/genetics ; Checkpoint Kinase 2/genetics ; BRCA2 Protein/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics ; Germ-Line Mutation/genetics ; BRCA1 Protein/genetics ; }, abstract = {IMPORTANCE: Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.
OBJECTIVE: To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.
This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024.
EXPOSURES: CHEK2 1100delC and deleterious variants in ATM, BRCA1, and BRCA2.
MAIN OUTCOME AND MEASURE: Development of CBC, measured as a rate ratio (RR).
RESULTS: A total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious ATM variants was 4 times higher than for women without deleterious ATM variants (RR, 4.84; 95% CI, 1.11-21.08; P = .04); no women with ER-negative CBC carried deleterious ATM variants. The ER-positive CBC rates for women with deleterious variants in BRCA2 or CHEK2 1100delC were 5 to 6 times higher than for women without deleterious variants in BRCA2 or CHEK2 1100delC, respectively (BRCA2: RR, 5.88; 95% CI, 2.61-13.26, P < .001; CHEK2 1100delC: RR, 6.06; 95% CI, 1.26-29.04; P = .02). The ER-negative CBC rate for women with deleterious BRCA1 variants was 26 times higher than for women without deleterious BRCA1 variants (RR, 26.16; 95% CI, 8.01-85.44; P < .001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development.
CONCLUSIONS AND RELEVANCE: In this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.}, }
@article {pmid39786387, year = {2025}, author = {Mina, A and McGraw, KL and Cunningham, L and Kim, N and Jen, EY and Calvo, KR and Ehrlich, LA and Aplan, PD and Garcia-Manero, G and Foran, JM and Garcia, JS and Zeidan, AM and DeZern, AE and Komrokji, R and Sekeres, MA and Scott, B and Buckstein, R and Tinsley-Vance, S and Verma, A and Wroblewski, T and Pavletic, S and Norsworthy, K}, title = {Advancing drug development in myelodysplastic syndromes.}, journal = {Blood advances}, volume = {9}, number = {5}, pages = {1095-1104}, pmid = {39786387}, issn = {2473-9537}, mesh = {Humans ; *Myelodysplastic Syndromes/drug therapy/diagnosis ; *Drug Development ; Clinical Trials as Topic ; }, abstract = {Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.}, }
@article {pmid39780444, year = {2025}, author = {Zainal, NH and Benjet, C and Albor, Y and Nuñez-Delgado, M and Zambrano-Cruz, R and Contreras-Ibáñez, CC and Cudris-Torres, L and de la Peña, FR and González, N and Guerrero-López, JB and Gutierrez-Garcia, RA and Jiménez-Peréz, AL and Medina-Mora, ME and Patiño, P and Cuijpers, P and Gildea, SM and Kazdin, AE and Kennedy, CJ and Luedtke, A and Sampson, NA and Petukhova, MV and Zubizarreta, JR and Kessler, RC}, title = {Statistical methods to adjust for the effects on intervention compliance in randomized clinical trials where precision treatment rules are being developed.}, journal = {International journal of methods in psychiatric research}, volume = {34}, number = {1}, pages = {e70005}, pmid = {39780444}, issn = {1557-0657}, support = {R01MH120648/MH/NIMH NIH HHS/United States ; R01MH120648/TW/FIC NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; Female ; Male ; Adult ; Young Adult ; Patient Compliance/statistics & numerical data ; Outcome Assessment, Health Care/standards ; Randomized Controlled Trials as Topic ; Data Interpretation, Statistical ; Anxiety Disorders/therapy ; }, abstract = {BACKGROUND: Heterogeneity of treatment effects (HTEs) can occur because of either differential treatment compliance or differential treatment effectiveness. This distinction is important, as it has action implications, but it is unclear how to distinguish these two possibilities statistically in precision treatment analysis given that compliance is not observed until after randomization. We review available statistical methods and illustrate a recommended method in secondary analysis in a trial focused on HTE.
METHODS: The trial randomized n = 880 anxious and/or depressed university students to guided internet-delivered cognitive behavioral therapy (i-CBT) or treatment-as-usual (TAU) and evaluated joint remission. Previously reported analyses documented superiority of i-CBT but significant HTE. In the reanalysis reported here, we used baseline (i.e., pre-randomization) covariates to predict compliance among participants randomized to guided i-CBT, generated a cross-validated within-person expected compliance score based on this model in both intervention groups, and then used this expected composite score as a predictor in an expanded HTE analysis.
RESULTS: The significant intervention effect was limited to participants with high expected compliance. Residual HTE was nonsignificant.
CONCLUSIONS: Future psychotherapy HTE trials should routinely develop and include expected compliance composite scores to distinguish the effects of differential treatment compliance from the effects of differential treatment effectiveness.}, }
@article {pmid39779669, year = {2025}, author = {Papier, K and Bradbury, KE and Balkwill, A and Barnes, I and Smith-Byrne, K and Gunter, MJ and Berndt, SI and Le Marchand, L and Wu, AH and Peters, U and Beral, V and Key, TJ and Reeves, GK}, title = {Diet-wide analyses for risk of colorectal cancer: prospective study of 12,251 incident cases among 542,778 women in the UK.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {375}, pmid = {39779669}, issn = {2041-1723}, support = {001/WHO_/World Health Organization/International ; C570/A16491 and A29186//Cancer Research UK (CRUK)/ ; }, mesh = {Humans ; Female ; *Colorectal Neoplasms/epidemiology/genetics ; United Kingdom/epidemiology ; Prospective Studies ; Middle Aged ; *Diet ; Risk Factors ; Adult ; Dairy Products ; Aged ; Incidence ; Alcohol Drinking/epidemiology/adverse effects ; Calcium, Dietary/administration & dosage ; }, abstract = {Uncertainty remains regarding the role of diet in colorectal cancer development. We examined associations of 97 dietary factors with colorectal cancer risk in 542,778 Million Women Study participants (12,251 incident cases over 16.6 years), and conducted a targeted genetic analysis in the ColoRectal Transdisciplinary Study, Colon Cancer Family Registry, and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Alcohol (relative risk per 20 g/day=1.15, 95% confidence interval 1.09-1.20) and calcium (per 300 mg/day=0.83, 0.77-0.89) intakes had the strongest associations, followed by six dairy-related factors associated with calcium. We showed a positive association with red and processed meat intake and weaker inverse associations with breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C. Genetically predicted milk consumption was inversely associated with risk of colorectal, colon, and rectal cancers. We conclude that dairy products help protect against colorectal cancer, and that this is driven largely or wholly by calcium.}, }
@article {pmid39778191, year = {2025}, author = {Marks, DI and Cassaday, RD and Ribera, JM and Schuh, AC and Park, JH and Chiaretti, S and Stelljes, M}, title = {Characterizing the ideal patient for treatment with inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: a systematic literature review.}, journal = {Expert review of hematology}, volume = {18}, number = {1}, pages = {91-103}, doi = {10.1080/17474086.2025.2450223}, pmid = {39778191}, issn = {1747-4094}, mesh = {Humans ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Hematopoietic Stem Cell Transplantation ; *Inotuzumab Ozogamicin/therapeutic use/adverse effects ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality/diagnosis ; Recurrence ; Salvage Therapy ; Sialic Acid Binding Ig-like Lectin 2/metabolism ; Treatment Outcome ; }, abstract = {INTRODUCTION: Inotuzumab ozogamicin (InO) is indicated for the treatment of adults with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL). This systematic literature review (CRD42022330496) assessed outcomes by baseline characteristics for patients with R/R ALL treated with InO to identify which patients may benefit most.
METHODS: In adherence with PRISMA guidelines, searches were run in Embase and MEDLINE. Inclusion criteria were real-world evidence, observational studies, and phase 2-4 trials. The Cochrane Risk of Bias tool and Newcastle-Ottawa instrument assessed quality.
RESULTS: 34 publications were included; 11 described the phase 3 INO-VATE trial. Patients treated with InO who were CD22-positive, in first salvage, and eligible for subsequent hematopoietic stem cell transplant (HSCT) had improved outcomes. Reduced incidence of veno-occlusive disease was observed in patients with normal transaminase levels and bilirubin, no prior liver disease, and who did not receive dual alkylators.
CONCLUSIONS: The ideal patient for InO treatment has CD22-positive disease (≥20% leukemic blasts), normal liver function, no history of liver disease, is in first salvage, has not previously received HSCT, prefers outpatient treatment, or has high disease burden. Limitations included potentially missing publications that were non-English, not identified in the searches, or available after the date the searches were conducted.
REGISTRATION: This systematic review was registered on the Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42022330496.}, }
@article {pmid39778123, year = {2025}, author = {Rotz, SJ and Stratton, K and Leisenring, WM and Smith, SA and Howell, RM and Bates, JE and Pappo, AS and Neglia, JP and Armstrong, GT and Turcotte, LM}, title = {Melanoma Among Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {10}, pages = {1219-1228}, pmid = {39778123}, issn = {1527-7755}, support = {KL2 TR002547/TR/NCATS NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/epidemiology/etiology/mortality ; Female ; Male ; *Cancer Survivors/statistics & numerical data ; Adult ; Incidence ; Risk Factors ; *Skin Neoplasms/epidemiology/etiology/mortality ; Young Adult ; Child ; Adolescent ; Middle Aged ; *Neoplasms, Second Primary/epidemiology ; *Neoplasms, Radiation-Induced/epidemiology ; United States/epidemiology ; Child, Preschool ; Proportional Hazards Models ; Bleomycin/adverse effects ; }, abstract = {PURPOSE: Melanoma as a subsequent malignant neoplasm has been described among childhood cancer survivors; however, the risk factors and long-term survival are not well understood.
METHODS: We assessed incidence, risk factors, and outcomes for melanoma among participants in the Childhood Cancer Survivor Study cohort. Cumulative incidence and standardized incidence ratios (SIRs) were calculated, and multivariable Cox models were used to determine hazard ratios (HRs) and associated 95% CI for melanoma risk factors. Radiation exposure to seven body regions and melanoma status for each of eight regions per survivor were integrated into the Cox model.
RESULTS: Among 25,716 participants, 177 melanomas developed in 160 survivors (110 invasive, 62 in situ cutaneous, five ocular). The 40-year melanoma cumulative incidence was 1.1% (95% CI, 0.9 to 1.4) for all participants and 1.5% (95% CI, 1.0 to 2.1) among those receiving a cumulative radiation dose of ≥40 Gy. Compared with the general population, the SIR for invasive skin or ocular melanoma was 2.0 (95% CI, 1.6 to 2.4). A cumulative radiation dose of ≥40 Gy to the corresponding body region(s) of the melanoma (HR, 2.0 [95% CI, 1.1 to 3.7]), a cumulative cyclophosphamide equivalent dose of ≥20,000 mg/m[2] (HR, 1.9 [95% CI, 1.1 to 3.6]), and bleomycin exposure (HR, 2.2 [95% CI, 1.2 to 4.1]) were associated with increased cutaneous melanoma. Invasive melanoma at any site was associated with an increased risk of death (HR, 2.4 [95% CI, 1.7 to 3.3]).
CONCLUSION: Childhood cancer survivors have more than a two-fold increased risk of melanoma compared with the general population, and those with an invasive melanoma have more than a two-fold risk of death. High-dose radiation and alkylating agent exposure, and bleomycin are important risk factors for melanoma and should be considered in future patient guidance and screening.}, }
@article {pmid39777681, year = {2025}, author = {Hall, MS and Harris, HR and As-Sanie, S and Upson, K}, title = {Early-Life Exposures and Odds of Adenomyosis: A Population-Based Case-Control Study.}, journal = {Paediatric and perinatal epidemiology}, volume = {39}, number = {2}, pages = {187-195}, pmid = {39777681}, issn = {1365-3016}, support = {R00 NR017191/NR/NINR NIH HHS/United States ; R01HD040398//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /NH/NIH HHS/United States ; R00NR017191/NR/NINR NIH HHS/United States ; R01 HD040398/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; *Adenomyosis/epidemiology/etiology ; Adult ; Case-Control Studies ; Middle Aged ; Adolescent ; Young Adult ; Risk Factors ; Washington/epidemiology ; Pregnancy ; *Prenatal Exposure Delayed Effects/epidemiology ; Odds Ratio ; Logistic Models ; }, abstract = {BACKGROUND: Adenomyosis can confer life-altering symptoms such as pelvic pain. Yet, the epidemiologic study of this uterine condition lags other gynaecologic conditions. This includes the investigation of intrauterine exposures that could disrupt foetal development and contribute to the presence of adenomyosis in adulthood.
OBJECTIVE: We investigated nine early-life factors and the odds of adenomyosis using data from a population-based case-control study of enrollees of an integrated healthcare system in Washington State ages 18-59.
METHODS: Cases (n = 386) had incident, pathology-confirmed adenomyosis diagnosed between 2001 and 2006. Two control groups were employed: hysterectomy controls (n = 233) and randomly selected age-matched enrollees with an intact uterus ('population controls', n = 323). The primary study activity was a structured in-person interview; participants were also mailed a family history questionnaire that included questions on early-life factors. We conducted logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between early-life factors and adenomyosis.
RESULTS: Comparing cases to population controls, our data suggested an 80% increased odds of adenomyosis with younger maternal age at participant's birth (≤ 19 vs. ages 25-29) (aOR 1.81, 95% CI 0.94, 3.50) and a 50% increased odds of adenomyosis for participants who were the fourth or later live birth (vs. firstborn) (aOR 1.51, 95% CI 0.88, 2.59). Among never-smoking participants, our data suggested a 50% increased odds of adenomyosis with intrauterine exposure to cigarette smoking (aOR 1.50, 95% CI 0.92, 2.46). In analyses using hysterectomy controls, these associations were attenuated.
CONCLUSIONS: These data suggested that several intrauterine exposures were associated with increased odds of adenomyosis in adulthood. The intrauterine period may be a susceptible window for subsequent development of adenomyosis and warrants further investigation.}, }
@article {pmid39777474, year = {2025}, author = {Tau, S and Chamberlin, MD and Yang, H and Marotti, JD and Muskus, PC and Roberts, AM and Carmichael, MM and Cressey, L and Dragnev, CPC and Demidenko, E and Hampsch, RA and Soucy, SM and Kolling, FW and Samkoe, KS and Alvarez, JV and Kettenbach, AN and Miller, TW}, title = {Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.}, journal = {Cancer research}, volume = {85}, number = {6}, pages = {1145-1161}, pmid = {39777474}, issn = {1538-7445}, support = {F31 CA278418/CA/NCI NIH HHS/United States ; S10 OD030242/OD/NIH HHS/United States ; P20 GM130454/GM/NIGMS NIH HHS/United States ; P20GM130454//National Institute of General Medical Sciences (NIGMS)/ ; P30 CA023108/CA/NCI NIH HHS/United States ; F31CA220936//National Cancer Institute (NCI)/ ; R01 CA211869/CA/NCI NIH HHS/United States ; P30CA023108//National Cancer Institute (NCI)/ ; R01CA200994//National Cancer Institute (NCI)/ ; F31 CA220936/CA/NCI NIH HHS/United States ; R01 CA267691/CA/NCI NIH HHS/United States ; R01 CA200994/CA/NCI NIH HHS/United States ; R01 CA262232/CA/NCI NIH HHS/United States ; F31CA278418//National Cancer Institute (NCI)/ ; S10OD030242//NIH Office of the Director (OD)/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/metabolism/drug therapy/pathology/genetics ; *Oxidative Phosphorylation/drug effects ; Animals ; *Receptors, Estrogen/metabolism ; Mice ; Mitochondria/metabolism/drug effects ; *Antineoplastic Agents, Hormonal/pharmacology/therapeutic use ; Letrozole/pharmacology/therapeutic use ; Drug Resistance, Neoplasm ; Aromatase Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; *Neoplasm Recurrence, Local/metabolism/pathology/drug therapy ; Xenograft Model Antitumor Assays ; Neoadjuvant Therapy ; }, abstract = {Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters, in which oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacologic inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the antiestrogen drug fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer. Significance: Persister cancer cells that survive endocrine therapy exhibit increased energetic dependence upon mitochondria for survival and tumor regrowth potential, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence.}, }
@article {pmid39777359, year = {2024}, author = {Suraci, CM and Morrison, ML and Roth, MB}, title = {Oxygen is toxic in the cold in C. elegans.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1471249}, pmid = {39777359}, issn = {1664-042X}, abstract = {INTRODUCTION: Temperature and oxygen are two factors that profoundly affect survival limits of animals; too much or too little of either is lethal. However, humans and other animals can exhibit exceptional survival when oxygen and temperature are simultaneously low. This research investigates the role of oxygen in the cold shock death of Caenorhabditis elegans.
METHODS: The survival of C. elegans populations in combinations of oxygen concentrations and was assayed. Additionally, the effect of cold acclimatization, mutations in the cold acclimatization pathway, compounds, and antioxidant proteins on survival in low temperatures and high oxygen were investigated.
RESULTS: We demonstrate that C. elegans have increased survival in 2°C when deprived of oxygen, and an increase to just 0.25 kPa of oxygen decreased survival. Additionally, we show that oxygen toxicity produced by a 35-fold increase above atmospheric oxygen levels was fatal for nematodes in 8 h at room temperature and 2 h at 2°C. We found that cold acclimatization and mutations in the cold acclimatization pathway improve survival in room temperature oxygen toxicity. Furthermore, we found that the compounds glucose, manganese (II), and ascorbate improve both cold shock and high oxygen survival, while the antioxidant proteins catalase and peroxiredoxin are essential to wild type survival in these conditions.
DISCUSSION: Our results suggest that oxygen toxicity contributes to the death of C. elegans during cold shock. The changes in survival induced by cold acclimatization and mutations in the cold acclimatization pathway suggest that oxygen toxicity in the cold exerts evolutionary pressure, leading to the development of protections against it. Additionally, the resistance provided by diverse compounds and antioxidant proteins in both low temperature and high oxygen suggests these conditions have similar chemical environments. We discuss evidence that similar phenomena may function in humans.}, }
@article {pmid39776913, year = {2024}, author = {Chen, XT and Leisegang, M and Gavvovidis, I and Pollack, SM and Lorenz, FKM and Schumacher, TN and Daumke, O and Blankenstein, T}, title = {Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1524629}, pmid = {39776913}, issn = {1664-3224}, mesh = {Animals ; Humans ; *Antigens, Neoplasm/immunology ; Mice ; *Receptors, Antigen, T-Cell/immunology/genetics ; *Mice, Transgenic ; *Membrane Proteins/immunology/genetics ; HLA-A2 Antigen/immunology ; Immunotherapy, Adoptive/methods ; T-Lymphocytes/immunology/metabolism ; Male ; Cell Line, Tumor ; }, abstract = {Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1157-165 restricted to HLA-A*02:01. We compared the functions of the murine-derived TCR with human-derived TCRs and an affinity matured TCR, using in vitro co-culture and in vivo adoptive T cell transfer in tumor-bearing mice. Alanine scan, x-scan, LCL assay were employed to address the cross-reactivity of the NY-ESO-1157-165 specific TCRs. We also used human tissue cDNA library and human primary cells to assess the safety of adoptive T cell therapies targeting NY-ESO-1 antigen in the clinic. One of the murine-derived human TCRs, TCR-ESO, exhibited higher functional avidity compared to human-derived NY-ESO-1157-165 specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an in vitro affinity-matured TCR, TCR 1G4-α95LY, which was applied in clinical trials. TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-α95LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies.}, }
@article {pmid39775835, year = {2025}, author = {Wooldridge, TB and Ford, SM and Conwell, HC and Hyde, J and Harris, K and Shapiro, B}, title = {Direct Measurement of the Mutation Rate and Its Evolutionary Consequences in a Critically Endangered Mollusk.}, journal = {Molecular biology and evolution}, volume = {42}, number = {1}, pages = {}, pmid = {39775835}, issn = {1537-1719}, support = {2307479//National Science Foundation Ocean Science Department (NSF-OCE/ ; }, mesh = {Animals ; *Mutation Rate ; *Endangered Species ; *Gastropoda/genetics ; Biological Evolution ; Evolution, Molecular ; Germ-Line Mutation ; Mollusca/genetics ; Population Density ; }, abstract = {The rate at which mutations arise is a fundamental parameter of biology. Despite progress in measuring germline mutation rates across diverse taxa, such estimates are missing for much of Earth's biodiversity. Here, we present the first estimate of a germline mutation rate from the phylum Mollusca. We sequenced three pedigreed families of the white abalone Haliotis sorenseni, a long-lived, large-bodied, and critically endangered mollusk, and estimated a de novo mutation rate of 8.60 × 10-9 single nucleotide mutations per site per generation. This mutation rate is similar to rates measured in vertebrates with comparable generation times and longevity to abalone, and higher than mutation rates measured in faster-reproducing invertebrates. The spectrum of de novo mutations is also similar to that seen in vertebrate species, although an excess of rare C > A polymorphisms in wild individuals suggests that a modifier allele or environmental exposure may have once increased C > A mutation rates. We use our rate to infer baseline effective population sizes (Ne) across multiple Pacific abalone and find that abalone persisted over most of their evolutionary history as large and stable populations, in contrast to extreme fluctuations over recent history and small census sizes in the present day. We then use our mutation rate to infer the timing and pattern of evolution of the abalone genus Haliotis, which was previously unknown due to few fossil calibrations. Our findings are an important step toward understanding mutation rate evolution and they establish a key parameter for conservation and evolutionary genomics research in mollusks.}, }
@article {pmid39775763, year = {2025}, author = {Levis, MJ and Hamadani, M and Logan, BR and Jones, RJ and Singh, AK and Litzow, MR and Wingard, JR and Papadopoulos, EB and Perl, AE and Soiffer, RJ and Ustun, C and Oshima, MU and Uy, GL and Waller, EK and Vasu, S and Solh, M and Mishra, A and Muffly, LS and Kim, HJ and Stelljes, M and Najima, Y and Onozawa, M and Thomson, K and Nagler, A and Wei, AH and Marcucci, G and Chen, C and Hasabou, N and Rosales, M and Hill, J and Gill, SC and Nuthethi, R and King, D and Mendizabal, A and Devine, SM and Horowitz, MM and Chen, YB}, title = {Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.}, journal = {Blood}, volume = {145}, number = {19}, pages = {2138-2148}, pmid = {39775763}, issn = {1528-0020}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Aniline Compounds/therapeutic use/administration & dosage ; *fms-Like Tyrosine Kinase 3/genetics ; *Hematopoietic Stem Cell Transplantation ; *Leukemia, Myeloid, Acute/genetics/mortality/pathology/therapy ; *Mutation ; Neoplasm, Residual ; *Pyrazines/therapeutic use/administration & dosage ; }, abstract = {BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 ("MORPHO") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.}, }
@article {pmid39774957, year = {2025}, author = {Liu, H and Zhang, W and Di, M and Lee, H and Shi, L and Wang, X and Xingyu, Z and Powers, CA and Sethi, V and Li, X and Xiao, Y and Crane, A and Kaltenmeier, C and Alberola, RB and Behari, J and Duarte-Rojo, A and Hughes, D and Malik, S and Jonassaint, N and Geller, D and Tohme, S and Gunabushanam, V and Tevar, A and Cruz, R and Hughes, C and Dharmayan, S and Ayloo, S and Humar, A and Molinari, M}, title = {Survival benefit associated with liver transplantation for hepatocellular carcinoma based on tumor burden scores at listing.}, journal = {Hepatology communications}, volume = {9}, number = {1}, pages = {}, pmid = {39774957}, issn = {2471-254X}, mesh = {Humans ; *Liver Transplantation/mortality ; *Carcinoma, Hepatocellular/surgery/mortality ; *Liver Neoplasms/surgery/mortality/pathology ; Male ; Female ; Middle Aged ; *Waiting Lists/mortality ; *Tumor Burden ; United States ; Aged ; Adult ; Survival Rate ; Tissue and Organ Procurement ; Registries ; }, abstract = {INTRODUCTION: Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing.
METHODS: We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (≤3), intermediate (3.1-5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT.
RESULTS: This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively (p<0.001).
CONCLUSIONS: Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.}, }
@article {pmid39774938, year = {2024}, author = {Munoz, FM and Beigi, R and Posavad, CM and Kelly, C and Badell, ML and Bunge, K and Mulligan, MJ and Parameswaran, L and Richardson, BA and Olsen-Chen, C and Novak, RM and Brady, RC and DeFranco, E and Gerber, JS and Shriver, M and Suthar, MS and Coler, R and Berube, BJ and Kim, SH and Piper, JM and Miedema, J and Pasetti, M and Neuzil, KM and Cardemil, CV and , }, title = {Enhanced D614G and Omicron Variants Antibody Persistence in Infants at 2 Months of Age Following Maternal mRNA Booster Vaccination During Pregnancy or Postpartum.}, journal = {The Pediatric infectious disease journal}, volume = {43}, number = {11}, pages = {1065-1073}, pmid = {39774938}, issn = {1532-0987}, support = {UM1 AI148372/AI/NIAID NIH HHS/United States ; UM1 AI148685/AI/NIAID NIH HHS/United States ; UM1 AI148452/AI/NIAID NIH HHS/United States ; UM1 AI148373/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; R38 AI174306/AI/NIAID NIH HHS/United States ; UM1 AI148574/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; UM1 AI148575/AI/NIAID NIH HHS/United States ; UM1 AI148576/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; *SARS-CoV-2/immunology ; *COVID-19/prevention & control/immunology ; *Antibodies, Viral/blood ; *Immunization, Secondary ; *Milk, Human/immunology ; Prospective Studies ; *COVID-19 Vaccines/immunology/administration & dosage ; Infant ; Adult ; *Postpartum Period ; Antibodies, Neutralizing/blood/immunology ; Immunoglobulin G/blood ; Vaccination ; Infant, Newborn ; Male ; Young Adult ; Spike Glycoprotein, Coronavirus/immunology ; }, abstract = {BACKGROUND: Following maternal COVID-19 vaccination, the persistence of antibodies in sera and breast milk for mothers and infants is not well characterized. We sought to describe the persistence of antibodies through 2 months after delivery in maternal and infant serum and breast milk following maternal COVID-19 mRNA vaccination and to examine differences by receipt of booster dose during pregnancy or postpartum.
METHODS: This is a prospective cohort study with enrollment from July 2021 to January 2022 at 9 US academic sites. Pregnant or postpartum participants and their infants were enrolled after COVID-19 mRNA monovalent vaccination during pregnancy (primary 2-dose series) with booster (third dose) vaccination during pregnancy or within 2 months post-partum. SARS-CoV-2-binding and functional antibody responses at delivery and 2 months after delivery in mothers and infants were measured by spike and receptor-binding domain immunoglobulin (Ig) G, pseudovirus and live neutralizing antibody (nAb) titers to ancestral and Omicron BA.1 and BA.5 strains. Breast milk spike and receptor-binding domain IgG and IgA titers were also measured.
RESULTS: A total of 237 maternal/infant dyads were included (110 primary series during pregnancy, 99 pregnancy booster and 28 postpartum booster). A pregnancy booster resulted in 2.2-4.7-fold higher IgG and nAb at delivery and 2 months for both mothers and infants compared to the primary series alone (P < 0.001 for all comparisons). While infant IgG and nAb titers decreased by 2 months of age, the proportion of infants with detectable nAb at 2 months was greater in infants of mothers boosted during pregnancy compared with primary series for all variants (D614G: 99% vs. 56%; BA.1: 56% vs. 4% and BA.5: 57% vs. 9%; P < 0.001 for all comparisons). Breast milk spike IgA and IgG were present in 64%-100% and 100% of participants, respectively, and those boosted during pregnancy or postpartum had 3.1-4.6-fold higher levels of breast milk antibodies at 2 months compared to primary series during pregnancy (P < 0.001).
CONCLUSIONS: mRNA COVID-19 monovalent booster vaccination during pregnancy results in significantly higher maternal and infant serum-binding IgG and nAb titers compared to a primary 2-dose series, including against Omicron variants, through 2 months of age. Breast milk antibodies following maternal vaccination during pregnancy or postpartum may provide additional protection during early infancy.}, }
@article {pmid39772633, year = {2025}, author = {Portuguese, AJ and Banerjee, R and Chen, G and Reddi, S and Cowan, AJ}, title = {Novel Treatment Options for Multiple Myeloma.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400752}, doi = {10.1200/OP-24-00752}, pmid = {39772633}, issn = {2688-1535}, abstract = {Multiple myeloma (MM), the second most common hematologic malignancy in the United States, is characterized by repeated cycles of remission and relapse, with increasing resistance to treatment after each line of therapy. Despite the virtually incurable nature of MM, recent therapeutic breakthroughs have fundamentally reshaped its treatment landscape. This review explores evolving care paradigms, spanning from newly diagnosed MM to relapsed or refractory disease. In the frontline setting, treatment strategies have shifted beyond their traditional emphasis on autologous stem-cell transplant eligibility to a broader categorization of patients on the basis of their suitability for quadruplet therapy. In the relapsed/refractory setting, novel immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, have revolutionized treatment, offering new hope for patients with previously limited options. Precision medicine is playing a growing role in MM treatment, with venetoclax showing significant efficacy in patients with t(11;14) translocation, advancing targeted therapy for this subgroup. On the horizon, investigational CAR-T products and cereblon E3 ligase modulators, such as mezigdomide and iberdomide, may provide faster, more durable responses compared with current therapies. In addition, belantamab mafodotin, an antibody-drug conjugate withdrawn from the US market in 2022, is on the verge of reapproval after positive results from recent randomized trials. While these therapies offer significant potential, challenges remain in managing toxicity, ensuring treatment accessibility, and optimizing sequencing strategies. As the therapeutic arsenal expands, the need for personalized MM treatment plans that balance efficacy with quality of life becomes even more essential.}, }
@article {pmid39767189, year = {2024}, author = {Masroori, Z and Haseli, S and Abbaspour, E and Pouramini, A and Azhideh, A and Fathi, M and Kafi, F and Chalian, M}, title = {Patellar Non-Traumatic Pathologies: A Pictorial Review of Radiologic Findings.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {24}, pages = {}, pmid = {39767189}, issn = {2075-4418}, abstract = {Patellar pathologies are a common cause of knee dysfunction, with Patellofemoral Pain Syndrome (PFPS) alone responsible for 25% of knee-related visits to sports medicine clinics. Non-traumatic conditions, while often overlooked, can also lead to significant discomfort and functional limitations, highlighting the importance of accurate and timely diagnosis for effective management and prevention of complications. This pictorial review examines the radiologic characteristics of various non-traumatic patellar disorders, focusing on imaging modalities such as radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Key diagnostic markers, including patellar tilt, tibial tuberosity-trochlear groove distance (TT-TG), and congruence angle (CA), are discussed for their significance in non-traumatic pathology identification. Furthermore, this review highlights specific radiologic features for a range of non-traumatic patellar conditions, including patellar tendinopathy, chondromalacia patellae, and trochlear dysplasia, emphasizing how distinct radiologic findings facilitate precise diagnosis and clinical assessment. Ultimately, it provides a practical guide for clinicians in diagnosing non-traumatic patellar pathologies through a comprehensive review of key radiologic features while also discussing advancements in imaging technologies and management strategies to support accurate diagnosis and effective clinical decision-making.}, }
@article {pmid39764056, year = {2024}, author = {Samorodnitsky, S and Campbell, K and Little, A and Ling, W and Zhao, N and Chen, YC and Wu, MC}, title = {Detecting Clinically Relevant Topological Structures in Multiplexed Spatial Proteomics Imaging Using TopKAT.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39764056}, issn = {2692-8205}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {Novel multiplexed spatial proteomics imaging platforms expose the spatial architecture of cells in the tumor microenvironment (TME). The diverse cell population in the TME, including its spatial context, has been shown to have important clinical implications, correlating with disease prognosis and treatment response. The accelerating implementation of spatial proteomic technologies motivates new statistical models to test if cell-level images associate with patient-level endpoints. Few existing methods can robustly characterize the geometry of the spatial arrangement of cells and also yield both a valid and powerful test for association with patient-level outcomes. We propose a topology-based approach that combines persistent homology with kernel testing to determine if topological structures created by cells predict continuous, binary, or survival clinical endpoints. We term our method TopKAT (Topological Kernel Association Test) and show that it can be more powerful than statistical tests grounded in the spatial point process model, particularly when cells arise along the boundary of a ring. We demonstrate the properties of TopKAT through simulation studies and apply it to two studies of triple negative breast cancer where we show that TopKAT recovers clinically relevant topological structures in the spatial distribution of immune and tumor cells.}, }
@article {pmid39764024, year = {2025}, author = {Arends, T and Bennett, SR and Tapscott, SJ}, title = {DUX4-induced HSATII RNA accumulation drives protein aggregation impacting RNA processing pathways.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39764024}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AR045203/AR/NIAMS NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; }, abstract = {RNA-driven protein aggregation leads to cellular dysregulation, disrupting normal cellular processes, and contributing to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar RNA and human satellite II (HSATII) RNA. Stable intranuclear RNAs drive protein aggregation in DUX4-expressing muscle cells. Specifically, HSATII RNA sequesters RNA methylation factors. HSATII-YBX1 ribonucleoprotein (RNP) complex formation is mediated by HSATII double-stranded RNA and NSUN2 activity. Aberrant HSATII-RNP complexes affect RNA processing pathways, including RNA splicing. Differential splicing of genes mediated by HSATII-RNP complexes are associated with pathways known to be dysregulated by DUX4 expression. These findings highlight the broader influence of DUX4 on nuclear RNA dynamics and suggest that HSATII RNA could be a critical mediator of RNA processing regulation. Understanding the impact of HSATII-RNP formation on RNA processing provides insight into the molecular mechanisms underlying FSHD.}, }
@article {pmid39763963, year = {2024}, author = {Frouard, J and Telwatte, S and Luo, X and Elphick, N and Thomas, R and Arneson, D and Roychoudhury, P and Butte, AJ and Wong, JK and Hoh, R and Deeks, SG and Lee, SA and Roan, NR and Yukl, S}, title = {HIV-SEQ REVEALS GLOBAL HOST GENE EXPRESSION DIFFERENCES BETWEEN HIV-TRANSCRIBING CELLS FROM VIREMIC AND SUPPRESSED PEOPLE WITH HIV.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763963}, issn = {2692-8205}, support = {P01 AI169606/AI/NIAID NIH HHS/United States ; UM1 AI164559/AI/NIAID NIH HHS/United States ; R01 AI183286/AI/NIAID NIH HHS/United States ; R01 DK120387/DK/NIDDK NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; UM1 AI164567/AI/NIAID NIH HHS/United States ; R01 AI132128/AI/NIAID NIH HHS/United States ; R21 AI170166/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 DK131526/DK/NIDDK NIH HHS/United States ; R01 AI147777/AI/NIAID NIH HHS/United States ; }, abstract = {"Active" reservoir cells transcribing HIV can perpetuate chronic inflammation in virally suppressed people with HIV (PWH) and likely contribute to viral rebound after antiretroviral therapy (ART) interruption, so they represent an important target for new therapies. These cells, however, are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. Here, we developed "HIV-seq" to enable more efficient capture of HIV transcripts - including non-polyadenylated ones - for scRNA-seq analysis of cells from PWH. By spiking in a set of custom-designed capture sequences targeting conserved regions of the HIV genome during scRNA-seq, we increased our ability to find HIV RNA+ cells from PWH by up to 44%. Implementing HIV-seq in conjunction with surface phenotyping by CITE-seq on paired blood specimens from PWH before vs. after ART suppression, we found that HIV RNA+ cells were enriched among T effector memory (Tem) cells during both viremia and ART suppression, but exhibited a cytotoxic signature during viremia only. By contrast, HIV RNA+ cells from the ART-suppressed timepoints exhibited a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. Overall, these findings demonstrate that active reservoir cells exhibit transcriptional features distinct from HIV RNA+ cells during viremia, and underscore HIV-seq as a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.}, }
@article {pmid39763936, year = {2024}, author = {Fang, A and Kumar, L and Creevy, KE and , and Promislow, DEL and Ma, J}, title = {The first comorbidity networks in companion dogs in the Dog Aging Project.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763936}, issn = {2692-8205}, support = {U19 AG057377/AG/NIA NIH HHS/United States ; }, abstract = {Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n=166) and included only dogs that had at least one of those health conditions (n=26,523). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with blindness and hypertension with chronic kidney disease. In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes occurs before cataracts, which is consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.}, }
@article {pmid39763889, year = {2024}, author = {Park, J and Prokopchuk, G and Popchock, AR and Hao, J and Liao, TW and Yan, S and Hedman, DJ and Larson, JD and Walther, BK and Becker, NA and Basu, A and Maher, LJ and Wheeler, RJ and Asbury, CL and Biggins, S and Lukeš, J and Ha, T}, title = {Probing mechanical selection in diverse eukaryotic genomes through accurate prediction of 3D DNA mechanics.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763889}, issn = {2692-8205}, support = {R35 GM143949/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R35 GM122569/GM/NIGMS NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; }, abstract = {Connections between the mechanical properties of DNA and biological functions have been speculative due to the lack of methods to measure or predict DNA mechanics at scale. Recently, a proxy for DNA mechanics, cyclizability, was measured by loop-seq and enabled genome-scale investigation of DNA mechanics. Here, we use this dataset to build a computational model predicting bias-corrected intrinsic cyclizability, with near-perfect accuracy, solely based on DNA sequence. Further, the model predicts intrinsic bending direction in 3D space. Using this tool, we aimed to probe mechanical selection - that is, the evolutionary selection of DNA sequence based on its mechanical properties - in diverse circumstances. First, we found that the intrinsic bend direction of DNA sequences correlated with the observed bending in known protein-DNA complex structures, suggesting that many proteins co-evolved with their DNA partners to capture DNA in its intrinsically preferred bent conformation. We then applied our model to large-scale yeast population genetics data and showed that centromere DNA element II, whose consensus sequence is unknown, leaving its sequence-specific role unclear, is under mechanical selection to increase the stability of inner-kinetochore structure and to facilitate centromeric histone recruitment. Finally, in silico evolution under strong mechanical selection discovered hallucinated sequences with cyclizability values so extreme that they required experimental validation, yet, found in nature in the densely packed mitochondrial(mt) DNA of Namystynia karyoxenos, an ocean-dwelling protist with extreme mitochondrial gene fragmentation. The need to transmit an extraordinarily large amount of mtDNA, estimated to be > 600 Mb, in combination with the absence of mtDNA compaction proteins may have pushed mechanical selection to the extreme. Similarly extreme DNA mechanics are observed in bird microchromosomes, although the functional consequence is not yet clear. The discovery of eccentric DNA mechanics in unrelated unicellular and multicellular eukaryotes suggests that we can predict extreme natural biology which can arise through strong selection. Our methods offer a way to study the biological functions of DNA mechanics in any genome and to engineer DNA sequences with desired mechanical properties.}, }
@article {pmid39763863, year = {2024}, author = {Farrell-Sherman, A and de la Force, N and Prator, C and Valieris, R and Azam, W and Da Silva, I and Deeks, SG and Thanh, C and Bosch, R and Henrich, TJ and Cohn, L}, title = {Inflammatory Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763863}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; K24 AI174971/AI/NIAID NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; INV-002707/GATES/Gates Foundation/United States ; R01 AI141003/AI/NIAID NIH HHS/United States ; }, abstract = {The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16[++] monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.}, }
@article {pmid39763728, year = {2024}, author = {Gauderman, WJ and Fu, Y and Queme, B and Kawaguchi, E and Wang, Y and Morrison, J and Brenner, H and Chan, A and Gruber, SB and Keku, T and Li, L and Moreno, V and Pellatt, AJ and Peters, U and Samadder, NJ and Schmit, SL and Ulrich, CM and Um, C and Wu, A and Lewinger, JP and Drew, DA and Mi, H}, title = {Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763728}, issn = {2692-8205}, support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA093326/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, abstract = {A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS × E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will 'water down' the underlying signal in former subset, leading to reduced power to detect PRS × E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS × E interaction can yield substantially greater power than testing overall PRS × E interaction. We also analyze a large study (N=78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS × NSAIDs interaction (p=0.41) is observed, a significant pPRS × NSAIDs interaction (p=0.0003) is identified based on SNPs within the TGF-β / gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5[th] percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95[th] percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.}, }
@article {pmid39763725, year = {2024}, author = {Aditham, AK and Radford, CE and Carr, CR and Jasti, N and King, NP and Bloom, JD}, title = {Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763725}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Rabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for rabies G's function, and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can help inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.}, }
@article {pmid39763680, year = {2024}, author = {Thomas, CE and Takashima, Y and Wesselink, E and Ugai, T and Steinfelder, RS and Buchanan, DD and Qu, C and Hsu, L and Dias Costa, A and Gallinger, S and Grant, RC and Huyghe, JR and Thomas, SS and Ogino, S and Phipps, AI and Nowak, JA and Peters, U}, title = {Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1505896}, pmid = {39763680}, issn = {1664-3224}, support = {R01 CA248857/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/genetics/immunology ; *Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; *Microsatellite Instability ; Mutation ; *T-Lymphocyte Subsets/immunology/metabolism ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown.
METHODS: Including 1,236 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay. MSI status was assessed through polymerase chain reaction or immunohistochemical assays. We used multivariable ordinal logistic regression to estimate odds ratios (OR per increasing quantile) and 95% confidence intervals (CIs) for the association of MSI status with quantiles of T cell densities in either tumor epithelial or stromal tissue areas.
RESULTS: Compared to microsatellite instability low or microsatellite stable (MSI-low/MSS) tumors, MSI-high status was associated with higher density for the majority of immune subsets (twelve out of eighteen) in both epithelial and stromal tissue areas. The strongest associations were for CD3[+]CD8[+] T cells in epithelial areas [OR (95% CI) for naive, memory, and regulatory subsets = 3.49 (2.57, 4.75); 2.82 (2.10, 3.78); 3.04 (2.24, 4.13), respectively]. Conversely, stromal area CD3[+]CD4[+] memory T cells were inversely associated [OR (95% CI) = 0.68 (0.51, 0.91)].
DISCUSSION: MSI-high status was strongly associated with higher densities of most T cell subsets in both epithelial and stromal tissue areas. Our investigation supports efforts to identify patients who may be more likely to respond to current immunotherapy treatments.
SIGNIFICANCE: This study helps us better understand how a clinically relevant tumor phenotype, microsatellite instability status, is related to different functioning T cell densities in colorectal tumors, which may impact future immunotherapy strategies.}, }
@article {pmid39763564, year = {2024}, author = {Huang, YJ and Kurniansyah, N and Goodman, MO and Spitzer, BW and Wang, J and Stilp, A and Laurie, C and de Vries, PS and Chen, H and Min, YI and Sims, M and Peloso, GM and Guo, X and Bis, JC and Brody, JA and Raffield, LM and Smith, JA and Zhao, W and Rotter, JI and Rich, SS and Redline, S and Fornage, M and Kaplan, R and Franceschini, N and Levy, D and Morrison, AC and Boerwinkle, E and Smith, NL and Kooperberg, C and Psaty, BM and Zöllner, S and , and Sofer, T}, title = {The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763564}, support = {R56 HG013163/HG/NHGRI NIH HHS/United States ; OT2 OD026556/OD/NIH HHS/United States ; R01 HL139553/HL/NHLBI NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; R01 HG011031/HG/NHGRI NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; R01 HL154385/HL/NHLBI NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; R01 HG013163/HG/NHGRI NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; }, abstract = {Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.}, }
@article {pmid39763555, year = {2025}, author = {Li, R and Taliun, SAG and Liao, K and Flickinger, M and Sobell, JL and Genovese, G and Locke, AE and Chiu, RR and LeFaive, J and Wang, J and Martins, T and Chapman, S and Neumann, A and Handsaker, RE and Arnett, DK and Barnes, KC and Boerwinkle, E and Braff, D and Cade, BE and Fornage, M and Gibbs, RA and Hoth, KF and Hou, L and Kooperberg, C and Loos, RJF and Metcalf, GA and Montgomery, CG and Morrison, AC and Qin, ZS and Redline, S and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Viaud-Martinez, KA and , and , and Bigdeli, TB and Gabriel, S and Zollner, S and Smith, AV and Abecasis, G and McCarroll, S and Pato, MT and Pato, CN and Boehnke, M and Knowles, J and Kang, HM and Ophoff, RA and Ernst, J and Scott, LJ}, title = {Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763555}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; DP1 DA044371/DA/NIDA NIH HHS/United States ; U01 HG012079/HG/NHGRI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; U01 MH105653/MH/NIMH NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; R01 HL098433/HL/NHLBI NIH HHS/United States ; R01 HL113326/HL/NHLBI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 MH115676/MH/NIMH NIH HHS/United States ; HHSN268201600033C/ES/NIEHS NIH HHS/United States ; R01 HL104608/HL/NHLBI NIH HHS/United States ; R01 HG009976/HG/NHGRI NIH HHS/United States ; }, abstract = {In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls. To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.}, }
@article {pmid39763516, year = {2024}, author = {Mazziotta, F and Martin, LE and Eagan, DN and Bar, M and Kinsella, S and Paulson, KG and Voillet, V and Lahman, MC and Hunter, D and Schmitt, TM and Duerkopp, N and Yeung, C and Tang, TH and Gottardo, R and Asano, Y and Wilcox, EC and Lee, B and Zhang, T and Lopedote, P and Penter, L and Wu, CJ and Milano, F and Greenberg, PD and Chapuis, AG}, title = {Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39763516}, support = {K08 CA169485/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8[+] T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (TTCR-C4). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCRC4-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting TTCR-C4 skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained TTCR-C4 effector-memory profile correlated with long-term TTCR-C4 persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.}, }
@article {pmid39762553, year = {2025}, author = {Granadier, D and Acenas, D and Dudakov, JA}, title = {Endogenous thymic regeneration: restoring T cell production following injury.}, journal = {Nature reviews. Immunology}, volume = {25}, number = {6}, pages = {407-424}, pmid = {39762553}, issn = {1474-1741}, mesh = {*Thymus Gland/physiology/immunology/injuries ; Animals ; *Regeneration/immunology ; Humans ; *T-Lymphocytes/immunology ; Mice ; }, abstract = {Despite its importance for generating and maintaining a healthy and broad T cell repertoire, the thymus is exquisitely sensitive to acute damage. Marked thymic involution occurs in response to stimuli as diverse as infection, stress, pregnancy, malnutrition, drug use and cytoreductive chemotherapy. However, the thymus also has a remarkable capacity for repair, although this regenerative capacity declines with age. Endogenous thymic regeneration is a crucial process that allows for the recovery of immune competence after acute damage and delay to this recovery can have important clinical effects. Until recently, the mechanisms that drive endogenous thymic regeneration were not well understood, but recent work in mice has revealed multiple distinct pathways of regeneration and the molecular mechanisms that trigger these pathways after damage. In this Review, we discuss the effects of different types of damage to the thymus, with a focus on an emerging body of work in mice that provides insight into the cellular and molecular mechanisms that regulate endogenous tissue regeneration in the thymus. We also highlight some of the clinical challenges that are presented by dysregulated thymic regeneration.}, }
@article {pmid39761503, year = {2025}, author = {Raghav, KPS and Guthrie, KA and Tan, B and Denlinger, CS and Fakih, M and Overman, MJ and Dasari, NA and Corum, LR and Hicks, LG and Patel, MS and Esparaz, BT and Kazmi, SM and Alluri, N and Colby, S and Gholami, S and Gold, PJ and Chiorean, EG and Kopetz, S and Hochster, HS and Philip, PA}, title = {Trastuzumab Plus Pertuzumab Versus Cetuximab Plus Irinotecan in Patients With RAS/BRAF Wild-Type, HER2-Positive, Metastatic Colorectal Cancer (S1613): A Randomized Phase II Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {11}, pages = {1348-1357}, pmid = {39761503}, issn = {1527-7755}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180868/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Colorectal Neoplasms/drug therapy/genetics/pathology/enzymology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Receptor, ErbB-2/metabolism/genetics/antagonists & inhibitors ; *Irinotecan/administration & dosage/adverse effects/therapeutic use ; Middle Aged ; Male ; Aged ; *Cetuximab/administration & dosage/adverse effects/therapeutic use ; Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects/therapeutic use ; Proto-Oncogene Proteins B-raf/genetics ; *Trastuzumab/administration & dosage/adverse effects/therapeutic use ; Adult ; Aged, 80 and over ; }, abstract = {PURPOSE: ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.
METHODS: Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m[2] and irinotecan 180 mg/m[2] once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN ≥20/<20) as a predictive factor.
RESULTS: Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (P = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively.
CONCLUSION: TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF-WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.}, }
@article {pmid39761015, year = {2024}, author = {Nguyen, HH and Talbot, J and Li, D and Raghavan, V and Littman, DR}, title = {Modulating intestinal neuroimmune VIPergic signaling attenuates the reduction in ILC3-derived IL-22 and hepatic steatosis in MASLD.}, journal = {Hepatology communications}, volume = {8}, number = {11}, pages = {}, pmid = {39761015}, issn = {2471-254X}, mesh = {Animals ; *Interleukin-22 ; *Interleukins ; Mice ; *Vasoactive Intestinal Peptide ; *Diet, High-Fat/adverse effects ; *Non-alcoholic Fatty Liver Disease/immunology ; *Lymphocytes/immunology/metabolism ; Disease Models, Animal ; Signal Transduction ; Male ; Mice, Inbred C57BL ; Immunity, Innate ; Fatty Liver/immunology ; Neurons/immunology/metabolism ; Neuroimmunomodulation ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a major driver of cirrhosis and liver-related mortality. However, therapeutic options for MASLD, including prevention of liver steatosis, are limited. We previously described that vasoactive intestinal peptide-producing neurons (VIP-neurons) regulate the efficiency of intestinal dietary fat absorption and IL-22 production by type 3 innate lymphoid cells (ILC3) in the intestine. Given the described hepatoprotective role of IL-22, we hypothesize that modulation of this neuroimmune circuit could potentially be an innovative approach for the control of liver steatosis.
METHODS: We used a model of diet-induced MASLD by exposing mice to a high-fat diet (HFD) for 16 weeks, when the development of liver steatosis was first observed in our animals. We characterized IL-22 production by intestinal ILC3 at this dietary endpoint. We then evaluated whether communication between VIP-neurons and ILC3 affected IL-22 production and MASLD development by exposing mice with a conditional genetic deletion of Vipr2 in ILC3 (Rorc(t)CreVipr2fl/fl) to the HFD. We also performed intermittent global inhibition of VIP-neurons using a chemogenetic inhibitory approach (VipIres-CrehM4DiLSL) in HFD-fed mice.
RESULTS: Production of IL-22 by intestinal ILC3 is reduced in steatotic mice that were exposed to an HFD for 16 weeks. Targeted deletion of VIP receptor 2 in ILC3 resulted in higher production of IL-22 in ILC3 and was associated with a significant reduction in liver steatosis in mice under HFD. Global inhibition of VIP-producing neurons also resulted in a significant reduction in liver steatosis.
CONCLUSIONS: Modulating VIPergic neuroimmune signaling can ameliorate the development of hepatic steatosis induced by a surplus of fat ingestion in the diet. This neuroimmune pathway should be further investigated as a potential therapeutic avenue in MASLD.}, }
@article {pmid39760096, year = {2024}, author = {McDougall, JA and Briant, KJ and Carosso, E and Cole, AM and Dee, C and Doody, DR and Hannon, PA and Henderson, V and Johnson, S and Parker, M and Schwartz, SM and Mendoza, JA}, title = {Data-Driven Community Engagement: Using Quantitative and Qualitative Data to Set Priorities and Launch New Initiatives in a Growing Catchment Area.}, journal = {Preventive oncology & epidemiology}, volume = {2}, number = {1}, pages = {}, pmid = {39760096}, issn = {2832-2134}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {In 2022, the catchment area of the Fred Hutchinson/University of Washington/Seattle Children's Cancer Consortium (the Consortium) grew from 13-counties in Western Washington State to include all 39 counties in Washington. Widening the catchment area provided new opportunities for the Consortium to monitor the cancer burden, identify cancer-related health disparities, use a bidirectional approach to develop cancer focused programming, and facilitate research in clinical and community settings. In this commentary, we describe the exploratory process of catchment area change led by the Consortium's Office of Community Outreach and Engagement and new initiatives that followed that growth. We hope that by sharing the ongoing, data-driven community engagement approach in the Consortium's current, statewide catchment area, our experience will be of value to other cancer centers looking to engage with communities and develop bidirectional partnerships in new areas.}, }
@article {pmid39759131, year = {2024}, author = {Biswas, D and Hippe, DS and Winter, AM and Li, I and Rahbar, H and Partridge, SC}, title = {Diffusion weighted imaging for improving the diagnostic performance of screening breast MRI: impact of apparent diffusion coefficient quantitation methods and cutoffs.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1437506}, pmid = {39759131}, issn = {2234-943X}, abstract = {INTRODUCTION: Diffusion weighted MRI (DWI) has emerged as a promising adjunct to reduce unnecessary biopsies prompted by breast MRI through use of apparent diffusion coefficient (ADC) measures. The purpose of this study was to investigate the effects of different lesion ADC measurement approaches and ADC cutoffs on the diagnostic performance of breast DWI in a high-risk MRI screening cohort to identify the optimal approach for clinical incorporation.
METHODS: Consecutive screening breast MRI examinations (August 2014-Dec 2018) that prompted a biopsy for a suspicious breast lesion (BI-RADS 4 or 5) were retrospectively evaluated. On DWI, ADC (b=0/100/600/800s/mm[2]) measures were calculated with three different techniques for defining lesion region-of-interest (ROI; single slice('2D'), whole volume('3D') and lowest ADC region('hotspot')). An optimal data-derived ADC cutoff for each technique was retrospectively identified to reduce benign biopsies while avoiding any false negatives, inherently producing cutoffs with 100% sensitivity in this particular cohort. Further, diagnostic performance of these measures was validated using two prespecified ADC cutoffs: 1.53x10[-3]mm[2]/s from the ECOG-ACRIN A6702 trial and 1.30x10[-3]mm[2]/s from the international EUSOBI group. Diagnostic performance was compared between ADC maps generated with 2(0/800s/mm[2]) and 4(0/100/600/800s/mm[2]) b-values. Benign biopsy reduction rate was calculated (number of benign lesions with ADC >cutoff)/(total number of benign lesions).
RESULTS: 137 suspicious lesions (in 121 women, median age 44 years [range, 20-75yrs]) were detected on contrast-enhanced screening breast MRI and recommended for biopsy. Of those, 30(21.9%) were malignant and 107(78.1%) were benign. Hotspot ADC measures were significantly lower (p<0.001) than ADCs from both 2D and 3D ROI techniques. Applying the optimal data-derived ADC cutoffs resulted in comparable reduction in benign biopsies across ROI techniques (range:16.8% -17.8%). Applying the prespecified A6702 and EUSOBI cutoffs resulted in benign biopsy reduction rates of 11.2-19.6%(with 90.0-100% sensitivity) and 36.4-51.4%(with 70.0-83.3% sensitivity), respectively, across ROI techniques. ADC measures and benign biopsy reduction rates were similar when calculated with only 2 b-values (0,800 s/mm[2]) versus all 4 b-values.
DISCUSSION: Our findings demonstrate that with appropriate ADC thresholds, comparable reduction in benign biopsies can be achieved using lesion ADC measurements computed from a variety of approaches. Choice of ADC cutoff depends on ROI approach and preferred performance tradeoffs (biopsy reduction vs sensitivity).}, }
@article {pmid39758135, year = {2024}, author = {Langley, BO and Rillamas-Sun, E and Huang, Y and Indorf, A and Robles, M and Feaster, R and D'Addario, L and Ergas, IJ and Roh, JM and Kushi, LH and Greenlee, H}, title = {Validation and Utility of Drug-Nutrient Interaction and Dietary Supplement Mechanistic Activity in the Natural Medicines Database.}, journal = {JCO oncology advances}, volume = {1}, number = {}, pages = {e2400062}, pmid = {39758135}, issn = {2994-9750}, abstract = {PURPOSE: The increasing use of dietary supplements by patients with cancer and other chronic diseases requires the systematized review of potential interactions between prescription drugs and nutrients from supplements by health care and clinical research teams. Dietary supplement interaction databases are positioned to fill a gap in quantifying potential risks for patients, although none have been assessed for reliability in data interpretation. The NatMed database, a source for comprehensive reports on mechanistic and safety data for dietary supplement ingredients, was evaluated for use in future investigations.
METHODS: Data from NatMed were retrieved using licensed end points for ingredient monographs with drug-nutrient interactions with doxorubicin across five pharmacokinetic and metabolic pathways, and for ingredient monographs with antioxidant activity. Interactions between dietary supplements and doxorubicin treatment and antioxidant monographs were independently reviewed and characterized by clinical pharmacists. Cohen's K was used to measure interrater reliability and the degree of agreement between pharmacists.
RESULTS: Three hundred fifteen potential interactions with doxorubicin (n = 115 monographs) and 455 other antioxidant ingredients were identified and reviewed by clinical pharmacists. There was substantial to near-perfect agreement for drug-nutrient interactions with doxorubicin (Cohen's K = 0.64-0.85) and for antioxidants (Cohen's K = 0.84). A small proportion of retrieved monographs were not validated by the clinical pharmacists for interactions with doxorubicin (n = 20 occurrences, 6.4%) or for antioxidant activity (n = 28, 6.2%).
CONCLUSION: A high degree of reliability in data on dietary supplement interactions with doxorubicin and mechanisms of action suggests NatMed may be a dependable source of data for future investigators. Additional procedures including independent data validation and use of multiple dietary supplement interaction databases will strengthen the quality of findings in future studies.}, }
@article {pmid39756456, year = {2025}, author = {Lapen, K and Feliciano, EJG and Dee, EC and Gillespie, EF and Yahalom, J and Imber, BS}, title = {Electronic patient-reported outcomes for CAR T-cell therapies.}, journal = {The Lancet. Oncology}, volume = {26}, number = {1}, pages = {e6}, doi = {10.1016/S1470-2045(24)00644-2}, pmid = {39756456}, issn = {1474-5488}, }
@article {pmid39756444, year = {2025}, author = {Choueiri, TK and Merchan, JR and Figlin, R and McDermott, DF and Arrowsmith, E and Michaelson, MD and Tykodi, SS and Heath, EI and Spigel, DR and D'Souza, A and Kassalow, L and Perini, RF and Vickery, D and Bauer, TM}, title = {Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study.}, journal = {The Lancet. Oncology}, volume = {26}, number = {1}, pages = {64-73}, doi = {10.1016/S1470-2045(24)00649-1}, pmid = {39756444}, issn = {1474-5488}, mesh = {Humans ; *Anilides/therapeutic use/administration & dosage/adverse effects ; Female ; Male ; Middle Aged ; *Carcinoma, Renal Cell/drug therapy/pathology ; *Pyridines/administration & dosage/therapeutic use/adverse effects ; Aged ; *Kidney Neoplasms/drug therapy/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Adult ; }, abstract = {BACKGROUND: Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial.
METHODS: LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing.
FINDINGS: Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57-72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24·3 months (IQR 13·9-32·0). 35 (70%, 95% CI 55-82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3-4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred.
INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2α inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted.
FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and the National Cancer Institute.}, }
@article {pmid39755942, year = {2025}, author = {Yan, L and He, Q and Verma, SP and Zhang, X and Giel, AS and Maj, C and Graz, K and Naderi, E and Chen, J and Ali, MW and Gharahkhani, P and Shu, X and Offit, K and Shah, PM and Gerdes, H and Molena, D and Srivastava, A and MacGregor, S and , and , and , and Palles, C and Thieme, R and Vieth, M and Gockel, I and Vaughan, TL and Schumacher, J and Buas, MF}, title = {Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.}, journal = {HGG advances}, volume = {6}, number = {2}, pages = {100399}, pmid = {39755942}, issn = {2666-2477}, support = {R01 CA266386/CA/NCI NIH HHS/United States ; R01 DK128615/DK/NIDDK NIH HHS/United States ; R03 CA223731/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Barrett Esophagus/genetics/pathology ; *Esophageal Neoplasms/genetics/pathology ; Genome-Wide Association Study ; *Adenocarcinoma/genetics/pathology ; Male ; Polymorphism, Single Nucleotide ; *Genetic Predisposition to Disease ; Female ; Risk Factors ; }, abstract = {Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (1) known/plausible links to BE/EAC pathogenesis (n = 493) or (2) prior evidence of biological interactions (n = 4,196). Approximately 75 × 10[6] SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2,000 interactions retained in each scan were prioritized using p values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied p < 0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (Pmeta = 2.19 × 10[-8]); rs3217992 "T" was associated with reduced risk only in individuals homozygous for rs17744726 "G." Rs3217992 maps to the CDKN2B 3' UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.}, }
@article {pmid39755595, year = {2025}, author = {Omollo, V and Roche, SD and Zhang, S and Asewe, M and Rono, BK and Kwach, B and Rota, G and Ong'wen, P and Harkey, K and Odoyo, J and Were, D and Ngure, K and Bukusi, EA and Ortblad, KF}, title = {Measuring the uptake of clinic-based HIV treatment and prevention services following HIV testing and referral at private pharmacies in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {23}, pmid = {39755595}, issn = {1472-6963}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; INV-033052/GATES/Bill & Melinda Gates Foundation/United States ; }, mesh = {Humans ; Kenya/epidemiology ; *HIV Infections/diagnosis/prevention & control/drug therapy/epidemiology ; Female ; Male ; Adult ; *Referral and Consultation/statistics & numerical data ; Pilot Projects ; *Pharmacies/statistics & numerical data ; *HIV Testing/statistics & numerical data ; Pre-Exposure Prophylaxis/statistics & numerical data ; Adolescent ; Young Adult ; Middle Aged ; Patient Acceptance of Health Care/statistics & numerical data ; }, abstract = {BACKGROUND: Despite their ubiquity across sub-Saharan Africa, private pharmacies are underutilized for HIV service delivery beyond the sale of HIV self-test kits. To understand what uptake of HIV prevention and treatment services might look like if private pharmacies offered clients free HIV self-testing and referral to clinic-based HIV services, we conducted a pilot study in Kenya.
METHODS: At 20 private pharmacies in Kisumu County, Kenya, pharmacy clients (≥ 18 years) purchasing sexual health-related products (e.g., contraception) were offered free HIV testing. Based on their test result and recent self-reported behaviors associated with HIV risk, clients were encouraged to consider pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), or antiretroviral therapy (ART) initiation, informed where they could access free services, and issued a referral. We called clients three months after study completion to see if they had initiated the recommended service. Among clients who reported PrEP referral, we used Poisson regression models to examine characteristics associated with PrEP initiation and calculated adjusted prevalence ratios (aPRs).
RESULTS: From March to June 2022, 1500 pharmacy clients completed HIV testing and were referred to clinic-based HIV services; in October 2022, 1178 (79%) were reached and meet our criteria for follow-up. Among those reached, the majority (63%, 742/1178) were women, the median age was 26 years (IQR 22-31), and few (4%, 51/1178) reported any prior PrEP use. At the pharmacy, most clients (96%, 1136/1178) tested HIV-negative and reported PrEP (95%, 1122/1178) or PEP (1%, 14/1178) referral; the remainder (4%, 42/1178) tested HIV-positive and reported ART referral. The uptake of ART (90%, 38/42) and PEP (86%, 12/14) among clients referred was high. The uptake of PrEP was only 9% (101/1122) among those referred and prior PrEP use was the only characteristic significantly associated with initiation (aPR 2.45, 95% confidence interval 1.19 to 5.07).
CONCLUSIONS: Although offering free HIV testing at private pharmacies led to the identification and referral of clients who could benefit from HIV services, additional interventions (e.g., incentives, patient navigators) may be needed to support PrEP referral follow-through. Alternatively, new delivery models that circumvent the need for referrals, such as same-day PrEP initiation at pharmacies, should be considered.}, }
@article {pmid39755256, year = {2025}, author = {Hickey, CL and Zhang, MJ and Allbee-Johnson, M and Romee, R and Majhail, NS and Malki, MMA and Antin, JH and Benjamin, CL and Bredeson, C and Chhabra, S and Grunwald, MR and Inamoto, Y and Kanakry, CG and Milano, F and Soiffer, RJ and Solomon, SR and Spellman, SR and Brunstein, CG and Cutler, C}, title = {Donor Type Does Not Impact Late Graft Failure Following Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3}, pages = {174.e1-174.e12}, pmid = {39755256}, issn = {2666-6367}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cyclophosphamide/therapeutic use/pharmacology ; *Graft vs Host Disease/prevention & control/etiology ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; *Transplantation Conditioning/methods ; Transplantation, Homologous/methods ; *Graft Rejection/prevention & control/etiology ; Aged ; *Tissue Donors ; Young Adult ; }, abstract = {BACKGROUND: Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12% to 20% in haplo-HCT recipients using PTCy. The objective of this study was to determine whether donor type influenced the risk of late graft failure following reduced-intensity conditioning (RIC) HCT using PTCy-based GVHD prophylaxis.
STUDY DESIGN: A retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database among adult patients who underwent first RIC haplo or 8/8 matched unrelated donor (MUD) HCT between 2011 and 2018 for acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse or poor graft function requiring a cellular therapy intervention.
RESULTS: A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs. 61 years), less ethnically diverse (95% vs. 72% White), received fewer bone marrow grafts (45% vs. 16%), and had younger donors (median age, 28 vs. 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide, and total body irradiation (TBI; 87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% (95% confidence interval [CI], 5.2-8.0) versus 5.9% (95% CI, 2.7%-10.9%) for the MUD group (P = .79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR, 1.98; 95% CI, 1.22-3.20; P = .005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR, 0.39; 95% CI, 0.24-0.64; P = .0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of peripheral blood stem cell (PBSC) grafts. Graft failure did not differ between haplo and MUD HCT (HR, 1.19; P = .67) when adjusted for donor age nor when restricted to PBSC grafts only (HR, 0.85; P = .70).
CONCLUSION: In this registry-based analysis of patients undergoing RIC HCT for AML, ALL, or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.}, }
@article {pmid39755170, year = {2025}, author = {Besse, B and Goto, K and Wang, Y and Lee, SH and Marmarelis, ME and Ohe, Y and Bernabe Caro, R and Kim, DW and Lee, JS and Cousin, S and Ichihara, E and Li, Y and Paz-Ares, L and Ono, A and Sanborn, RE and Watanabe, N and de Miguel, MJ and Helissey, C and Shu, CA and Spira, AI and Tomasini, P and Yang, JC and Zhang, Y and Felip, E and Griesinger, F and Waqar, SN and Calles, A and Neal, JW and Baik, CS and Jänne, PA and Shreeve, SM and Curtin, JC and Patel, B and Gormley, M and Lyu, X and Chen, J and Chu, PL and Mahoney, J and Trani, L and Bauml, JM and Thayu, M and Knoblauch, RE and Cho, BC}, title = {Amivantamab Plus Lazertinib in Patients With EGFR-Mutant NSCLC After Progression on Osimertinib and Platinum-Based Chemotherapy: Results From CHRYSALIS-2 Cohort A.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {5}, pages = {651-664}, doi = {10.1016/j.jtho.2024.12.029}, pmid = {39755170}, issn = {1556-1380}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Acrylamides/therapeutic use/pharmacology/administration & dosage ; Aniline Compounds/therapeutic use/pharmacology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/genetics ; Cohort Studies ; Disease Progression ; ErbB Receptors/genetics ; *Lung Neoplasms/drug therapy/pathology/genetics ; *Morpholines/therapeutic use ; Mutation ; Survival Rate ; Indoles ; Pyrimidines ; Antibodies, Bispecific ; }, abstract = {INTRODUCTION: Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited.
METHODS: CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib.
RESULTS: In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).
CONCLUSIONS: For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable.}, }
@article {pmid39754855, year = {2025}, author = {Hill, M and Garcia, LR and Nguyen, E and Korolkova, A and Cohn, L and Rodriguez, A and Hoh, R and Deeks, SG and Peluso, MJ and Sauceda, JA and Dubé, K}, title = {Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States.}, journal = {Social science & medicine (1982)}, volume = {366}, number = {}, pages = {117644}, pmid = {39754855}, issn = {1873-5347}, support = {K01 MH134744/MH/NIMH NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; R01 MH126768/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Qualitative Research ; Longitudinal Studies ; Male ; *HIV Infections/psychology/drug therapy ; Female ; Adult ; Adaptation, Psychological ; United States ; *Stress, Psychological/psychology/etiology ; Middle Aged ; Interviews as Topic/methods ; *Research Subjects/psychology ; }, abstract = {The lack of socio-behavioral research on stress and psychosocial experiences among research participants who undergo analytical treatment interruption (ATI) in HIV cure studies underscores a critical gap in cure science. Existing literature acknowledges mixed and potentially adverse mental health impacts of ATIs among trial participants, but empirical insights before, during, and after clinical studies are scarce. We used longitudinal in-depth interviews with 11 participants in HIV cure-related research to explore their experiences with stress, coping, and psychological well-being before, during, and after an ATI. Our framework analyses of participant interviews suggest an evolving interplay between person- and environment-oriented factors that shape psychosocial well-being through multiple pathways. Key emergent themes surrounding stress, coping, and psychological adaptation before the ATI encompass the stress-protective effects of pill (in)significance, curiosity in natural immunological control, and perceived support, and trust with professional help networks comprised of providers and research staff. Themes that promoted positive secondary appraisals of stressors during ATIs involved generativity and meaning-based coping, and the stress-adaptive benefits of support-seeking and actualization. Finally, a theme exposing post-ATI stress revolved around the disappointment that participants noted feeling from needing to restart their HIV medications after the ATI and accepting the permanency of HIV and medications in their lives. Our findings emphasize the importance of building supportive and trusting relationships with research teams, and specify the stress-buffering mechanisms between emotional, informational, and appraisal support on ATI-related stress. Additionally, we outline multiple implications that advocate for the adoption of several precautionary measures in HIV cure research to mitigate psychosocial risks. By documenting the evolution of psychosocial experiences, we offer valuable insights to inform the design of future studies, ensuring their ethicality, acceptability, and inclusivity.}, }
@article {pmid39753771, year = {2025}, author = {Jia, G and Chen, Z and Ping, J and Cai, Q and Tao, R and Li, C and Bauer, JA and Xie, Y and Ambs, S and Barnard, ME and Chen, Y and Choi, JY and Gao, YT and Garcia-Closas, M and Gu, J and Hu, JJ and Iwasaki, M and John, EM and Kweon, SS and Li, CI and Matsuda, K and Matsuo, K and Nathanson, KL and Nemesure, B and Olopade, OI and Pal, T and Park, SK and Park, B and Press, MF and Sanderson, M and Sandler, DP and Shen, CY and Troester, MA and Yao, S and Zheng, Y and Ahearn, T and Brewster, AM and Falusi, A and Hennis, AJM and Ito, H and Kubo, M and Lee, ES and Makumbi, T and Ndom, P and Noh, DY and O'Brien, KM and Ojengbede, O and Olshan, AF and Park, MH and Reid, S and Yamaji, T and Zirpoli, G and Butler, EN and Huang, M and Low, SK and Obafunwa, J and Weinberg, CR and Zhang, H and Zhao, H and Cote, ML and Ambrosone, CB and Huo, D and Li, B and Kang, D and Palmer, JR and Shu, XO and Haiman, CA and Guo, X and Long, J and Zheng, W}, title = {Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.}, journal = {Nature genetics}, volume = {57}, number = {1}, pages = {80-87}, pmid = {39753771}, issn = {1546-1718}, support = {R01CA235553//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 CA089085/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; R01 CA242929/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; R01 CA124558/CA/NCI NIH HHS/United States ; R01 MD013452/MD/NIMHD NIH HHS/United States ; ZIA ES102245/ImNIH/Intramural NIH HHS/United States ; R50 CA211206/CA/NCI NIH HHS/United States ; R01 CA202981/CA/NCI NIH HHS/United States ; S10 OD028719/OD/NIH HHS/United States ; R01 CA142996/CA/NCI NIH HHS/United States ; R01 CA235553/CA/NCI NIH HHS/United States ; R01CA202981//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 CA228198/CA/NCI NIH HHS/United States ; P20 CA233307/CA/NCI NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R01CA148667//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Female ; Humans ; Asian People/genetics ; *Breast Neoplasms/ethnology/genetics ; Case-Control Studies ; Chromosome Mapping/methods ; *Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; White People/genetics ; Black People/genetics ; }, abstract = {Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses.}, }
@article {pmid39749518, year = {2025}, author = {O'Halloran, K and Christodoulou, E and Paulson, VA and Cole, BL and Margol, AS and Biegel, JA and Leary, SES and Lockwood, CM and Crotty, EE}, title = {Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors.}, journal = {Clinical chemistry}, volume = {71}, number = {1}, pages = {87-96}, doi = {10.1093/clinchem/hvae140}, pmid = {39749518}, issn = {1530-8561}, mesh = {Humans ; *Central Nervous System Neoplasms/cerebrospinal fluid/genetics/diagnosis ; Child ; *Cell-Free Nucleic Acids/cerebrospinal fluid ; *Whole Genome Sequencing/methods ; Liquid Biopsy/methods ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters. Alternatively, cfDNA is often present in the CSF from pediatric patients with both malignant and nonmalignant CNS tumors and can be accessed by minimally invasive lumbar puncture and other CSF-liberating procedures, offering a promising alternative for longitudinal molecular disease analysis and surveillance.
CONTENT: This review explores the use of low-pass whole genome sequencing (LP-WGS) to analyze cfDNA from the CSF of pediatric patients with CNS tumors. This platform is uniquely poised for the detection of tumors harboring copy number variants, which are prevalent in this population. The utility and sensitivity of LP-WGS as a clinical tool is explored and discussed in the context of alternative CSF liquid biopsy interrogation modalities, including nanopore sequencing and methylation array.
SUMMARY: Analysis of CSF-derived cfDNA by LP-WGS has broad diagnostic, prognostic, and clinical implications for pediatric patients with CNS tumors. Careful interpretation of LP-WGS results may aid in therapeutic targeting of pediatric CNS tumors and may provide insight into tumor heterogeneity and evolution over time, without the need for invasive and potentially risky tissue sampling.}, }
@article {pmid39749508, year = {2025}, author = {Casto, AM and Paredes, MI and Bennett, JC and Luiten, KG and Han, PD and Gamboa, LS and McDermot, E and Gottlieb, GS and Acker, Z and Lo, NK and McDonald, D and McCaffrey, KM and Figgins, MD and Lockwood, CM and Shendure, J and Uyeki, TM and Starita, LM and Bedford, T and Chu, HY and Weil, AA}, title = {SARS-CoV-2 Diversity and Transmission on a University Campus across Two Academic Years during the Pandemic.}, journal = {Clinical chemistry}, volume = {71}, number = {1}, pages = {192-202}, doi = {10.1093/clinchem/hvae194}, pmid = {39749508}, issn = {1530-8561}, mesh = {Humans ; *COVID-19/transmission/epidemiology/virology ; Universities ; *SARS-CoV-2/genetics/isolation & purification ; *Genome, Viral ; Washington/epidemiology ; Phylogeny ; Students ; }, abstract = {BACKGROUND: Institutions of higher education (IHE) have been a focus of SARS-CoV-2 transmission studies but there is limited information on how viral diversity and transmission at IHE changed as the pandemic progressed.
METHODS: Here we analyze 3606 viral genomes from unique COVID-19 episodes collected at a public university in Seattle, Washington from September 2020 to September 2022.
RESULTS: Across the study period, we found evidence of frequent viral transmission among university affiliates with 60% (n = 2153) of viral genomes from campus specimens genetically identical to at least one other campus specimen. Moreover, viruses from students were observed in transmission clusters at a higher frequency than in the overall dataset while viruses from symptomatic infections were observed in transmission clusters at a lower frequency. Although only a small percentage of community viruses were identified as possible descendants of viruses isolated in university study specimens, phylodynamic modeling suggested a high rate of transmission events from campus into the local community, particularly during the 2021-2022 academic year.
CONCLUSIONS: We conclude that viral transmission was common within the university population throughout the study period but that not all university affiliates were equally likely to be involved. In addition, the transmission rate from campus into the surrounding community may have increased during the second year of the study, possibly due to return to in-person instruction.}, }
@article {pmid39749107, year = {2024}, author = {He, Q and Gao, F and Dukes, O and Delany-Moretlwe, S and Zhang, B}, title = {Generalizing the intention-to-treat effect of an active control from historical placebo-controlled trials: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study.}, journal = {Journal of the American Statistical Association}, volume = {119}, number = {548}, pages = {2478-2492}, pmid = {39749107}, issn = {0162-1459}, support = {R01 AI177078/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point versus partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP).}, }
@article {pmid39748218, year = {2025}, author = {Delany-Moretlwe, S and Hanscom, B and Guo, X and Nkabiito, C and Mandima, P and Nahirya, PN and Mpendo, J and Bhondai-Mhuri, M and Mgodi, N and Berhanu, R and Farrior, J and Piwowar-Manning, E and Ford, SL and Hendrix, CW and Rinehart, AR and Rooney, JF and Adeyeye, A and Landovitz, RJ and Cohen, MS and Hosseinipour, MC and Marzinke, MA and , }, title = {Evaluation of long-acting cabotegravir safety and pharmacokinetics in pregnant women in eastern and southern Africa: a secondary analysis of HPTN 084.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {1}, pages = {e26401}, pmid = {39748218}, issn = {1758-2652}, support = {//National Institute of Allergy and Infectious Diseases/ ; /NH/NIH HHS/United States ; /DA/NIDA NIH HHS/United States ; UM1AI068619/MH/NIMH NIH HHS/United States ; UM1AI068617/MH/NIMH NIH HHS/United States ; UM1AI068613/MH/NIMH NIH HHS/United States ; OPP1154174/GATES/Bill & Melinda Gates Foundation/United States ; //ViiV Healthcare/ ; }, mesh = {Humans ; Female ; Pregnancy ; Adult ; *Anti-HIV Agents/pharmacokinetics/adverse effects/therapeutic use ; *HIV Infections/drug therapy ; Young Adult ; *Pyridones/pharmacokinetics/adverse effects ; Africa, Eastern/epidemiology ; Pre-Exposure Prophylaxis ; Africa, Southern/epidemiology ; Pregnancy Complications, Infectious/drug therapy ; Pregnancy Outcome ; Tenofovir/pharmacokinetics/adverse effects/therapeutic use/administration & dosage ; Adolescent ; Emtricitabine/pharmacokinetics/therapeutic use/adverse effects/administration & dosage ; Diketopiperazines ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB-LA pharmacokinetics in pregnant women during the blinded period of HPTN 084.
METHODS: Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open-label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half-life (t1/2app) of CAB-LA in pregnant women in HPTN 084 was compared to non-pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t1/2app. RESULTS: Fifty-seven pregnancies (30 CAB-LA, 27 TDF/FTC) were confirmed over 3845 person-years [py] (incidence 1.5/100 py, 95% CI 1.1-1.9). CAB-LA group participants had a median 342 days (IQR 192, 497) of CAB-LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91-271 per 100 py vs. TDF/FTC 217, 95% CI 124-380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB-LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t1/2app geometric mean was 52.8 days (95% CI 40.7-68.4) in pregnant women compared to 60.3 days (95% CI 47.7-76.3; p = 0.66) in non-pregnant women; neither pregnancy nor body mass index were significantly associated with t1/2app.
CONCLUSIONS: CAB-LA concentrations post-cessation of injections were generally well tolerated in pregnant women. The t1/2app was comparable between pregnant and non-pregnant women. Ongoing studies will examine the safety and pharmacology of CAB-LA in women who choose to continue CAB-LA through pregnancy and lactation.}, }
@article {pmid39747003, year = {2025}, author = {Alsaed, B and Lin, L and Son, J and Li, J and Smolander, J and Lopez, T and Eser, PÖ and Ogino, A and Ambrogio, C and Eum, Y and Thai, T and Wang, H and Sutinen, E and Mutanen, H and Duàn, H and Bobik, N and Borenius, K and Feng, WW and Nabet, B and Mustjoki, S and Laaksonen, S and Eschle, BK and Poitras, MJ and Barbie, D and Ilonen, I and Gokhale, P and Jänne, PA and Haikala, HM}, title = {Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {28}, pmid = {39747003}, issn = {2041-1723}, support = {K22 CA258805/CA/NCI NIH HHS/United States ; R35 CA220497/CA/NCI NIH HHS/United States ; }, mesh = {*ErbB Receptors/metabolism/genetics/antagonists & inhibitors ; *Tumor Microenvironment/drug effects/genetics ; *Drug Resistance, Neoplasm/genetics ; Humans ; *Carcinoma, Non-Small-Cell Lung/genetics/drug therapy/metabolism/pathology ; *Lung Neoplasms/genetics/drug therapy/metabolism/pathology ; Cell Line, Tumor ; *Protein Kinase Inhibitors/pharmacology ; Animals ; Mutation ; Epithelial-Mesenchymal Transition/genetics/drug effects ; Mice ; Cancer-Associated Fibroblasts/metabolism/drug effects/pathology ; Transforming Growth Factor beta/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.}, }
@article {pmid39746969, year = {2025}, author = {Duan, S and Nodelman, IM and Zhou, H and Tsukiyama, T and Bowman, GD and Zhang, Z}, title = {H3K56 acetylation regulates chromatin maturation following DNA replication.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {134}, pmid = {39746969}, issn = {2041-1723}, support = {R01 GM084192/GM/NIGMS NIH HHS/United States ; R35 GM139429/GM/NIGMS NIH HHS/United States ; R35GM118015//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 CA013696/CA/NCI NIH HHS/United States ; R35 GM118015/GM/NIGMS NIH HHS/United States ; }, mesh = {*Histones/metabolism ; *DNA Replication ; Acetylation ; Humans ; *Chromatin/metabolism ; *Nucleosomes/metabolism ; *Saccharomyces cerevisiae/metabolism/genetics ; Chromatin Assembly and Disassembly ; Transcription Factors/metabolism/genetics ; Adenosine Triphosphatases/metabolism/genetics ; Genomic Instability ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Chromosomal Proteins, Non-Histone ; }, abstract = {Following DNA replication, the newly reassembled chromatin is disorganized and must mature to its steady state to maintain both genome and epigenome integrity. However, the regulatory mechanisms governing this critical process remain poorly understood. Here, we show that histone H3K56 acetylation (H3K56ac), a mark on newly-synthesized H3, facilitates the remodeling of disorganized nucleosomes in nascent chromatin, and its removal at the subsequent G2/M phase of the cell cycle marks the completion of chromatin maturation. In vitro, H3K56ac enhances the activity of ISWI chromatin remodelers, including yeast ISW1 and its human equivalent SNF2h. In vivo, a deficiency of H3K56ac in nascent chromatin results in the formation of closely packed di-nucleosomes and/or tetra-nucleosomes. In contrast, abnormally high H3K56ac levels disrupt chromatin maturation, leading to genome instability. These findings establish a central role of H3K56ac in chromatin maturation and reveal a mechanism regulating this critical aspect of chromosome replication.}, }
@article {pmid39745736, year = {2025}, author = {Baumrin, E and Cronholm, PF and Kearney, MD and Mengesha, M and Cesar, LG and Keddem, S and Schapira, MM and Lee, SJ and Loren, AW and Gelfand, JM}, title = {Outcomes of Importance to Patients Living With Cutaneous Chronic Graft-vs-Host Disease.}, journal = {JAMA dermatology}, volume = {161}, number = {3}, pages = {281-290}, pmid = {39745736}, issn = {2168-6084}, mesh = {Humans ; *Graft vs Host Disease/psychology/etiology ; Male ; Female ; Middle Aged ; *Quality of Life ; Chronic Disease ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Aged ; *Skin Diseases/psychology/etiology/pathology ; Qualitative Research ; Interviews as Topic ; Adult ; }, abstract = {IMPORTANCE: Cutaneous chronic graft-vs-host disease (GVHD) is independently associated with morbidity and mortality after allogeneic hematopoietic cell transplant. However, the health-related quality-of-life (HRQOL) domains that are most important to patients are poorly understood.
OBJECTIVE: To perform a concept elicitation study to define HRQOL in cutaneous chronic GVHD from the patient perspective and to compare experiences of patients with epidermal vs sclerotic disease.
A single-center qualitative analysis from open-ended, semistructured interviews and free-listing terms conducted between April and September 2023. Participants were 18 years or older with a diagnosis of active cutaneous chronic GVHD, purposefully sampled for epidermal and sclerotic disease features, with ongoing sampling until thematic saturation.
MAIN OUTCOMES: HRQOL domains and codes from patient perspectives of living with cutaneous chronic GVHD were identified by inductive analysis of semistructured interviews. Smith salience index (Smith S) score, a measure of saliency for each list term, was calculated from free-listing terms from deidentified patient interviews.
RESULTS: A total of 31 adults with cutaneous chronic GVHD (median [IQR] age, 61.1 [52.9-68.7] years) participated in interviews; 17 participants (54.8%) were male and 14 (45.2%) were female. Nine participants (29.0%) had epidermal, 13 (41.9%) sclerotic, and 9 (29.0%) a combination of disease types. The study identified 40 codes of importance grouped within 5 HRQOL domains: skin changes and symptoms, social functioning, psychological and emotional functioning, physical functioning, and general health perceptions. The most frequent symptoms were dry skin (n = 20 [65%]), tight skin (n = 19 [61%]), itch (n = 15 [48%]), and discoloration (n = 14 [45%]), which were seen in all disease subtypes. Impairment in social functioning was noted by all participants. Psychological and emotional functioning, including frustration (Smith S score, 0.32) and worry or concern (Smith S score, 0.12), and symptoms including discomfort (Smith S score, 0.20) were the most salient to patients. Individual and environmental factors, such as social comparison, illness comparison with cancer, anatomic location of disease involvement, and disease duration, affected the relationship between skin changes and symptoms and downstream functioning and general health perceptions.
CONCLUSIONS AND RELEVANCE: This qualitative analysis demonstrated the direct relationship between cutaneous chronic GVHD and HRQOL domains and identified codes not represented in existing GVHD- and dermatology-specific patient-reported outcome measures. These results can guide patient-reported outcome development and instrument selection for clinical trials and improve clinical decision-making.}, }
@article {pmid39745448, year = {2025}, author = {Arnold, EA and Smith, JR and Leung, K and Nguyen, DH and Kelnhofer-Millevolte, LE and Guo, MS and Smith, JG and Avgousti, DC}, title = {Post-translational modifications on protein VII are important during the early stages of adenovirus infection.}, journal = {Journal of virology}, volume = {99}, number = {2}, pages = {e0146224}, pmid = {39745448}, issn = {1098-5514}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; R00 GM134153/GM/NIGMS NIH HHS/United States ; R00GM134153//HHS | National Institutes of Health (NIH)/ ; R01 AI104920/AI/NIAID NIH HHS/United States ; R01AI104920//HHS | National Institutes of Health (NIH)/ ; R35 GM133441/GM/NIGMS NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R35GM133441//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Protein Processing, Post-Translational ; Humans ; Acetylation ; *Adenoviruses, Human/genetics/metabolism ; *Adenoviridae Infections/virology/metabolism ; Adenovirus E1A Proteins/metabolism/genetics ; *Adenovirus Infections, Human/virology/metabolism ; *Viral Proteins/metabolism/genetics ; *Adenoviridae/genetics/metabolism ; Virus Replication ; HEK293 Cells ; Gene Expression Regulation, Viral ; }, abstract = {UNLABELLED: Due to the importance of post-translational modification (PTM) in cellular function, viruses have evolved to both take advantage of and be susceptible to such modification. Adenovirus encodes a multifunctional protein called protein VII, which is packaged with the viral genome in the core of virions and disrupts host chromatin during infection. Protein VII has several PTMs whose addition contributes to the subnuclear localization of protein VII. Here, we used mutant viruses that abrogate or mimic these PTMs on protein VII to interrogate their impact on protein VII function during adenovirus infection. We discovered that acetylation of the lysine in positions 2 or 3 (K2 or K3) is deleterious during early infection as mutation to alanine led to greater intake of protein VII and viral DNA to the nucleus and enhanced early gene expression. Furthermore, we determined that protein VII is acetylated at alternative residues late during infection which may compensate for the mutated sites. Lastly, due to the role of the early viral protein E1A in viral gene activation, we investigated the interaction between protein VII and E1A and demonstrated that protein VII interacts with E1A through a chromatin-mediated interaction. Together, these results emphasize that the complexity of virus-host interactions is intimately tied to post-translational modification.
IMPORTANCE: Adenoviruses are ubiquitous human pathogens that cause a variety of diseases, such as respiratory infections, gastroenteritis, and conjunctivitis. While often viewed as a self-limiting infection in healthy individuals, adenoviruses are particularly harmful to immunocompromised patients. Here, we investigate the functional role of post-translational modifications (PTMs) on an essential adenovirus core protein, protein VII, describing how they regulate its function during the early and late stages of infection. Our study focuses on how specific PTMs on protein VII influence transcription, localization, and interactions with other proteins, highlighting how PTMs are employed by viruses to alter protein function.}, }
@article {pmid39743015, year = {2025}, author = {Unger, JM and Szarama, K}, title = {Cancer clinical trial participation in socioeconomically vulnerable patients; A risk model to aid in targeted interventions.}, journal = {Contemporary clinical trials}, volume = {149}, number = {}, pages = {107803}, doi = {10.1016/j.cct.2024.107803}, pmid = {39743015}, issn = {1559-2030}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Neoplasms/therapy ; *Clinical Trials as Topic/statistics & numerical data ; Adult ; Aged ; *Patient Participation/statistics & numerical data ; Socioeconomic Factors ; United States ; *Vulnerable Populations/statistics & numerical data ; Risk Factors ; Risk Assessment ; Depression/epidemiology ; Anxiety/epidemiology ; Patient Selection ; Trust ; Poverty ; }, abstract = {BACKGROUND: In patients with cancer, those with lower incomes are less likely to participate in clinical trials. A broad-based evaluation of variables that could contribute to this disparity has not been conducted.
METHODS: We used data from Health Information National Trends Survey (HINTS) databases for survey years 2014, 2017, and 2020, the survey years that included questions about whether patients with cancer participated in a clinical trial. We examined 21 demographic, socioeconomic, behavioral, geographic, and health information questions. We derived a risk model to predict clinical trial participation using a training/validation approach with best subset selection and k-fold cross-validation. Logistic regression was used.
RESULTS: We examined N = 1023 participants with household income <$75,000 (the U.S. median). In the training dataset (n = 614), a 5-variable model was identified including race/ethnicity, education, trust, anxiety/depression, and geographic locale. A quartile-level risk score was constructed based on the sum of adverse risk factors. In the validation cohort (n = 409), each increase in quartile level was associated with a 73 % increase in the odds of trial nonparticipation (OR = 1.73, 95 %-CI, 1.19-2.53, p = 0.004), indicating successful model validation. Among all individuals, trial participation rates decreased from 18.6 % to 7.5 % to 4.6 % to 2.8 %, respectively, as the number of adverse risk factors increased from 0 to 1 to 2 to 3 to 4-5.
CONCLUSIONS: We developed and validated a 5-variable risk model that identified a large set of lower-income individuals at lower risk of trial participation. These findings could aid in identification of patients who may benefit from additional support to navigate the treatment trial decision-making process.}, }
@article {pmid39741979, year = {2024}, author = {Ahmed, M and Beyreuther, E and Gantz, S and Horst, F and Meyer, J and Pawelke, J and Schmid, TE and Stolz, J and Wilkens, JJ and Bartzsch, S}, title = {Design and dosimetric characterization of a transportable proton minibeam collimation system.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1473625}, pmid = {39741979}, issn = {2234-943X}, abstract = {BACKGROUND: Proton Minibeam Radiation Therapy has shown to widen the therapeutic window compared to conventional radiation treatment in pre-clinical studies. The underlying biological mechanisms, however, require more research.
PURPOSE: The purpose of this study was to develop and characterize a mechanical collimation setup capable of producing 250µm wide proton minibeams with a center-to-center distance of 1000µm.
METHODS: To find the optimal arrangement Monte Carlo simulations were employed using the Geant4 toolkit TOPAS to maximize key parameters such as the peak-to-valley dose ratio (PVDR) and the valley dose rate. The experimental characterization of the optimized setup was carried out with film dosimetry at the University Proton Therapy beamline in Dresden and the proton beamline of the University of Washington Medical Center in Seattle with 150MeV and 50.5MeV, respectively. A microDiamond detector (PTW, Freiburg, Germany) was utilized at both beamlines for online proton minibeam dosimetry.
RESULTS: A PVDR of 10 was achieved in Dresden and a PVDR of 14 in Seattle. Dosimetry measurements were carried out with EBT3 films at a depth of 5mm in a polymethylmethacrylate (PMMA) phantom. When comparing film dosimetry with the microDiamond, excellent agreement was observed in the valleys. However, the peak dose showed a discrepancy of approximately 10% in the 150MeV beam and 20% in the 50.5MeV beam between film and microDiamond.
DISCUSSION: The characteristics of the minibeams generated with our system compares well with those of other collimated minibeams despite being smaller. The deviations of microDiamond measurements from film readings might be subject to the diamond detector responding differently in the peak and valley regions. Applying previously reported correction factors aligns the dose profile measured by the microDiamond with the profile acquired with EBT3 films in Dresden.
CONCLUSION: The novel proton minibeam system can be operated independently of specific beamlines. It can be transported easily and hence used for inter-institutional comparative studies. The quality of the minibeams allows us to perform in vitro and in vivo experiments in the future. The microDiamond was demonstrated to have great potential for online dosimetry for proton minibeams, yet requires more research to explain the observed discrepancies.}, }
@article {pmid39741337, year = {2024}, author = {Braun, C and Takeuchi, T and Lambert, J and Liu, L and Roberts, S and Carter, S and Beaubien-Souligny, W and Tolwani, A and Neyra, JA}, title = {Association of continuous renal replacement therapy downtime with fluid balance gap and clinical outcomes: a retrospective cohort analysis utilizing EHR and machine data.}, journal = {Journal of intensive care}, volume = {12}, number = {1}, pages = {55}, pmid = {39741337}, issn = {2052-0492}, support = {R01DK133539/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Fluid balance gap (FBgap-prescribed vs. achieved) is associated with hospital mortality. Downtime is an important quality indicator for the delivery of continuous renal replacement therapy (CRRT). We examined the association of CRRT downtime with FBgap and clinical outcomes including mortality.
METHODS: This is a retrospective cohort study of critically ill adults receiving CRRT utilizing both electronic health records (EHR) and CRRT machine data. FBgap was calculated as achieved minus prescribed fluid balance. Downtime, or percent treatment time loss (%TTL), was defined as CRRT downtime in relation to the total CRRT time. Data collection stopped upon transition to intermittent hemodialysis when applicable. Linear and logistic regression models were used to analyze the association of %TTL with FBgap and hospital mortality, respectively. Covariates included demographics, Sequential Organ Failure Assessment (SOFA) score at CRRT initiation, use of organ support devices, and the interaction between %TTL and machine alarms.
RESULTS: We included 3630 CRRT patient-days from 500 patients with a median age of 59.5 years (IQR 50-67). Patients had a median SOFA score at CRRT initiation of 13 (IQR 10-16). Median %TTL was 8.1% (IQR 4.3-12.5) and median FBgap was 17.4 mL/kg/day (IQR 8.2-30.4). In adjusted models, there was a significant positive relationship between FBgap and %TTL only in the subgroup with higher alarm frequency (6 + alarms per CRRT-day) (β = 0.87 per 1% increase, 95%CI 0.48-1.26). No association was found in the subgroups with lower alarm frequency (0-2 and 3-5 alarms). There was no statistical evidence for an association between %TTL and hospital mortality in the adjusted model with the interaction term of alarm frequency.
CONCLUSIONS: In critically ill adult patients undergoing CRRT, %TTL was associated with FBgap only in the subgroup with higher alarm frequency, but not in the other subgroups with lower alarms. No association between %TTL and mortality was observed. More frequent alarms, possibly indicating unexpected downtime, may suggest compromised CRRT delivery and could negatively impact FBgap.}, }
@article {pmid39738571, year = {2025}, author = {Antony, A and Mukherjee, S and Bi, Y and Collisson, EA and Nagaraj, M and Murlidhar, M and Wallace, MB and Goenka, AH}, title = {AI-Driven insights in pancreatic cancer imaging: from pre-diagnostic detection to prognostication.}, journal = {Abdominal radiology (New York)}, volume = {50}, number = {7}, pages = {3214-3224}, pmid = {39738571}, issn = {2366-0058}, support = {R01 CA239604/CA/NCI NIH HHS/United States ; N/A//Hoveida Family Foundation/ ; N/A//Mayo Clinic Comprehensive Cancer Center/ ; N/A//Centene Charitable Foundation/ ; N/A//Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation/ ; R01CA256969/NH/NIH HHS/United States ; R01CA256969/NH/NIH HHS/United States ; R01CA256969/NH/NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/diagnostic imaging/pathology ; *Artificial Intelligence ; Prognosis ; *Carcinoma, Pancreatic Ductal/diagnostic imaging/pathology ; Early Detection of Cancer/methods ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, largely due to its poor five-year survival rate and frequent late-stage diagnosis. A significant barrier to early detection even in high-risk cohorts is that the pancreas often appears morphologically normal during the pre-diagnostic phase. Yet, the disease can progress rapidly from subclinical stages to widespread metastasis, undermining the effectiveness of screening. Recently, artificial intelligence (AI) applied to cross-sectional imaging has shown significant potential in identifying subtle, early-stage changes in pancreatic tissue that are often imperceptible to the human eye. Moreover, AI-driven imaging also aids in the discovery of prognostic and predictive biomarkers, essential for personalized treatment planning. This article uniquely integrates a critical discussion on AI's role in detecting visually occult PDAC on pre-diagnostic imaging, addresses challenges of model generalizability, and emphasizes solutions like standardized datasets and clinical workflows. By focusing on both technical advancements and practical implementation, this article provides a forward-thinking conceptual framework that bridges current gaps in AI-driven PDAC research.}, }
@article {pmid39737444, year = {2025}, author = {Parino, F and Gustani-Buss, E and Bedford, T and Suchard, MA and Trovão, NS and Rambaut, A and Colizza, V and Poletto, C and Lemey, P}, title = {Integrating dynamical modeling and phylogeographic inference to characterize global influenza circulation.}, journal = {PNAS nexus}, volume = {4}, number = {1}, pages = {pgae561}, pmid = {39737444}, issn = {2752-6542}, support = {R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; U19 AI135995/AI/NIAID NIH HHS/United States ; }, abstract = {Global seasonal influenza circulation involves a complex interplay between local (seasonality, demography, host immunity) and global factors (international mobility) shaping recurrent epidemic patterns. No studies so far have reconciled the two spatial levels, evaluating the coupling between national epidemics, considering heterogeneous coverage of epidemiological, and virological data, integrating different data sources. We propose a novel-combined approach based on a dynamical model of global influenza spread (GLEAM), integrating high-resolution demographic, and mobility data, and a generalized linear model of phylogeographic diffusion that accounts for time-varying migration rates. Seasonal migration fluxes across countries simulated with GLEAM are tested as phylogeographic predictors to provide model validation and calibration based on genetic data. Seasonal fluxes obtained with a specific transmissibility peak time and recurrent travel outperformed the raw air-transportation predictor, previously considered as optimal indicator of global influenza migration. Influenza A subtypes supported autumn-winter reproductive number as high as 2.25 and an average immunity duration of 2 years. Similar dynamics were preferred by influenza B lineages, with a lower autumn-winter reproductive number. Comparing simulated epidemic profiles against FluNet data offered comparatively limited resolution power. The multiscale approach enables model selection yielding a novel computational framework for describing global influenza dynamics at different scales-local transmission and national epidemics vs. international coupling through mobility and imported cases. Our findings have important implications to improve preparedness against seasonal influenza epidemics. The approach can be generalized to other epidemic contexts, such as emerging disease outbreaks to improve the flexibility and predictive power of modeling.}, }
@article {pmid39733839, year = {2025}, author = {Rotz, SJ and Wiener, L and Baker, KS and Choi, SW and Phelan, R and Cuvelier, GDE and Duncan, C and Williams, KM and Qayed, M}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part IV. Patient Important Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {4}, pages = {224.e1-224.e13}, pmid = {39733839}, issn = {2666-6367}, support = {R13 HL172559/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/psychology/therapy ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Child ; Quality of Life ; Chronic Disease ; Survivorship ; }, abstract = {Chronic graft-versus-host disease (cGVHD) occurs in approximately 1 in 5 pediatric allogeneic HCT patients and is a leading cause of late morbidity and mortality. Late effects of hematopoietic cell transplantation (HCT) may lead to long-term chronic health conditions and shortened life expectancy. In addition to direct physiologic challenges from cGVHD and other late effects, numerous patient-important outcomes impact the quality of life (QOL) of patients and their families. The Research and Education towards Solutions for Late Effects to Innovate, Excel, and Nurture (RESILIENT) after GVHD Consensus Conference was convened to better understand the overlap of cGVHD and late effects in pediatric HCT survivors. Working Committee IV: Patient Important Outcomes identified 4 key areas for focus: (1) What are the key mental health and QOL concerns of survivors of pediatric cGVHD? (2) What is the impact of cGVHD on cognitive performance and social development? (3) What multilevel social determinants of health impact cGVHD survivors, families, and communities? (4) What is the role of racial, ethnic, and socioeconomic factors on the development of cGVHD and the risk for adverse outcomes related to survivorship? For each focus area, the Working Committee reviewed the current state of the field, developed recommendations for clinical practice, and highlighted areas to prioritize for future research. Eleven recommendations were adapted and approved. Substantial overlap exists between the role of cGVHD and late effects on the QOL and mental health of childhood HCT survivors. Recommendations based on available data and consensus opinion may be helpful to improve outcomes for these patients. However, several gaps remain that need further study.}, }
@article {pmid39733276, year = {2024}, author = {Landy, R and Katki, HA and Huang, WY and Wang, D and Thomas, M and Qu, F and Freedman, ND and Loftfield, E and Shi, J and Peters, U and Hsu, L and Schoen, RE and Berndt, SI}, title = {Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.}, journal = {Clinical and translational gastroenterology}, volume = {15}, number = {12}, pages = {e00782}, pmid = {39733276}, issn = {2155-384X}, support = {//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/diagnosis/epidemiology ; Male ; Female ; *Colonoscopy ; Middle Aged ; Aged ; *Early Detection of Cancer/methods ; Risk Factors ; Risk Assessment/methods ; *Adenoma/genetics/diagnosis/epidemiology ; Sigmoidoscopy ; United States/epidemiology ; Time Factors ; Genetic Risk Score ; }, abstract = {INTRODUCTION: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an "equal management of equal risks" framework.
METHODS: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score for colorectal cancer. Ten-year absolute cancer risks for each diagnostic colonoscopy finding (advanced adenomas [N = 2,446], ≥3 non-advanced adenomas [N = 483], 1-2 non-advanced adenomas [N = 4,400], and no adenoma [N = 7,183]) were used as implicit risk thresholds for recommended surveillance intervals.
RESULTS: The area under the curve for the model including colonoscopy findings, baseline characteristics, and polygenic risk score was 0.658. Applying the equal management of equal risks framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval.
DISCUSSION: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.}, }
@article {pmid39730463, year = {2024}, author = {Touré, H and Durand, N and Rincheval, V and Girard-Misguich, F and Guénal, I and Herrmann, JL and Szuplewski, S}, title = {Remote disruption of intestinal homeostasis by Mycobacterium abscessus is detrimental to Drosophila survival.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30775}, pmid = {39730463}, issn = {2045-2322}, mesh = {Animals ; *Drosophila melanogaster/microbiology ; *Homeostasis ; *Intestines/microbiology ; *Mycobacterium abscessus ; Mycobacterium Infections, Nontuberculous/microbiology ; Enterocytes/microbiology/metabolism ; Receptors, Notch/metabolism ; Drosophila Proteins/metabolism ; Signal Transduction ; Janus Kinases/metabolism ; STAT Transcription Factors/metabolism ; Cell Differentiation ; }, abstract = {Mycobacterium abscessus (Mabs), an intracellular and opportunistic pathogen, is considered the most pathogenic fast-growing mycobacterium, and causes severe pulmonary infections in patients with cystic fibrosis. While bacterial factors contributing to its pathogenicity are well studied, the host factors and responses that worsen Mabs infection are not fully understood. Here, we report that Mabs systemic infection alters Drosophila melanogaster intestinal homeostasis. Mechanistically, Mabs remotely induces a self-damaging oxidative burst, leading to excessive differentiation of intestinal stem cells into enterocytes. We demonstrated that the subsequent increased intestinal renewal is mediated by both the Notch and JAK/STAT pathways and is deleterious to Drosophila survival. In conclusion, this work highlights that the ability of Mabs to induce an exacerbated and self-damaging response in the host contributes to its pathogenesis.}, }
@article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, pmid = {39724103}, issn = {1553-7404}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *HSP90 Heat-Shock Proteins/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; Phosphorylation ; Mutation ; Heat-Shock Response/genetics ; TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, }
@article {pmid39724000, year = {2024}, author = {Stacey, AW and Nakamichi, K and Huey, J and Stevens, J and Waligorski, N and Crotty, EE and Van Gelder, RN and Mustafi, D}, title = {Prognostic importance of direct assignment of parent of origin via long-read genome and epigenome sequencing in retinoblastoma.}, journal = {JCI insight}, volume = {10}, number = {4}, pages = {}, pmid = {39724000}, issn = {2379-3708}, support = {K08 EY033789/EY/NEI NIH HHS/United States ; P30 EY001730/EY/NEI NIH HHS/United States ; }, mesh = {Humans ; *Retinoblastoma/genetics/pathology/diagnosis ; DNA Methylation/genetics ; Male ; Female ; Prognosis ; *Epigenome/genetics ; *Retinal Neoplasms/genetics ; Child, Preschool ; Infant ; Epigenomics/methods ; Child ; CpG Islands ; Alleles ; }, abstract = {BACKGROUNDCurrent clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease, and the inability to assign parent of origin in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects.METHODSTo directly assign parent of origin in patients with retinoblastoma, we extracted genomic DNA from blood samples for sequencing using a programmable, targeted, single-molecule, long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in participants with familial (n = 7) and de novo (n = 9) retinoblastoma.RESULTSTargeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the retinoblastoma gene to confirm parent of origin in known familial samples. This approach allowed us to directly assign parent of origin in simple and complex de novo cases from the proband alone. The ability to assign parent of origin in all retinoblastoma cases showed that harboring disease-causing variants on the paternally inherited allele, whether arising familially or de novo, was associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (P = 0.002).CONCLUSIONThis study demonstrates the diagnostic potential of multiomic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent of origin to other genetic diseases using local and distant imprinting signals in the genome.FUNDINGNational Eye Institute, NIH; Gerber Foundation; Research to Prevent Blindness; Angie Karalis Johnson Fund; Dawn's Light Foundation; and Mark J. Daily, MD Research Fund.}, }
@article {pmid39723472, year = {2025}, author = {de la Fuente, MI and Touat, M and van den Bent, MJ and Preusser, M and Peters, KB and Young, RJ and Huang, RY and Ellingson, BM and Capper, D and Phillips, JJ and Halasz, LM and Shih, HA and Rudà, R and Lim-Fat, MJ and Blumenthal, DT and Weller, M and Arakawa, Y and Whittle, JR and Ducray, F and Reardon, DA and Bi, WL and Minniti, G and Rahman, R and Hervey-Jumper, S and Chang, SM and Wen, PY}, title = {The role of vorasidenib in the treatment of isocitrate dehydrogenase-mutant glioma.}, journal = {Neuro-oncology}, volume = {27}, number = {5}, pages = {1135-1148}, pmid = {39723472}, issn = {1523-5866}, support = {P50 CA211015/CA/NCI NIH HHS/United States ; R01 CA270027/CA/NCI NIH HHS/United States ; R01 CA279984/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Isocitrate Dehydrogenase/genetics/antagonists & inhibitors ; *Glioma/drug therapy/genetics/pathology ; *Brain Neoplasms/drug therapy/genetics ; *Mutation ; *Triazines/therapeutic use ; *Antineoplastic Agents/therapeutic use ; *Pyrimidines/therapeutic use ; }, abstract = {Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant primary brain tumors in young adults. This condition imposes a substantial burden on patients and their caregivers, marked by neurocognitive deficits and high mortality rates due to tumor progression, coupled with significant morbidity from current treatment modalities. Although surgery, radiation therapy, and chemotherapy improve survival, these treatments can adversely affect cognitive function, quality of life, finances, employment status, and overall independence. Consequently, there is an urgent need for innovative strategies that delay progression and the use of radiation therapy and chemotherapy. The recent Federal Drug Administration (FDA) approval of vorasidenib, a brain-penetrant small molecule targeting mutant IDH1/2 proteins, heralds a shift in the therapeutic landscape for IDH-mutant gliomas. In this review, we address the role of vorasidenib in the treatment of IDH-mutant gliomas, providing a roadmap for its incorporation into daily practice. We discuss ongoing clinical trials with vorasidenib and other IDH inhibitors, as single-agent or in combination with other therapies, as well as current challenges and future directions.}, }
@article {pmid39722539, year = {2025}, author = {Zepeda-Rivera, MA and Eisele, Y and Baryiames, A and Wu, H and Mengoni, C and Piccinno, G and McMahon, EF and LaCourse, KD and Jones, DS and Hauner, H and Minot, SS and Segata, N and Dewhirst, FE and Johnston, CD and Bullman, S}, title = {Fusobacterium sphaericum sp. nov., isolated from a human colon tumor adheres to colonic epithelial cells and induces IL-8 secretion.}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2442522}, doi = {10.1080/19490976.2024.2442522}, pmid = {39722539}, issn = {1949-0984}, mesh = {Humans ; *Interleukin-8/metabolism/genetics ; *Colonic Neoplasms/microbiology/pathology ; *Fusobacterium/isolation & purification/genetics ; *Epithelial Cells/microbiology ; *Phylogeny ; Bacterial Adhesion ; Colon/microbiology/pathology ; Feces/microbiology ; Adenocarcinoma/microbiology/pathology ; Gastrointestinal Microbiome ; RNA, Ribosomal, 16S/genetics ; Genome, Bacterial ; }, abstract = {Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.}, }
@article {pmid39722322, year = {2025}, author = {Qu, X and Stevens, E and Fitzgibbon, MP and Beppu, L and Monahan, TM and Yeung, C and Stirewalt, DL and Wu, D and Radich, JP and Deeg, HJ and Fang, M}, title = {Pretransplant Chromosome Genomic Array Testing Improves Prognostication for Myelofibrosis Patients Undergoing Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {3}, pages = {170.e1-170.e8}, doi = {10.1016/j.jtct.2024.12.018}, pmid = {39722322}, issn = {2666-6367}, mesh = {Humans ; *Primary Myelofibrosis/genetics/therapy/diagnosis/mortality ; Female ; Male ; Middle Aged ; Prognosis ; *Hematopoietic Stem Cell Transplantation/methods ; Adult ; Aged ; Retrospective Studies ; }, abstract = {BACKGROUND: Despite its known superior diagnostic yield for chromosomal anomalies compared with karyotype and fluorescence in situ hybridization (FISH) studies, chromosome genomic array testing (CGAT) is not used as a routine clinical test for myelofibrosis. Although many prognostic systems exist that risk stratify patients at diagnosis, limited tools are available to prognosticate transplant outcome.
OBJECTIVE: The current study aimed at testing whether CGAT results obtained before transplantation improves prognosis of post-transplant outcome in patients with myelofibrosis compared with current risk categorization systems, for example, DIPSS plus (Dynamic International Prognostic Scoring System).
STUDY DESIGN: We studied patients with myelofibrosis who underwent hematopoietic cell transplantation between 2000 and 2017 at our center (N = 44). We assessed the prognostic significance of CGAT, DIPSS plus, and the total count of gene mutations for post-transplant clinical outcomes, including relapse-free survival (RFS), overall survival (OS), and graft-versus-host-disease (GVHD).
RESULTS: Abnormal CGAT results were seen in 24 patients (55%), including 18 with copy-neutral loss of heterozygosity (cnLOH, 41%). With a median follow-up of 91 (range 2-258) months starting from the CGAT sample date, RFS was 59% and OS was 68%. The outcome analysis showed significant prognostic implication from CGAT (normal vs. abnormal), specifically for patients with intermediate risk by DIPSS-plus scores and those with 0∼2 mutations. CGAT alone significantly stratified the patients' RFS outcome (P = .03). The addition of CGAT to DIPSS-plus improved the significance from a P value of .08 to .003, whereas the addition of CGAT to mutation count improved the P value from .02 to .01. The best stratification system for RFS was achieved when CGAT, DIPSS-plus, and mutation count were all considered (P = 1e-08). The current study also confirmed individual anomalies that are prognostically significant, including U2AF1 mutation (n = 5, P = .03) and 1q gain (n = 3, P = .01), which were associated with worse RFS. ASXL1 mutations (n = 14) appeared to associate with a later onset of chronic GVHD (P =.03).
CONCLUSION: Pretransplant CGAT analysis augments the existing risk stratification tools and may be considered as routine clinical testing for myelofibrosis.}, }
@article {pmid39720913, year = {2025}, author = {Omole, TE and Nguyen, HM and Marcinow, A and Oo, MM and Jahan, N and Ssemaganda, A and Severini, G and Thomas, KK and Celum, C and Mugo, N and Mujugira, A and Kublin, J and Corey, L and Sivro, A and Lingappa, JR and Gray, G and McKinnon, LR}, title = {Pre-Human Immunodeficiency Virus (HIV) α4β7hi CD4+ T Cells and HIV Risk Among Heterosexual Individuals in Africa.}, journal = {The Journal of infectious diseases}, volume = {231}, number = {4}, pages = {e770-e780}, pmid = {39720913}, issn = {1537-6613}, support = {//International Congress of Immunology/ ; }, mesh = {Humans ; Male ; *HIV Infections/epidemiology/immunology/virology ; Female ; *Heterosexuality ; *CD4-Positive T-Lymphocytes/immunology ; Adult ; Retrospective Studies ; Case-Control Studies ; South Africa/epidemiology ; Young Adult ; Risk Factors ; Middle Aged ; HIV-1 ; Africa, Eastern/epidemiology ; Integrins ; }, abstract = {BACKGROUND: CD4+ T cells expressing α4β7 are optimal targets for human immunodeficiency virus (HIV) infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men or people who inject drugs in the Americas, indicating need for further research.
METHODS: This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network [HVTN] 503) and East Africa (Partners Preexposure Prophylaxis/Couples' Observational Study [PP/COS]), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses.
RESULTS: Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T-cell decline, similar to what was observed previously in South Africa.
CONCLUSIONS: These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.}, }
@article {pmid39720621, year = {2025}, author = {Reiner, AP and Raffield, LM and Ekunwe, L and Olson, NC and Auer, PL and Doyle, MF}, title = {Alterations of T Cell Subsets Associated with Sickle Cell Trait.}, journal = {Blood and genomics discovery}, volume = {9}, number = {1}, pages = {}, pmid = {39720621}, issn = {3078-221X}, support = {R01 HL132947/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; }, abstract = {Sickle cell trait (SCT) has been associated with alterations in various immune-related laboratory parameters including lower circulating lymphocyte counts. To further characterize the impact of SCT on the immune system, we performed flow cytometry of monocyte and lymphocyte immune cell subsets from peripheral blood mononuclear cells collected in a large, community-based cohort of SCT-positive (n = 68) and SCT-negative (n = 959) Black adults. SCT was significantly associated with lower proportions of CD8[+] and CD4[+] T cell subsets that include senescent-like markers of repeated immune system challenges. These immune alterations could have potential implications for the susceptibility of individuals with SCT to various infectious diseases.}, }
@article {pmid39719543, year = {2025}, author = {Guo, H and Malone, KE and Heckbert, SR and Li, CI}, title = {Statin use after cancer diagnosis and survival among patients with cancer.}, journal = {Cancer causes & control : CCC}, volume = {36}, number = {4}, pages = {443-455}, doi = {10.1007/s10552-024-01939-4}, pmid = {39719543}, issn = {1573-7225}, support = {T32CA09168/NH/NIH HHS/United States ; T32CA09168/NH/NIH HHS/United States ; }, mesh = {Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Male ; Aged ; Female ; SEER Program/statistics & numerical data ; *Neoplasms/mortality/diagnosis/drug therapy ; United States/epidemiology ; Aged, 80 and over ; Urinary Bladder Neoplasms/mortality ; Follow-Up Studies ; Survival Rate ; Lung Neoplasms/mortality ; }, abstract = {PURPOSE: The association between statin use and cancer survival has been investigated in previous studies with conflicting findings. This study aimed to assess the association between statin use following cancer diagnosis and survival in six common cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.
METHODS: Individuals aged ≥ 66 years diagnosed with prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, or non-Hodgkin lymphoma (NHL) from 2008 through 2017 were identified. Statin use was defined as two or more statin prescription fills after cancer diagnosis. Time-dependent Cox proportional hazard regression models were used to estimate the association between statin use and cancer-specific mortality for each cancer.
RESULTS: This study included 34,618 patients with prostate cancer (median follow-up 4.0 years), 20,579 with colorectal cancer (2.9 years), 20,133 with lung cancer (1.7 years), 6,163 with bladder cancer (2.1 years), 4,538 with pancreatic cancer (0.8 years), and 3,270 with NHL (2.9 years). Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality in lung cancer (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.74-0.88) and pancreatic cancer (HR, 0.72; 95% CI, 0.59-0.87). The association was not statistically significant for prostate cancer, colorectal cancer, bladder cancer, or NHL. A dose-response relationship by duration of statin use was observed in lung cancer and pancreatic cancer.
CONCLUSION: Statin use after cancer diagnosis appears associated with improved survival in lung cancer and pancreatic cancer. Clinical trials of statin therapy in lung and pancreatic cancer patients are warranted to confirm these findings.}, }
@article {pmid39719506, year = {2024}, author = {Phelps, A and Pazos-Castro, D and Urselli, F and Grydziuszko, E and Mann-Delany, O and Fang, A and Walker, TD and Guruge, RT and Tome-Amat, J and Diaz-Perales, A and Waserman, S and Boonyaratanakornkit, J and Jordana, M and Taylor, JJ and Koenig, JFE}, title = {Author Correction: Production and use of antigen tetramers to study antigen-specific B cells.}, journal = {Nature protocols}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41596-024-01131-7}, pmid = {39719506}, issn = {1750-2799}, }
@article {pmid39718987, year = {2025}, author = {Yalagapati, SP and Ahmadli, U and Sinha, A and Kalidass, M and Dabravolski, S and Zuo, S and Yadala, R and Rutten, T and Talbert, P and Berr, A and Lermontova, I}, title = {Centromeric localization of αKNL2 and CENP-C proteins in plants depends on their centromere-targeting domain and DNA-binding regions.}, journal = {Nucleic acids research}, volume = {53}, number = {4}, pages = {}, pmid = {39718987}, issn = {1362-4962}, support = {LE2299/3-1//German Research Foundation/ ; 03THWST001//WIPANO Wissens und Technologietransfer durch Patente und Nomen/ ; }, mesh = {*Centromere/metabolism/genetics ; *Arabidopsis/genetics/metabolism ; *Chromosomal Proteins, Non-Histone/metabolism/genetics/chemistry ; Nicotiana/genetics/metabolism ; *Arabidopsis Proteins/metabolism/genetics/chemistry ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; Protein Domains ; Binding Sites ; Protein Binding ; Kinetochores/metabolism ; Amino Acid Motifs ; *Plant Proteins/metabolism/genetics/chemistry ; }, abstract = {In eukaryotes, accurate chromosome segregation during cell division relies on the centromeric histone H3 variant, CENH3. Our previous work identified KINETOCHORE NULL2 (αKNL2) as a plant CENH3 assembly factor, which contains a centromere-targeting motif, CENPC-k, analogous to the CENPC motif found in CENP-C. We also demonstrated that αKNL2 can bind DNA in vitro in a sequence-independent manner, without the involvement of its CENPC-k motif. In this study, we show that the CENPC-k and CENPC motifs alone are insufficient for centromere targeting in Nicotiana benthamiana and Arabidopsis thaliana. In silico analysis identified adjacent DNA-binding regions near the CENPC-k and CENPC motifs, suggesting their role in centromeric DNA interaction. We further demonstrated that protein fragments containing these motifs effectively target centromeres. Deletion of these DNA-binding domains reduced the centromeric localization of αKNL2-C, while fusing CENPC-k to the non-specific DNA-binding domain of histone-like nucleoid structuring protein from Escherichia coli successfully targeted it to centromeres. Our findings suggest that the centromeric targeting of αKNL2 and CENP-C proteins relies on the CENPC-k/CENPC motifs, and that their sequence-independent DNA-binding activity enhances their centromere anchoring. These insights into the mechanisms of αKNL2 and CENP-C targeting may facilitate the engineering of kinetochore structures by directing chromatin-modifying proteins to centromeres.}, }
@article {pmid39718828, year = {2024}, author = {Li, D and Geng, K and Hao, Y and Gu, J and Kumar, S and Olson, AT and Kuismi, CC and Kim, HM and Pan, Y and Sherman, F and Williams, AM and Li, Y and Li, F and Chen, T and Thakurdin, C and Ranieri, M and Meynardie, M and Levin, DS and Stephens, J and Chafitz, A and Chen, J and Donald-Paladino, MS and Powell, JM and Zhang, ZY and Chen, W and Ploszaj, M and Han, H and Gu, SS and Zhang, T and Hu, B and Nacev, BA and Kaiza, ME and Berger, AH and Wang, X and Li, J and Sun, X and Liu, Y and Zhang, X and Bruno, TC and Gray, NS and Nabet, B and Wong, KK and Zhang, H}, title = {Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {2}, pages = {}, pmid = {39718828}, issn = {1558-8238}, support = {U01 CA282109/CA/NCI NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA254112/CA/NCI NIH HHS/United States ; K22 CA258805/CA/NCI NIH HHS/United States ; P41 EB017183/EB/NIBIB NIH HHS/United States ; K22 CA276357/CA/NCI NIH HHS/United States ; K22 CA279077/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Proto-Oncogene Proteins p21(ras)/genetics/immunology/metabolism ; *Lung Neoplasms/immunology/genetics/pathology ; Mice ; Mice, Transgenic ; *Tumor Microenvironment/immunology/genetics ; Humans ; *Proteolysis ; CD8-Positive T-Lymphocytes/immunology/pathology ; Disease Models, Animal ; *Mutation, Missense ; Adenocarcinoma of Lung/immunology/genetics/pathology ; }, abstract = {Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.}, }
@article {pmid39718776, year = {2025}, author = {Nascimento de Lima, P and Rutter, CM and van den Puttelaar, R and Hahn, AI and Ozik, J and Collier, N and Zauber, AG and Lansdorp-Vogelaar, I and Inadomi, JM}, title = {Response to Hu, Yang, and Sun.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {3}, pages = {572-573}, pmid = {39718776}, issn = {1460-2105}, support = {U01-CA253913/CA/NCI NIH HHS/United States ; //Cancer Intervention and Surveillance Modeling Network/ ; /NH/NIH HHS/United States ; P30 CA008748/BC/NCI NIH HHS/United States ; }, }
@article {pmid39718625, year = {2024}, author = {Beigrezaei, S and Dianati, M and Salehi-Abargouei, A and Fararouei, M and Akbari-Beni, A and Brinkman, M and White, E and Weiderpass, E and Le Calvez-Kelm, F and Gunter, MJ and Huybrechts, I and Liedberg, F and Skeie, G and Tjonneland, A and Riboli, E and Zeegers, MP and Wesselius, A}, title = {The association between animal protein, plant protein, and their substitution with bladder cancer risk: a pooled analysis of 10 cohort studies.}, journal = {European journal of nutrition}, volume = {64}, number = {1}, pages = {55}, pmid = {39718625}, issn = {1436-6215}, support = {001/WHO_/World Health Organization/International ; FP7-PEOPLE-618308//European Commission/ ; WCRF 2012/590//World Cancer Research Fund International/ ; }, mesh = {Adult ; Aged ; Animals ; Female ; Humans ; Male ; Middle Aged ; Animal Proteins, Dietary/administration & dosage ; Cohort Studies ; Diet/methods/statistics & numerical data ; Dietary Proteins/administration & dosage ; Europe/epidemiology ; Follow-Up Studies ; Plant Proteins/administration & dosage ; Plant Proteins, Dietary/administration & dosage ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; United Kingdom/epidemiology ; United States/epidemiology ; *Urinary Bladder Neoplasms/epidemiology ; }, abstract = {PURPOSE: Although total dietary protein intake has been associated with bladder cancer (BC) risk, the effect of the origin (plant or animal) and the substitutions remain to be understood. This study aimed to investigate the effect of total dietary protein, animal-based protein, plant-based protein, and their substitutions with each other on the risk of BC using a pooled analysis of 10 cohort studies.
METHODS: The study was conducted within the "BLadder cancer Epidemiology and Nutritional Determinants" (BLEND) study, including 10 prospective cohort studies from several European countries, the United Kingdom, and the United States. Individual data from 10 prospective cohorts containing 434,412 participants (overall male/female ratio was almost 3:1) with a total of 4,224,643.8 person-years of follow-up was analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) for BC risk for animal and plant-based protein substitutions of 30gram (g) per day (g/day) were estimated by multivariable adjusted HRs using Cox proportional hazards models.
RESULTS: During 11.4 years of follow-up, among 434,412 participants (73.28% female), 1,440 new cases of BC were identified. After multivariable adjustment, no association was observed between the intake of total, animal-based protein, and plant-based protein and BC risk. Replacement of every 30 g/day of animal-based protein intake by the same amount of plant-based protein intake or vice versa was not associated with the risk of BC.
CONCLUSION: In conclusion, our study found no association between protein intake-whether from animal or plant sources-and the risk of BC. Substituting animal-based protein with plant-based protein, or the reverse, did not influence BC risk. Future studies are required to provide information on the link between animal- and plant-based proteins and BC risk.}, }
@article {pmid39718528, year = {2025}, author = {Drover, CM and Srinivasan, S and Tapia, KA and Munch, M and Rowlinson, E and Chambers, LC and Fiedler, TL and Lowens, MS and Khosropour, CM and Manhart, LE and Fredricks, DN}, title = {Fannyhessea vaginae and Clearance of Lactobacillus iners Are Associated With Incident Nonchlamydial Non- Mycoplasma genitalium Urethritis in Men Who Have Sex With Women.}, journal = {Sexually transmitted diseases}, volume = {52}, number = {5}, pages = {317-324}, pmid = {39718528}, issn = {1537-4521}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI110666/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Urethritis/microbiology/epidemiology ; Male ; Adult ; *Lactobacillus/isolation & purification ; Female ; Mycoplasma genitalium/isolation & purification ; RNA, Ribosomal, 16S/genetics ; Sexual and Gender Minorities ; Young Adult ; Incidence ; Mycoplasma Infections ; }, abstract = {BACKGROUND: The etiology of nongonococcal urethritis (NGU) is incompletely understood. We sought to determine if genitourinary bacterial diversity or specific taxa were associated with incident NGU.
METHODS: From August 2014 to July 2018, men who have sex with women attending a sexual health clinic were clinically evaluated, including Mycoplasma genitalium (MG) and Chlamydia trachomatis (CT) testing, at enrollment and 6 monthly visits. New cases of NGU (≥5 polymorphonuclear leukocytes per high-power field in urethral exudates plus either symptoms or visible discharge) and their visit preceding NGU diagnosis were matched 1:1 to 2 sequential visits without NGU (controls). We determined associations with incident NGU and applied broad-range 16S rRNA gene polymerase chain reaction and sequencing to urine samples from each visit. We used conditional logistic regression to evaluate the association of Shannon Diversity Index, species richness, Haemophilus influenzae , Fannyhessea vaginae, Lactobacillus iners, and Streptococcus mitis group with incident non-CT-non-MG-NGU (NCNM-NGU).
RESULTS: Of 62 matched case-control pairs, median age was 32 years. Higher Shannon Diversity Index the previous month was associated with higher odds of incident NCNM-NGU (adjusted odds ratio [aOR], 2.8 per unit increase; 95% confidence interval [CI], 1.03-7.47), as was F. vaginae at NGU diagnosis (aOR, 5.1; 95% CI, 1.28-20.15), F. vaginae acquisition (aOR, 13.8; 95% CI, 1.96-97.33), and consistent carriage of F. vaginae (aOR, 16.1; 95% CI, 1.66-156.29). Odds of NCNM-NGU were higher when L. iners cleared between visits (aOR, 18.0; 95% CI, 1.08-299.24). Neither the H. influenzae nor S. mitis group was associated with incident NCNM-NGU.
CONCLUSIONS: F. vaginae acquisition/detection and L. iners clearance were associated with urethritis. This merits investigation in larger longitudinal studies using species-specific detection methods.}, }
@article {pmid39717769, year = {2024}, author = {Hou, J and Nakaya, HI}, title = {Editorial: Systems immunology to advance vaccine development.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1527238}, doi = {10.3389/fimmu.2024.1527238}, pmid = {39717769}, issn = {1664-3224}, }
@article {pmid39713477, year = {2024}, author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A}, title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713477}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {In Bayesian phylogenetic and phylodynamic studies it is common to summarise the posterior distribution of trees with a time-calibrated consensus phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel consensus tree method - the highest independent posterior subtree reconstruction, or HIPSTR - contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both consensus trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the consensus tree. HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 data sets show that HIPSTR yields consensus trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥ 0.95) as well as a large number of clades with moderate to high posterior probability (≥ 0.50), whereas HIPSTR achieves near-perfect performance in this respect. HIPSTR also exhibits favorable computational performance over MCC in TreeAnnotator X. Comparison to the recently developed CCD0-MAP algorithm yielded mixed results, and requires more in-depth exploration in follow-up studies. TreeAnnotator X - which is part of the BEAST X (v10.5.0) software package - is available at https://github.com/beast-dev/beast-mcmc/releases.}, }
@article {pmid39713455, year = {2024}, author = {Cucinotta, C and Dell, R and Alavattam, K and Tsukiyama, T}, title = {Sir2 is required for the quiescence-specific condensed three-dimensional chromatin structure of rDNA.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713455}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM139429/GM/NIGMS NIH HHS/United States ; }, abstract = {Quiescence in Saccharomyces cerevisiae is a reversible G0 crucial for long-term survival under nutrient-deprived conditions. During quiescence, the genome is hypoacetylated and chromatin undergoes significant compaction. However, the 3D structure of the ribosomal DNA (rDNA) locus in this state is not well understood. Here, we report that the rDNA locus in quiescent cells forms a distinct condensed loop-like structure, different from structures observed during the mitotic cell cycle. Deletion of SIR2 disrupts this structure, causing it to collapse into a small dot and resulting in quiescence entry and exit defects. In contrast, Sir2 affects rDNA structure only modestly in G2/M phase. In the absence of Sir2, occupancy of both RNA Polymerase II and histone H3 increase at the rDNA locus during quiescence and through quiescence exit, further indicating gross defects in chromatin structure. Together, these results uncover a previously undescribed rDNA chromatin structure specific to quiescent cells and underscore the importance of Sir2 in facilitating the transition between cellular states.}, }
@article {pmid39713327, year = {2024}, author = {Malladi, SK and Jaiswal, D and Ying, B and Alsoussi, WB and Darling, TL and Dadonaite, B and Civljak, A and Horvath, SC and Zhou, JQ and Kim, W and Turner, JS and Schmitz, AJ and Han, F and Scheaffer, SM and Farnsworth, CW and Nachbagauer, R and Nestorova, B and Chalkias, S and Klebert, MK and Edwards, DK and Paris, R and Strnad, BS and Middleton, WD and O'Halloran, JA and Presti, RM and Bloom, JD and Boon, ACM and Diamond, MS and Bajic, G and Ellebedy, AH}, title = {Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713327}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 AI168178/AI/NIAID NIH HHS/United States ; P01 AI172531/AI/NIAID NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; 75N93019C00051/AI/NIAID NIH HHS/United States ; 75N93021C00016/AI/NIAID NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; P01 AI168347/AI/NIAID NIH HHS/United States ; }, abstract = {SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization. We show that 77.8% of the B cell clones in the GC expressed as representative monoclonal antibodies recognized the spike protein, with a third (37.8%) of these targeting the receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent KP.2 variant. mAb-52 utilizes the IGHV3-66 public clonotype, protects hamsters challenged against the EG.5.1 variant and targets the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Finally, we show that the remarkable breadth of mAb-52 is due to the somatic hypermutations accumulated within vaccine-induced GC reaction.}, }
@article {pmid39713041, year = {2024}, author = {Dmello, C and Brenner, A and Piccioni, D and Wen, PY and Drappatz, J and Mrugala, M and Lewis, LD and Schiff, D and Fadul, CE and Chamberlain, M and Kesari, S and Ahluwalia, M and Ghosh, D and Sonabend, AM and Kumthekar, P}, title = {Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae186}, pmid = {39713041}, issn = {2632-2498}, support = {P50 CA221747/CA/NCI NIH HHS/United States ; R01 CA245969/CA/NCI NIH HHS/United States ; R01 NS110703/NS/NINDS NIH HHS/United States ; U19 CA264338/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).
METHODS: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).
RESULTS: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.
CONCLUSION: A dose of 600 mg/m[2] was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.}, }
@article {pmid39712972, year = {2024}, author = {Abad, PJB and Tumulak, MJR and Yoon, SY and Laurino, MY and Hasan, Q}, title = {Bibliometric analysis of genetic counseling publications in Asia: Insights and implications.}, journal = {Genetics in medicine open}, volume = {2}, number = {Suppl 2}, pages = {101861}, pmid = {39712972}, issn = {2949-7744}, abstract = {PURPOSE: Investigation of genetic counseling-related published papers offers a historical assessment of the cumulative scientific knowledge produced by members of the profession and can be the basis for future practice, training, and research. This paper aims to present a bibliometric analysis of genetic counseling publications in Asia.
METHODS: We conducted a bibliometric analysis of genetic counseling-related manuscripts published in Asia from 1947 to 2023. We excluded articles published in 2024 given an incomplete year of data source. The articles were retrieved through the Scopus database using the search terms "genetic counsel∗" OR "genomic counsel∗" in the article titles. The bibliographic information was downloaded and analyzed descriptively through Microsoft Excel. Network visualization was done through VOSViewer.
RESULTS: A total of 449 genetic counseling-related publications authored by at least one researcher from Asian countries were identified. The most common publication type was original articles (332, 74%) and a total of 299 manuscripts were published from 2012 to 2023, representing 66.5% (299/449) of total publications. Among Asian countries, India had the highest number of publications accounting for 19.4% of the total (n = 87) and publications from Israel had the most citations (n = 1882). Out of the 29 Asian countries represented in the document corpus, 15 have links with other Asian countries. The most common keywords used are genetic counseling, prenatal diagnosis, genetic counselling, genetic testing, and genetics.
CONCLUSION: There is an overall increase in the number of genetic counseling publications authored by at least one researcher affiliated with an Asian institution. This increase has corresponded to various developments in genetic counseling in the continent and is possibly driven by collaboration between and among Asian researchers and other researchers outside of Asia. The analysis of keywords also shows the evolution of topics of genetic counseling publications which also corresponded to the development of genetic counseling as a profession in the region.}, }
@article {pmid39712486, year = {2024}, author = {Song, H and Wu, MC}, title = {Multivariate differential association analysis.}, journal = {Stat (International Statistical Institute)}, volume = {13}, number = {2}, pages = {}, pmid = {39712486}, issn = {2049-1573}, support = {R01 GM129512/GM/NIGMS NIH HHS/United States ; }, abstract = {Identifying how dependence relationships vary across different conditions plays a significant role in many scientific investigations. For example, it is important for the comparison of biological systems to see if relationships between genomic features differ between cases and controls. In this paper, we seek to evaluate whether relationships between two sets of variables are different or not across two conditions. Specifically, we assess: do two sets of high-dimensional variables have similar dependence relationships across two conditions? We propose a new kernel-based test to capture the differential dependence. Specifically, the new test determines whether two measures that detect dependence relationships are similar or not under two conditions. We introduce the asymptotic permutation null distribution of the test statistic and it is shown to work well under finite samples such that the test is computationally efficient, significantly enhancing its usability in analyzing large datasets. We demonstrate through numerical studies that our proposed test has high power for detecting differential linear and non-linear relationships. The proposed method is implemented in an R package kerDAA.}, }
@article {pmid39711614, year = {2024}, author = {Visani, GM and Pun, MN and Angaji, A and Nourmohammad, A}, title = {Holographic-(V)AE: An end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space.}, journal = {Physical review research}, volume = {6}, number = {2}, pages = {}, pmid = {39711614}, issn = {2643-1564}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {Group-equivariant neural networks have emerged as an efficient approach to model complex data, using generalized convolutions that respect the relevant symmetries of a system. These techniques have made advances in both the supervised learning tasks for classification and regression, and the unsupervised tasks to generate new data. However, little work has been done in leveraging the symmetry-aware expressive representations that could be extracted from these approaches. Here, we present holographic-(variational) autoencoder [H-(V)AE], a fully end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space, suitable for unsupervised learning and generation of data distributed around a specified origin in 3D. H-(V)AE is trained to reconstruct the spherical Fourier encoding of data, learning in the process a low-dimensional representation of the data (i.e., a latent space) with a maximally informative rotationally invariant embedding alongside an equivariant frame describing the orientation of the data. We extensively test the performance of H-(V)AE on diverse datasets. We show that the learned latent space efficiently encodes the categorical features of spherical images. Moreover, the low-dimensional representations learned by H-VAE can be used for downstream data-scarce tasks. Specifically, we show that H-(V)AE's latent space can be used to extract compact embeddings for protein structure microenvironments, and when paired with a random forest regressor, it enables state-of-the-art predictions of protein-ligand binding affinity.}, }
@article {pmid39711573, year = {2024}, author = {Lamba, J and Marchi, F and Landwehr, M and Schade, AK and Shastri, V and Ghavami, M and Sckaff, F and Marrero, R and Nguyen, N and Mansinghka, V and Cao, X and Slayton, W and Starostik, P and Ribeiro, R and Rubnitz, J and Klco, J and Gamis, A and Triche, T and Ries, R and Kolb, EA and Aplenc, R and Alonzo, T and Pounds, S and Meshinchi, S and Cogle, C and Elsayed, A}, title = {Long-read epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711573}, issn = {2693-5015}, support = {R01 CA132946/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; P30 CA247796/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, abstract = {Acute Myeloid Leukemia (AML) is an aggressive cancer with dismal outcomes, vast subtype heterogeneity, and suboptimal risk stratification. In this study, we harmonized DNA methylation data from 3,314 patients across 11 cohorts to develop the Acute Leukemia Methylome Atlas (ALMA) of diagnostic relevance that predicted 27 WHO 2022 acute leukemia subtypes with an overall accuracy of 96.3% in discovery and 90.1% in validation cohorts. Specifically, for AML, we also developed AML Epigenomic Risk, a prognostic classifier of overall survival (OS) (HR=4.40; 95% CI=3.45-5.61; P<0.0001), and a targeted 38CpG AML signature using a stepwise EWAS-CoxPH-LASSO model predictive of OS (HR=3.84; 95% CI=3.01-4.91; P<0.0001). Finally, we developed a specimen-to-result protocol for simultaneous whole-genome and epigenome sequencing that accurately predicted diagnoses and prognoses from twelve prospectively collected patient samples using long-read sequencing. Our study unveils a new paradigm in acute leukemia management by leveraging DNA methylation for diagnostic and prognostic applications.}, }
@article {pmid39711146, year = {2025}, author = {Nguyen, T and Koric, A and Chang, CE and Barul, C and Radoi, L and Serraino, D and Purdue, MP and Kelsey, KT and McClean, MD and Negri, E and Edefonti, V and Moysich, K and Zhang, ZF and Morgenstern, H and Levi, F and Vaughan, TL and La Vecchia, C and Garavello, W and Hayes, RB and Benhamou, S and Schantz, SP and Yu, GP and Brenner, H and Chuang, SC and Boffetta, P and Hashibe, M and Lee, YA}, title = {Coffee and tea consumption and the risk of head and neck cancer: An updated pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.}, journal = {Cancer}, volume = {131}, number = {2}, pages = {e35620}, pmid = {39711146}, issn = {1097-0142}, support = {T32 CA190194/CA/NCI NIH HHS/United States ; R01 DA011386/DA/NIDA NIH HHS/United States ; R01 CA030022/CA/NCI NIH HHS/United States ; T32CA190194/CA/NCI NIH HHS/United States ; R01 CA100679/CA/NCI NIH HHS/United States ; R03 CA113157/CA/NCI NIH HHS/United States ; P50 CA090388/CA/NCI NIH HHS/United States ; T32CA009142/CA/NCI NIH HHS/United States ; R01 CA078609/CA/NCI NIH HHS/United States ; T32 CA009142/CA/NCI NIH HHS/United States ; U01 CA096134/CA/NCI NIH HHS/United States ; R03 CA077954/CA/NCI NIH HHS/United States ; R21 ES011667/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Coffee/adverse effects ; *Tea ; *Head and Neck Neoplasms/epidemiology/prevention & control ; Male ; Female ; Case-Control Studies ; Middle Aged ; Aged ; Risk Factors ; Adult ; Odds Ratio ; }, abstract = {INTRODUCTION: The relations between coffee and tea consumption and head and neck cancer (HNC) incidence are unclear. With increasing global HNC burden, this study aims to examine the association between coffee, tea, and HNC.
METHODS: A pooled analysis of 9548 HNC cases and 15,783 controls from 14 individual-level case-control studies was conducted from the International Head and Neck Cancer Epidemiology consortium. Random-effects logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for HNC and its subsites, adjusting for sociodemographic and lifestyle factors.
RESULTS: Compared to non-coffee drinkers, drinking >4 cups of caffeinated coffee daily was inversely associated with HNC (OR, 0.83; 95% CI, 0.69-1.00), oral cavity (OR, 0.70; 95% CI, 0.55-0.89), and oropharyngeal cancers (OR, 0.78; 95% CI, 0.61-0.99). Drinking 3-4 cups of caffeinated coffee was inversely associated with hypopharyngeal cancer (OR, 0.59; 95% CI, 0.39-0.91). Drinking decaffeinated coffee and drinking between >0 to <1 cup daily were inversely associated with oral cavity cancer (OR, 0.75; 95% CI, 0.64-0.87 and OR, 0.66; 95% CI, 0.54-0.81). Drinking tea was inversely associated with hypopharyngeal cancer (OR, 0.71; 95% CI, 0.59-0.87). Daily tea consumption of >0 to ≤1 cup was inversely associated with HNC (OR, 0.91; 95% CI, 0.84-0.98) and hypopharyngeal cancer (OR, 0.73; 95% CI, 0.59-0.91), but drinking >1 cup was associated with laryngeal cancer (OR, 1.38; 95% CI, 1.09-1.74).
CONCLUSION: These findings support reduced HNC risk among coffee and tea drinkers. Future studies are needed to address geographical differences in types of coffee and tea to improve our understanding of the association of coffee and tea and global HNC risk.}, }
@article {pmid39710572, year = {2025}, author = {Donzella, SM and VoPham, T and Patel, AV and McCullough, ML and Phipps, AI and Zhong, C}, title = {Associations of sleep duration and weekend catch up sleep with cancer risk among US adults in the Cancer Prevention Study-3 cohort.}, journal = {Sleep health}, volume = {11}, number = {1}, pages = {105-112}, doi = {10.1016/j.sleh.2024.10.011}, pmid = {39710572}, issn = {2352-7226}, mesh = {Humans ; Female ; Middle Aged ; *Sleep/physiology ; United States/epidemiology ; *Neoplasms/epidemiology/prevention & control ; Adult ; Male ; Prospective Studies ; Aged ; Time Factors ; Risk Factors ; Incidence ; Cohort Studies ; Sleep Duration ; }, abstract = {OBJECTIVE: Our objective was to investigate the associations of sleep duration and weekend catch-up sleep with cancer risk among US adults in the Cancer Prevention Study-3.
METHODS: Cancer Prevention Study-3 is a prospective cohort of approximately 250,000 US adults aged 30-65years. At baseline (2006-2013), participants were asked to report their average daily sleep duration over the past year for weekdays and weekends separately. Using the midpoint of each sleep duration category, a 5:2 weekday:weekend weighted average was created. Weekend catch-up sleep was calculated using the difference of weekend and weekday sleep duration category midpoints and categorized as -4 or -2, 0, 2, and 4 hours. Cancer incidence (overall and female breast) was determined via linkage to state registries; follow-up time ended at the time of cancer diagnosis, time of death, or end of follow-up (12/31/2018). We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the associations of sleep duration and weekend catch-up sleep with cancer risk adjusted for sociodemographics, socioeconomic status, comorbidities, and lifestyle behaviors.
RESULTS: A total of 10,256 incident cancer cases were reported among the 248,086 participants included in the study. We found no statistically significant associations between the examined sleep characteristics with overall or breast cancer-specific risk.
CONCLUSION: Our research strengthens the existing null findings of the association between sleep duration and cancer risk. This was the first study to investigate the relationship of weekend catch-up sleep with cancer risk and more research is necessary to further elucidate this relationship.}, }
@article {pmid39709975, year = {2025}, author = {Pelzer, PT and Stuck, L and Martinez, L and Richards, AS and Acuña-Villaorduña, C and Aronson, NE and Bonnet, M and Carvalho, AC and Chan, PC and Huang, LM and Fang, CT and Churchyard, G and Corral-Londoño, HD and Datta, M and Espinal, MA and Fielding, K and Fiore-Gartland, AJ and Garcia-Basteiro, A and Hanekom, W and Hatherill, M and Hill, PC and Huerga, H and Jones-López, EC and Kritski, A and Mandalakas, AM and Mangtani, P and Martins Netto, E and Mayanja, H and Mazahir, R and Murray, M and Rangaka, M and Scriba, T and Singh, J and Singh, S and Stein, CM and Vekemans, J and Verhagen, LM and Villalba, JA and Wajja, A and Watson, B and White, RG and Cobelens, FGJ}, title = {Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data.}, journal = {The Lancet. Microbe}, volume = {6}, number = {2}, pages = {100961}, doi = {10.1016/j.lanmic.2024.100961}, pmid = {39709975}, issn = {2666-5247}, mesh = {Humans ; *BCG Vaccine/immunology/administration & dosage ; *Tuberculosis/prevention & control/epidemiology/immunology ; *Mycobacterium tuberculosis/immunology ; Infant ; Tuberculin Test ; Male ; Female ; Vaccination ; Child, Preschool ; Incidence ; Longitudinal Studies ; Adult ; Adolescent ; Child ; Interferon-gamma Release Tests ; }, abstract = {BACKGROUND: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.
METHODS: We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON IFN-γ release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2 years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.
FINDINGS: We identified 79 studies eligible for full screening and of these, IPD datasets from 14 studies were included in our analysis: 11 household contact studies (29 147 participants), two adolescent cohort studies (11 368 participants), and one randomised controlled trial (2963 participants). Among 28 188 participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491 household contacts, but not among 5644 adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0·7 IU/mL or more with the adjusted hazard ratio (0·65, 95% CI 0·51-0·82) being consistent with that for protection against disease (0·68, 0·18-2·59). Protection against QuantiFERON conversion at cutoff of 0·35 IU/mL or more (0·64, 0·51-0·81) was similar.
INTERPRETATION: Protection from the BCG vaccination against M tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.
FUNDING: Bill & Melinda Gates Foundation.}, }
@article {pmid39709604, year = {2025}, author = {Poluben, L and Nouri, M and Liang, J and Chen, S and Varkaris, A and Ersoy-Fazlioglu, B and Voznesensky, O and Lee, II and Qiu, X and Cato, L and Seo, JH and Freedman, ML and Sowalsky, AG and Lack, NA and Corey, E and Nelson, PS and Brown, M and Long, HW and Russo, JW and Balk, SP}, title = {Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115089}, pmid = {39709604}, issn = {2211-1247}, support = {P50 CA090381/CA/NCI NIH HHS/United States ; R01 CA227237/CA/NCI NIH HHS/United States ; U54 CA156732/CA/NCI NIH HHS/United States ; R01 CA262577/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA259058/CA/NCI NIH HHS/United States ; P50 CA272390/CA/NCI NIH HHS/United States ; R01 CA251555/CA/NCI NIH HHS/United States ; R01 CA272934/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Receptors, Androgen/metabolism/genetics ; *Chromatin/metabolism ; Cell Line, Tumor ; Benzamides ; *NFI Transcription Factors/metabolism ; *Prostatic Neoplasms/genetics/metabolism/pathology ; *Alternative Splicing ; Phenylthiohydantoin/pharmacology/analogs & derivatives ; Nitriles ; Gene Expression Regulation, Neoplastic ; Protein Isoforms/metabolism/genetics ; Prostatic Neoplasms, Castration-Resistant/genetics/metabolism ; }, abstract = {Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.}, }
@article {pmid39709257, year = {2025}, author = {Jindal, T and Jiang, C and Alhalabi, O and Nizam, A and Nguyen, C and Talukder, R and Bakaloudi, D and Davidsohn, M and Freeman, D and Glover, M and Khaki, AR and Evans, S and Lemke, E and Bose, R and Sim, W and Pywell, C and Basu, A and Kilari, D and Barata, PC and Bilen, MA and Zakharia, Y and Milowsky, MI and Shah, SA and Bellmunt, J and Grivas, P and Emamekhoo, H and Davis, NB and Gupta, S and Hoimes, C and Campbell, MT and Alva, A and Koshkin, VS}, title = {Genomic Biomarkers Associated with Enfortumab Vedotin Outcomes for Patients with Advanced Urothelial Carcinoma: Analysis of UNITE Study Data.}, journal = {European urology oncology}, volume = {8}, number = {2}, pages = {258-262}, doi = {10.1016/j.euo.2024.12.006}, pmid = {39709257}, issn = {2588-9311}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Carcinoma, Transitional Cell/drug therapy/genetics/pathology/mortality ; *Antibodies, Monoclonal/therapeutic use ; *Biomarkers, Tumor/genetics ; *Urologic Neoplasms/drug therapy/genetics/pathology ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {Enfortumab vedotin (EV) is used as monotherapy or combined with pembrolizumab in advanced urothelial carcinoma (aUC), but biomarker data associated with EV outcomes are limited. We identified 170 patients in the UNITE study who received EV monotherapy and had molecular biomarker data available. Outcomes for groups with and without a particular biomarker were compared using logistic regression (unadjusted) for the objective response rate (ORR), and a log-rank test and Cox proportional-hazard models (CPHMs) for progression-free survival (PFS) and overall survival (OS) from EV initiation. Molecular biomarkers were also evaluated in separate multivariable analyses using CPHMs that accounted for clinical characteristics. Median patient age was 70 yr; 78% of the cohort were male and 65% had pure UC histology. Median PFS was shorter for patients with CDKN2A alterations (4.6 vs 6 mo; p = 0.024) and for patients with CDKN2B alterations (4.4 vs 6 mo; p = 0.008). Median OS was longer for patients with high tumor mutational burden (13.6 vs 8.3 mo; p = 0.014). ORR was higher for patients with TSC1 alterations (87% vs 51%; p = 0.018). In multivariable analyses, CDKN2A and CDKN2B alterations were associated with inferior median PFS. This multi-institutional retrospective study of patients with aUC identified potential biomarkers associated with EV monotherapy outcomes that should be further investigated. PATIENT SUMMARY: We investigated genetic changes in urinary tract tumors that might be associated with response to enfortumab vedotin (EV) treatment in patients with advanced disease. Survival after EV treatment was longer for tumors with a higher number of mutations than for tumors with fewer mutations. However, mutations in two genes (CDKN2A and CDKN2B) were associated with worse outcomes after EV treatment. These findings will not affect current clinical practice, but should be investigated further in future studies.}, }
@article {pmid39708145, year = {2024}, author = {Klein-Murrey, L and Tirschwell, DL and Hippe, DS and Kharaji, M and Sanchez-Vizcaino, C and Haines, B and Balu, N and Hatsukami, TS and Yuan, C and Akoum, NW and Lila, E and Mossa-Basha, M}, title = {Using clinical data to reclassify ESUS patients to large artery atherosclerotic or cardioembolic stroke mechanisms.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {87}, pmid = {39708145}, issn = {1432-1459}, support = {R01NS125635/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Embolic Stroke/etiology/diagnostic imaging/blood ; Aged ; Middle Aged ; Retrospective Studies ; *Atherosclerosis/complications ; *Machine Learning ; Ischemic Stroke/classification/blood ; Aged, 80 and over ; }, abstract = {PURPOSE: Embolic stroke of unidentified source (ESUS) represents 10-25% of all ischemic strokes. Our goal was to determine whether ESUS could be reclassified to cardioembolic (CE) or large-artery atherosclerosis (LAA) with machine learning (ML) using conventional clinical data.
METHODS: We retrospectively collected conventional clinical features, including patient, imaging (MRI, CT/CTA), cardiac, and serum data from established cases of CE and LAA stroke, and factors with p < 0.2 in univariable analysis were used for creating a ML predictive tool. We then applied this tool to ESUS cases, with ≥ 75% likelihood serving as the threshold for reclassification to CE or LAA. In patients with longitudinal data, we evaluated future cardiovascular events.
RESULTS: 191 ischemic stroke patients (80 CE, 61 LAA, 50 ESUS) were included. Seven and 6 predictors positively associated with CE and LAA etiology, respectively. The c-statistic for discrimination between CE and LAA was 0.88. The strongest predictors for CE were left atrial volume index (OR = 2.17 per 1 SD increase) and BNP (OR = 1.83 per 1 SD increase), while the number of non-calcified stenoses ≥ 30% upstream (OR = 0.34 per 1 SD increase) and not upstream (OR = 0.74 per 1 SD increase) from the infarct were for LAA. When applied to ESUS cases, the model reclassified 40% (20/50), with 11/50 reclassified to CE and 9/50 reclassified to LAA. In 21/50 ESUS with 30-day cardiac monitoring, 1/4 in CE and 3/16 equivocal reclassifications registered cardiac events, while 0/1 LAA reclassifications showed events.
CONCLUSION: ML tools built using standard ischemic stroke workup clinical biomarkers can potentially reclassify ESUS stroke patients into cardioembolic or atherosclerotic etiology categories.}, }
@article {pmid39707483, year = {2024}, author = {Byrne, A and Diener, C and Brown, BP and Maust, BS and Feng, C and Alinde, BL and Gibbons, SM and Koch, M and Gray, CM and Jaspan, HB and Nyangahu, DD}, title = {Neonates exposed to HIV but uninfected exhibit an altered gut microbiota and inflammation associated with impaired breast milk antibody function.}, journal = {Microbiome}, volume = {12}, number = {1}, pages = {261}, pmid = {39707483}, issn = {2049-2618}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Milk, Human/immunology ; *Gastrointestinal Microbiome ; *HIV Infections/immunology/microbiology ; Female ; Infant, Newborn ; *Inflammation ; *Immunoglobulin A/blood ; Feces/microbiology/virology ; Pregnancy ; Bacteria/classification/isolation & purification ; Adult ; Male ; Virome ; C-Reactive Protein/analysis ; }, abstract = {BACKGROUND: Infants exposed to HIV but uninfected have altered immune profiles which include heightened systemic inflammation. The mechanism(s) underlying this phenomenon is unknown. Here, we investigated differences in neonatal gut bacterial and viral microbiome and associations with inflammatory biomarkers in plasma. Further, we tested whether HIV exposure impacts antibody-microbiota binding in neonatal gut and whether antibodies in breast milk impact the growth of commensal bacteria.
RESULTS: Neonates exposed to HIV but uninfected (nHEU) exhibited altered gut bacteriome and virome compared to unexposed neonates (nHU). In addition, HIV exposure differentially impacted IgA-microbiota binding in neonates. The relative abundance of Blautia spp. in the whole stool or IgA-bound microbiota was positively associated with plasma concentrations of C-reactive protein. Finally, IgA from the breast milk of mothers living with HIV displayed a significantly lower ability to inhibit the growth of Blautia coccoides which was associated with inflammation in nHEU.
CONCLUSION: nHEU exhibits profound alterations in gut bacterial microbiota with a mild impact on the enteric DNA virome. Elevated inflammation in nHEU could be due to a lower capacity of breast milk IgA from mothers living with HIV to limit growth the of gut bacteria associated with inflammation. Video Abstract.}, }
@article {pmid39706832, year = {2024}, author = {Jaberi-Douraki, M and Xu, X and Dima, D and Ailawadhi, S and Anwer, F and Mazzoni, S and Valent, J and Habib, MH and Riviere, JE and Raza, S}, title = {Global disparities in drug-related adverse events of patients with multiple myeloma: a pharmacovigilance study.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {223}, pmid = {39706832}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/epidemiology ; Male ; Female ; *Pharmacovigilance ; *Drug-Related Side Effects and Adverse Reactions/epidemiology/etiology ; Middle Aged ; Aged ; Adult ; Antineoplastic Agents/adverse effects/therapeutic use ; }, abstract = {Multiple myeloma (MM) is a complex hematological malignancy of clonal plasma cells driven by alterations to the chromosomal material leading to uncontrolled proliferation in the bone marrow. Ethnic and racial disparities persist in the prevalence, diagnosis, management, and outcomes of MM. These disparities are multifaceted and intersect with various factors, including demographics, geography, socioeconomic status, genetics, and access to healthcare. This study utilized the openFDA human drug adverse events (AEs) to analyze global data pertaining to MM patients and patterns of treatment-related AEs. We identified ten most frequently used drugs and drug regimens in six distinct regions, including North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC), and Latin America & the Caribbean (LA). AE patterns were evaluated using the reporting odds ratio combined with a 95% confidence interval. AE reports were more prevalent in men than in women across all regions. Cardiotoxicities were more likely observed in AS and EU, while secondary neoplasms were more frequently reported in the EU. Nephropathies were prominent in OC, AF (in males), and AS (in females), while vascular toxicity, including embolism and thrombosis, was more common in NA (in males). A notable improvement in survival, particularly in AS, EU, and NA, with a significant decline in death rates was observed. Hospitalization rates displayed less variation in AS and EU but exhibited more pronounced fluctuations in AF, LA, and OC. In conclusion, this comprehensive analysis offers valuable insights into the demographic, geographic, and AE patterns of MM patients across the globe.}, }
@article {pmid39706786, year = {2025}, author = {St-Laurent, MP and Bochner, B and Catto, J and Davies, BJ and Fankhauser, CD and Garg, T and Hamilton-Reeves, J and Master, V and Jensen, BT and Lauridsen, SV and Wulff-Burchfield, E and Psutka, SP}, title = {Increasing Life Expectancy in Patients with Genitourinary Malignancies: Impact of Treatment Burden on Disease Management and Quality of Life.}, journal = {European urology}, volume = {88}, number = {1}, pages = {11-20}, doi = {10.1016/j.eururo.2024.11.026}, pmid = {39706786}, issn = {1873-7560}, mesh = {Humans ; *Quality of Life ; *Life Expectancy ; *Urogenital Neoplasms/therapy/mortality/psychology ; *Cost of Illness ; Patient Reported Outcome Measures ; Disease Management ; Male ; }, abstract = {BACKGROUND AND OBJECTIVE: Treatment burden refers to the overall impact of medical treatments on a patient's well-being and daily life. Our objective is to evaluate the impact of treatment burden on quality of life (QoL) in patients with genitourinary (GU) malignancies, highlighting the importance of patient-reported outcomes (PROs) in clinical trials to inform treatment decisions and improve patient care.
METHODS: We conducted a narrative review of clinical trials focused on GU malignancy (prostate, bladder, and kidney) between January 2000 and June 2024, analyzing related PROs and findings regarding treatment burden.
KEY FINDINGS AND LIMITATIONS: Recent landmark clinical trials demonstrate significant improvements in overall survival across GU malignancies with novel therapies. However, the reporting of QoL outcomes in these trials is often inadequate, with many lacking comprehensive data or long-term impact. Current publications are increasingly evaluating treatment burden and its impact on patient well-being as a critical outcome, but most clinical trials to date have failed to assess treatment burden across key domains including financial, time and travel, and medication management.
While advancements in treatment have extended longevity in patients with GU malignancies, the treatment burden associated with the receipt of novel agents and its implications for QoL remain inadequately uncharacterized.}, }
@article {pmid39706336, year = {2025}, author = {Goyal, L and DiToro, D and Facchinetti, F and Martin, EE and Peng, P and Baiev, I and Iyer, R and Maurer, J and Reyes, S and Zhang, K and Majeed, U and Berchuck, JE and Chen, CT and Walmsley, C and Pinto, C and Vasseur, D and Gordan, JD and Mody, K and Borad, M and Karasic, T and Damjanov, N and Danysh, BP and Wehrenberg-Klee, E and Kambadakone, AR and Saha, SK and Hoffman, ID and Nelson, KJ and Iyer, S and Qiang, X and Sun, C and Wang, H and Li, L and Javle, M and Lin, B and Harris, W and Zhu, AX and Cleary, JM and Flaherty, KT and Harris, T and Shroff, RT and Leshchiner, I and Parida, L and Kelley, RK and Fan, J and Stone, JR and Uboha, NV and Hirai, H and Sootome, H and Wu, F and Bensen, DC and Hollebecque, A and Friboulet, L and Lennerz, JK and Getz, G and Juric, D}, title = {A model for decoding resistance in precision oncology: acquired resistance to FGFR inhibitors in cholangiocarcinoma.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {4}, pages = {426-443}, doi = {10.1016/j.annonc.2024.12.011}, pmid = {39706336}, issn = {1569-8041}, mesh = {Humans ; *Cholangiocarcinoma/drug therapy/genetics/pathology ; *Drug Resistance, Neoplasm/genetics ; *Bile Duct Neoplasms/drug therapy/genetics/pathology ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Precision Medicine/methods ; *Receptor, Fibroblast Growth Factor, Type 2/genetics/antagonists & inhibitors ; Mutation ; Female ; Male ; Middle Aged ; Aged ; *Receptors, Fibroblast Growth Factor/antagonists & inhibitors/genetics ; }, abstract = {BACKGROUND: Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. As with many targeted therapies, however, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.
PATIENTS AND METHODS: This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.
RESULTS: Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared with those without clinical benefit (65% versus 10%, P < 0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.
CONCLUSION: Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.}, }
@article {pmid39705656, year = {2025}, author = {Olivieri, DJ and Banerjee, R}, title = {Impatient for Outpatient: Operationalizing Bispecific Antibodies for Multiple Myeloma in the Ambulatory Setting.}, journal = {JCO oncology practice}, volume = {21}, number = {5}, pages = {596-598}, doi = {10.1200/OP-24-00921}, pmid = {39705656}, issn = {2688-1535}, }
@article {pmid39705106, year = {2024}, author = {Lee, J and Wein, PY and Heffner, JL and Weinberger, AH and Hinds, JT and , }, title = {Practicing inclusive language related to people who are lesbian, gay, bisexual, transgender, queer, intersex, asexual and other sexual and gender identities (LGBTQIA+) in nicotine and tobacco research.}, journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae305}, pmid = {39705106}, issn = {1469-994X}, }
@article {pmid39703032, year = {2025}, author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y}, title = {Response to Zhang and Lv.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {4}, pages = {803-804}, pmid = {39703032}, issn = {1460-2105}, support = {//Irene M. & Fredrick J. Stare Nutrition Education Fund Doctoral Scholarship/ ; //Mayer Fund Doctoral Scholarship/ ; R01CA194393/GF/NIH HHS/United States ; R01 CA260352/GF/NIH HHS/United States ; }, }
@article {pmid39701546, year = {2025}, author = {Perlow, HK and Raleigh, DR and Wang, TJC and Pollom, EL and Milano, MT and Breen, WG and Detsky, J and Chang, EL and Tom, MC and Shiue, KR and Lehrer, EJ and Saeed, H and Pike, LRG and Lo, SS and Mishra, MV and Knisely, JPS and Chao, ST and Sahgal, A and Palmer, JD}, title = {Consensus Radiation Treatment Planning Guidelines Using (68)Ga-DOTATATE PET/CT For Resected Meningiomas.}, journal = {International journal of radiation oncology, biology, physics}, volume = {122}, number = {1}, pages = {150-158}, doi = {10.1016/j.ijrobp.2024.12.003}, pmid = {39701546}, issn = {1879-355X}, mesh = {Humans ; Magnetic Resonance Imaging ; *Meningeal Neoplasms/diagnostic imaging/radiotherapy/surgery ; *Meningioma/diagnostic imaging/radiotherapy/surgery ; *Organometallic Compounds ; *Positron Emission Tomography Computed Tomography/methods ; Prospective Studies ; *Radiopharmaceuticals ; Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods/standards ; *Radiotherapy, Image-Guided/methods ; }, abstract = {PURPOSE: Meningiomas are the most common primary intracranial tumor. Somatostatin receptor 2 is almost universally expressed in meningioma tissue. For patients who require adjuvant radiation, somatostatin receptor based (68)Ga-DOTATATE positron emission tomography (PET) imaging can detect additional or residual disease not discernible on magnetic resonance imaging. PET guided radiation treatments may improve local control, minimize toxicity by allowing for more precise radiation therapy plans, and allow for more precise dose-escalation to maximize local control. The aim of this study was to develop consensus PET guided treatment planning guidelines for common meningioma presentations.
METHODS AND MATERIALS: Five postoperative clinically relevant meningioma cases were selected from a prospective single-institutional registry of patients. Each patient had a preoperative and postoperative contrast-enhanced T1-weighted volumetric magnetic resonance imaging, and a postoperative (68)Ga-DOTATATE PET/CT, to assist with target delineation. The full treatment scenario including clinical history, histology, surgical history, and imaging were provided for each patient. Nineteen international experts who have published on the treatment and management of meningiomas, and who use (68)Ga-DOTATATE PET/CT in their practice, evaluated each case. Individual prescription recommendations were created, pooled, and discussed to create consensus recommendations.
RESULTS: Consensus recommendations were created for each case. In most cases, PET-based contouring allowed for more precise dose-escalation to 66-70 Gy targeting residual disease. When compared to RTOG 0539 and modern clinical trial contouring guidelines, a smaller clinical target volume expansion from the surgical cavity was recommended using PET guided radiation plans in the absence of radiographic or pathologic evidence of brain or bone invasion.
CONCLUSIONS: This report provides consensus target volume delineation guidelines for meningiomas receiving postoperative radiation in common clinical situations. Integration of these guidelines into clinical practice may allow for more precise biomarker guided radiation treatments and standardize radiation therapy on future meningioma clinical trials.}, }
@article {pmid39701289, year = {2025}, author = {Bhatt, NS and Harris, AC and Gorfinkel, L and Ibanez, K and Tkaczyk, ER and Mitchell, SA and Albuquerque, S and Schechter, T and Pavletic, S and Duncan, CN and Rotz, SJ and Williams, K and Carpenter, PA and Cuvelier, GDE}, title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part I. Phases of Chronic GVHD, Supportive Care, and Systemic Therapy Discontinuation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {2}, pages = {69.e1-69.e18}, pmid = {39701289}, issn = {2666-6367}, support = {I01 CX002721/CX/CSRD VA/United States ; IK2 CX001785/CX/CSRD VA/United States ; R01 HL169944/HL/NHLBI NIH HHS/United States ; R13 HL172559/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/therapy/etiology/mortality ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Child ; Chronic Disease ; Adolescent ; Child, Preschool ; *Cell- and Tissue-Based Therapy/methods ; Survivorship ; }, abstract = {Current literature lacks details on the impact of pediatric chronic graft-versus-host disease (cGVHD) on long-term survivorship after allogeneic hematopoietic cell transplantation (HCT). Nonetheless, cGVHD remains a leading cause of post-transplant morbidity and mortality in children and adolescents, which is particularly relevant given the longer life-expectancy after HCT (measured in decades) compared to older adults. To address this knowledge gap, leaders of the Pediatric Transplant and Cellular Therapy Consortium convened a multidisciplinary taskforce of experts in pediatric cGVHD and HCT late effects known as RESILIENT after Chronic GVHD (Research and Education towards Solutions for Late effects to Innovate, Excel, and Nurture after cGVHD). Our goals were to define: (1) the current state of understanding about how cGVHD impacts long-term survivorship in children transplanted <18 yr of age; (2) practical aspects of care to help clinicians managing long-term pediatric cGVHD survivors; and (3) develop a research framework for the next decade to further our knowledge. Four working groups were formed, each tasked with addressing a unique theme: (1) cGVHD natural history (phases of cGVHD) and its impact on clinicians' ability to taper and durably discontinue systemic therapy; (2) organ dysfunction and immune reconstitution in relation to survivorship; (3) how cGVHD and its treatment impact growth, metabolism, and development in children; and (4) psychosocial health and patient reported outcomes. The 4 groups met before the 2024 BMT Tandem Meeting in San Antonio, Texas, and then convened a larger in-person RESILIENT conference held on February 20, 2024, at the Tandem meeting to put forth recommendations from their respective working groups and garner feedback. These recommendations are now presented in a series of 4 manuscripts. This current manuscript focuses on the first theme and discusses the phases of cGVHD, challenges in differentiating clinically active from quiescent cGVHD in clinical practice, and the resultant difficulties in determining when and if to taper systemic therapy. To overcome these challenges, we propose revised categorization of long-term cGVHD outcomes and practical recommendations for clinicians and researchers around the long-term follow-up for these patients, including determining when and if to taper systemic therapy, along with the integration of non-immunosuppressive supportive care interventions.}, }
@article {pmid39701282, year = {2025}, author = {Daoudlarian, D and Segot, A and Latifyan, S and Bartolini, R and Joo, V and Mederos, N and Bouchaab, H and Demicheli, R and Abdelhamid, K and Ferahta, N and Doms, J and Stalder, G and Noto, A and Mencarelli, L and Mosimann, V and Berthold, D and Stravodimou, A and Sartori, C and Shabafrouz, K and Thompson, JA and Wang, Y and Peters, S and Pantaleo, G and Obeid, M}, title = {Tocilizumab and immune signatures for targeted management of cytokine release syndrome in immune checkpoint therapy.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {4}, pages = {444-459}, doi = {10.1016/j.annonc.2024.12.004}, pmid = {39701282}, issn = {1569-8041}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; Male ; Retrospective Studies ; Middle Aged ; *Cytokine Release Syndrome/drug therapy/immunology/blood/diagnosis/chemically induced ; Aged ; *Immune Checkpoint Inhibitors/adverse effects ; *Lymphohistiocytosis, Hemophagocytic/immunology/drug therapy/diagnosis/chemically induced/blood ; *Neoplasms/drug therapy/immunology ; Adult ; Aged, 80 and over ; Sepsis/immunology/diagnosis/drug therapy/blood ; Biomarkers/blood ; Cytokines/blood ; }, abstract = {BACKGROUND: This study aimed to identify specific biomarkers in oncology patients experiencing immune-related cytokine release syndrome (irCRS)-like symptoms during immune checkpoint inhibitor (ICI) therapy, including severe cases like hemophagocytic lymphohistiocytosis (irHLH), and to distinguish these from sepsis. A secondary objective was to retrospectively analyze the efficacy of tocilizumab (TCZ) in treating corticosteroid (CS)-refractory high-grade irCRS.
PATIENTS AND METHODS: A cohort of 35 patients presenting with irCRS-like symptoms was studied, including 9 with irHLH-like manifestations and 8 with sepsis. Immune profiling was carried out using 48 mass cytometry markers, along with an analysis of 45 serum biomarkers, including 27 cytokines and 18 additional markers from the HScore. Twelve patients with high-grade irCRS refractory to CS were treated with TCZ.
RESULTS: Twenty-four biomarkers significantly distinguished between irHLH and grade 3 irCRS (P = 0.0027-0.0455). Hepatocyte growth factor (HGF) and ferritin had superior predictive values compared with the traditional HScore, both with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. CXCL9 differentiated irHLH from grade 3 irCRS and predicted the need for TCZ treatment intensification (PPV = 90%, NPV = 100%). Additional biomarkers, including leukocyte count, neutrophils, ferritin, interleukin (IL)-6, IL-7, epidermal growth factor, fibrinogen, and granulocyte-macrophage colony-stimulating factor (GM-CSF), discriminated sepsis from high-grade irCRS (PPV = 75%-80%, NPV = 100%). Elevated frequencies of CXCR5+ or CCR4+ CD8 memory cells, CD38+ intermediate monocytes, and CD62L+ neutrophils were observed in high-grade irCRS compared with sepsis. All 12 patients with high-grade irCRS refractory to CS treated with TCZ experienced complete resolution.
CONCLUSIONS: This study highlights the importance of specific immunologic biomarkers in determining irCRS severity, predicting outcomes, and distinguishing between irHLH, irCRS, and sepsis. It also demonstrates the efficacy of TCZ in managing high-grade irCRS, underscoring the need for personalized therapeutic strategies based on these biomarkers.}, }
@article {pmid39699563, year = {2024}, author = {Singal, AG and Quirk, L and Boike, J and Chernyak, V and Feng, Z and Giamarqo, G and Kanwal, F and Ioannou, GN and Manes, S and Marrero, JA and Mehta, N and Pillai, A and Shaheen, NJ and Shaukat, A and Sirlin, CB and Verna, E and Wani, S and Wilson Woods, A and Yang, JD and Parikh, ND}, title = {Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified Delphi panel.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, pmid = {39699563}, issn = {1527-3350}, support = {R01 CA212008/CA/NCI NIH HHS/United States ; U01 CA283935/CA/NCI NIH HHS/United States ; U01 CA288375/CA/NCI NIH HHS/United States ; R01 CA255621/CA/NCI NIH HHS/United States ; R01 CA233794/CA/NCI NIH HHS/United States ; R01 CA256977/CA/NCI NIH HHS/United States ; R01 CA282178/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; }, abstract = {HCC surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The experts had high agreement on 21 statements about primary prevention, HCC surveillance benefits, HCC surveillance harms, and the evaluation of emerging surveillance modalities. The experts agreed that current data have methodologic limitations as well as unclear generalizability to Western populations. Although a randomized clinical trial of surveillance versus no surveillance is unlikely feasible, they concurred that alternative designs, such as a comparison of 2 surveillance modalities, could provide indirect evidence of surveillance efficacy. The panel acknowledged the presence of surveillance harms, but concurred the overall value of surveillance appears high, particularly given a greater emphasis on benefits over harms by both patients and clinicians. The experts underscored the importance of a framework for measuring both benefits and harms when evaluating emerging surveillance strategies. The panel acknowledged performance metrics of emerging methods may differ from other cancer screening programs given differences in populations, including higher risk of cancer development and competing risk of morality, and differences in diagnostic workflow in patients at risk of HCC. These data provide insights into the perceived value of HCC surveillance in an era of emerging blood- and imaging-based surveillance strategies.}, }
@article {pmid39699239, year = {2025}, author = {Weiss, NS}, title = {Reducing-a little-the high price of randomized trials of the efficacy of multicancer early detection.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {3}, pages = {391-392}, pmid = {39699239}, issn = {1460-2105}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; }, }
@article {pmid39699103, year = {2025}, author = {Choe, M and Campbell, M and Albert, CM}, title = {Advances in cellular therapies for children and young adults with solid tumors.}, journal = {Current opinion in pediatrics}, volume = {37}, number = {1}, pages = {67-74}, pmid = {39699103}, issn = {1531-698X}, mesh = {Humans ; *Neoplasms/therapy/immunology ; Child ; *Immunotherapy, Adoptive/methods ; *Tumor Microenvironment/immunology ; Young Adult ; Adolescent ; Receptors, Chimeric Antigen/immunology ; }, abstract = {PURPOSE OF REVIEW: Adoptive immunotherapy brings hope to children and young adults diagnosed with high-risk solid tumors. Cellular (cell) therapies such as chimeric antigen receptor (CAR) T cell, CAR natural killer (NK) cell, and T cell receptor (TCR) T cell therapy are potential avenues of targeted therapy with limited long-term toxicities. However, development of cell therapies for solid tumors is in its nascent stages. Here, we will review the current clinical experience, barriers to efficacy, and strategies to improve clinical response and patient access.
RECENT FINDINGS: Cell therapies are shown to be generally safe and well tolerated. Strategies to optimize antitumor activity have now moved into early-phase trials. The immunosuppressive tumor microenvironment remains a major barrier to efficacy, and efforts are underway to gain better understanding. This will inform future treatment strategies to enhance the antitumor activity of cell therapies.
SUMMARY: Clinical experiences to date provide important insights on how to leverage cell therapies against solid tumors. Key factors in advancing the field include a better understanding of immune cell biology, tumor cell behavior, and the tumor microenvironment. Lastly, improving access to novel cell therapies remains an important consideration in the conduct of clinical trials and for future implementation into standard practice.}, }
@article {pmid39698781, year = {2025}, author = {Ghosh, N and Eyre, TA and Brown, JR and Lamanna, N and Manzoor, BS and Coombs, CC and Tuncer, HH and Ujjani, C and Leslie, LA and Roeker, LE and Davids, MS and Rhodes, JM and Skarbnik, AP and Sinai, W and Fleury, I and Hill, BT and Martinez-Calle, N and Barr, PM and Jawaid, D and Emechebe, N and Pearson, L and Lansigan, F and Choi, Y and Jensen, CE and Fakhri, B and Stephens, DM and Marx, SE and Schuster, SJ and Coyle, M and Pivneva, I and Watson, T and Guerin, A and Shadman, M}, title = {Treatment Effectiveness of Venetoclax-Based Therapy After Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: An International Real-World Study.}, journal = {American journal of hematology}, volume = {100}, number = {3}, pages = {511-515}, pmid = {39698781}, issn = {1096-8652}, support = {//AbbVie/ ; }, }
@article {pmid39695226, year = {2025}, author = {Lee, S and Kibler, RD and Ahn, G and Hsia, Y and Borst, AJ and Philomin, A and Kennedy, MA and Huang, B and Stoddard, B and Baker, D}, title = {Four-component protein nanocages designed by programmed symmetry breaking.}, journal = {Nature}, volume = {638}, number = {8050}, pages = {546-552}, pmid = {39695226}, issn = {1476-4687}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R01 AG063845/AG/NIA NIH HHS/United States ; S10 OD018483/OD/NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; }, mesh = {Models, Molecular ; *Nanostructures/chemistry/ultrastructure ; Protein Multimerization ; *Proteins/chemistry/ultrastructure ; }, abstract = {Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures[1,2]. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry[3-9], but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein-protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates[10,11] and targeted delivery vehicles[12,13].}, }
@article {pmid39695145, year = {2024}, author = {Kibler, RD and Lee, S and Kennedy, MA and Wicky, BIM and Lai, SM and Kostelic, MM and Carr, A and Li, X and Chow, CM and Nguyen, TK and Carter, L and Wysocki, VH and Stoddard, BL and Baker, D}, title = {Design of pseudosymmetric protein hetero-oligomers.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10684}, pmid = {39695145}, issn = {2041-1723}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; R01 GM139752/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; ALTF 139-2018//European Molecular Biology Organization (EMBO)/ ; S10 OD021832/OD/NIH HHS/United States ; HHSN272201700059C/AI/NIAID NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; shared instrumentation grant S10OD021832//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RM1 GM149374/GM/NIGMS NIH HHS/United States ; #OPP1156262//Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)/ ; DGE-1762114//National Science Foundation (NSF)/ ; INV-010680/GATES/Gates Foundation/United States ; S10 OD018483/OD/NIH HHS/United States ; }, mesh = {*Protein Multimerization ; Models, Molecular ; Protein Engineering/methods ; Protein Subunits/chemistry/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging unsolved problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign tasks, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 19 new homo-oligomers and structurally recombined them to make 24 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system have identical or nearly identical backbones, and hence are ideal building blocks for generating and functionalizing larger symmetric and pseudosymmetric assemblies.}, }
@article {pmid39693737, year = {2025}, author = {Zhang, Y and Spitzer, BW and Zhang, Y and Wallace, DA and Yu, B and Qi, Q and Argos, M and Avilés-Santa, ML and Boerwinkle, E and Daviglus, ML and Kaplan, R and Cai, J and Redline, S and Sofer, T}, title = {Untargeted metabolome atlas for sleep-related phenotypes in the Hispanic community health study/study of Latinos.}, journal = {EBioMedicine}, volume = {111}, number = {}, pages = {105507}, pmid = {39693737}, issn = {2352-3964}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Biomarkers ; *Hispanic or Latino ; *Metabolome ; *Metabolomics/methods ; Phenotype ; *Sleep ; *Sleep Wake Disorders/metabolism ; United States ; }, abstract = {BACKGROUND: Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep-related phenotypes and blood metabolites.
METHODS: Utilising data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep-related phenotypes, grouped in several domains (sleep disordered breathing (SDB), sleep duration, sleep timing, self-reported insomnia symptoms, excessive daytime sleepiness (EDS), and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualise and interpret the associations between sleep phenotypes and metabolites.
FINDINGS: The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, primary bile acid metabolism showed the highest cumulative percentage of statistically significant associations across all sleep phenotype domains except for SDB and EDS phenotypes. Several metabolites were associated with multiple sleep phenotypes, from a few domains. Glycochenodeoxycholate, vanillyl mandelate (VMA) and 1-stearoyl-2-oleoyl-GPE (18:0/18:1) were associated with the highest number of sleep phenotypes, while pregnenolone sulfate was associated with all sleep phenotype domains except for sleep duration. N-lactoyl amino acids such as N-lactoyl phenylalanine (lac-Phe), were associated with sleep duration, SDB, sleep timing and heart rate during sleep.
INTERPRETATION: This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.
FUNDING: R01HL161012, R35HL135818, R01AG80598.}, }
@article {pmid39693591, year = {2025}, author = {Kalinsky, K and Bianchini, G and Hamilton, E and Graff, SL and Park, KH and Jeselsohn, R and Demirci, U and Martin, M and Layman, RM and Hurvitz, SA and Sammons, S and Kaufman, PA and Muñoz, M and Lai, JI and Knoderer, H and Sandoval, C and Chawla, AR and Nguyen, B and Zhou, Y and Ravenberg, E and Litchfield, LM and Smyth, L and Wander, SA}, title = {Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {9}, pages = {1101-1112}, pmid = {39693591}, issn = {1527-7755}, mesh = {Humans ; Female ; *Fulvestrant/administration & dosage/adverse effects ; *Aminopyridines/administration & dosage/adverse effects ; *Breast Neoplasms/drug therapy/pathology/genetics/enzymology ; *Benzimidazoles/administration & dosage/adverse effects ; Double-Blind Method ; *Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Aged ; Adult ; Disease Progression ; Progression-Free Survival ; Protein Kinase Inhibitors/therapeutic use/adverse effects ; }, abstract = {PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.
METHODS: This double-blind, randomized phase III study enrolled patients with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i + ET. Patients were randomly assigned (1:1) to abemaciclib + fulvestrant or placebo + fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review, objective response rate (ORR), and safety.
RESULTS: This study randomly assigned 368 patients (abemaciclib + fulvestrant, n = 182 placebo + fulvestrant, n = 186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; nominal P = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; nominal P < .001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib + fulvestrant versus placebo + fulvestrant (17% v 7%; nominal P = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.
CONCLUSION: Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.}, }
@article {pmid39693117, year = {2025}, author = {Kresovich, JK and Richards, AR and Ergas, IJ and Cannioto, R and Thomsen, C and Laurent, CA and Shariff-Marco, S and Rillamas-Sun, E and Kolevska, T and Yao, S and Ambrosone, C and Kushi, L and Greenlee, H and Kwan, ML}, title = {Physical activity and incident cardiovascular disease in breast cancer survivors: the Pathways Study.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {1}, pages = {}, pmid = {39693117}, issn = {2515-5091}, support = {R01 CA214057/CA/NCI NIH HHS/United States ; U01 CA195565/CA/NCI NIH HHS/United States ; R01CA214057/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/therapy/epidemiology ; *Cardiovascular Diseases/epidemiology/prevention & control/etiology ; *Exercise ; Middle Aged ; *Cancer Survivors/statistics & numerical data ; Prospective Studies ; Aged ; Incidence ; Adult ; Proportional Hazards Models ; Risk Factors ; }, abstract = {BACKGROUND: Breast cancer survivors experience higher rates of cardiovascular disease (CVD) than women without breast cancer, due in part to cardiotoxic cancer treatments and shared lifestyle risk factors. Physical activity is associated with lower mortality risk in breast cancer survivors, but associations with CVD have not been examined in detail.
METHODS: The Pathways Study is a prospective cohort study of 4504 women diagnosed with invasive breast cancer between 2005 and 2013. At enrollment, women self-reported their physical activities during the previous 6 months, which were dichotomized as meeting the Centers for Disease Control and Prevention's Physical Activity Guidelines for Americans (≥150 minutes of moderate-intensity or ≥75 minutes of vigorous-intensity activity per week) vs not. Incident CVD events (heart failure, cardiomyopathy, cardiac arrest, ischemic heart disease, stroke) occurring between enrollment and December 2021 were identified from electronic health records. Covariate-adjusted, competing-risks Cox regression models estimated associations between meeting physical activity guidelines and CVD risk.
RESULTS: Compared with women who did not meet physical activity guidelines at their diagnosis, those who did had a 25% lower risk of CVD (HR = 0.75, 95% CI = 0.60 to 0.94). Among the individual CVD outcomes, meeting physical activity guidelines was protective against incident cardiomyopathy (hazard ratio [HR] = 0.54, 95% CI = 0.31 to 0.95), heart failure (HR = 0.66, 95% CI = 0.50 to 0.87), and cardiac arrest (HR = 0.68, 95% CI = 0.49 to 0.99).
CONCLUSIONS: Meeting physical activity guidelines at breast cancer diagnosis was associated with lower risk of CVD after diagnosis. Studies investigating changes in physical activity after a breast cancer diagnosis and CVD risk are warranted.}, }
@article {pmid39691260, year = {2024}, author = {Ho, C and Zhu, S and Gooley, T and Gujral, TS and Lynch, RC and Poh, C and Shadman, M and Smith, SD and Tseng, Y and Gopal, AK}, title = {A phase 2 study of frontline pembrolizumab in follicular lymphoma.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1173-1181}, pmid = {39691260}, issn = {2688-6146}, abstract = {BACKGROUND: The tumor microenvironment (TME), including infiltrating T-cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death-1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B-cell lymphoma.
METHODS: Adults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200 mg IV in 21-day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1.
RESULTS: Nine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high-tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET-CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow-up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune-related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected.
CONCLUSION: Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.}, }
@article {pmid39691254, year = {2024}, author = {Naru, J and Othus, M and Lin, C and Biernacki, MA and Bleakley, M and Chauncey, TR and Erba, HP and Fang, M and Fitzgibbon, MP and Gafken, PR and Ivey, RG and Kennedy, JJ and Lorentzen, TD and Meshinchi, S and Moseley, A and Pogosova-Agadjanyan, EL and Liu, VM and Radich, JP and Voytovich, UJ and Wang, P and Whiteaker, JR and Willman, CL and Wu, F and Paulovich, AG and Stirewalt, DL}, title = {Proteogenomic characterization of highly enriched viable leukemic blasts in acute myeloid leukemia: A SWOG report.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1243-1251}, pmid = {39691254}, issn = {2688-6146}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; U01 CA214114/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Acute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.
METHODS: Given the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next-generation sequencing and mass spectrometry-based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.
RESULTS: We identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein-RNA correlation.
CONCLUSION: Together, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.}, }
@article {pmid39691239, year = {2024}, author = {Teymouri, F and Sebastian, G and Gem, H and Minot, SS and Rashidi, A}, title = {Oral acute graft-versus-host disease.}, journal = {EJHaem}, volume = {5}, number = {6}, pages = {1290-1294}, pmid = {39691239}, issn = {2688-6146}, abstract = {Oral acute graft-versus-host disease (aGVHD) is rare and with no diagnostic criteria. We report a case of oral aGVHD with three clinical phases. A self-limited prodrome of largely subjective oral symptoms was followed by concurrent oral and upper gastrointestinal aGVHD. Six months after transplantation, the patient was diagnosed with severe oral and upper gastrointestinal chronic GVHD. We compared the salivary microbiota of our patient at the time of diagnosis of aGVHD with 50 contemporaneous transplant recipients and found no evidence for oral microbiota involvement in pathogenesis. This in-depth N-of-1 analysis reveals novel aspects of oral aGVHD pathogenesis.}, }
@article {pmid39690453, year = {2025}, author = {Do, OA and Ohlsen, TJD and Shipman, KJ and Ballard, SA and Jenssen, KM and Baker, KS and Rosenberg, AR and Barton, KS and Bhatt, NS}, title = {Return-to-School Experiences of Adolescents After Allogeneic Hematopoietic Cell Transplant: A Qualitative Interview Study of Transplant Recipients.}, journal = {Pediatric blood & cancer}, volume = {72}, number = {3}, pages = {e31481}, doi = {10.1002/pbc.31481}, pmid = {39690453}, issn = {1545-5017}, support = {//Ben Towne Center for Childhood Cancer and Blood Disorders Research Pilot Award program/ ; //Seattle Children's Research Institute and Rally Foundation for Childhood Cancer Research/ ; //Independent Investigator Award/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; Adolescent ; Male ; Female ; Child ; *Quality of Life ; Qualitative Research ; *Schools ; Transplantation, Homologous ; *Transplant Recipients/psychology ; Follow-Up Studies ; Prognosis ; Social Support ; }, abstract = {BACKGROUND: Returning to school after allogeneic hematopoietic cell transplant (HCT) can improve quality of life and promote positive adjustment. However, this process may be challenging, and there is a limited understanding of school-aged children and adolescents' perspectives on this process.
METHODS: We conducted semi-structured interviews over video with pediatric recipients of HCT (10-18 years of age at HCT; 1-7 years post HCT) who were treated at our institution and had returned to in-person school post HCT. We performed a thematic network analysis focused on exploring salient challenges regarding the return-to-school process post HCT and potential areas for improvement.
RESULTS: We interviewed 16 participants (mean age 13.8 years at HCT). Four themes emerged: (i) challenges of returning to school, (ii) keys for a successful return-to-school experience, (iii) overall perceptions of the process, and (iv) recommendations for improvement. HCT recipients described several social/emotional, physical, and academic challenges while returning to school and cited strong sources of support as critical to a successful transition. Recommendations for a better transition process included the following: (a) fostering peer support, (b) establishing social connections, (c) providing mental health support, (d) identifying a go-to point of contact for issues, and (e) maintaining academic support.
CONCLUSIONS: Our findings highlight perspectives from school-aged recipients of HCT regarding gaps in support and areas for improvement to facilitate successful return to school after HCT. Additional assistance throughout the process may optimize academic and social reintegration and support recovery after HCT.}, }
@article {pmid39689462, year = {2025}, author = {Biesma, NC and Graus, MUJE and Cirkel, GA and Besselink, MG and de Groot, JWB and Koerkamp, BG and Herbschleb, KH and Los, M and Verdonk, RC and Wilmink, JW and Cervantes, A and Valle, JW and Valkenburg-van Iersel, LBJ and Froeling, FEM and Molenaar, IQ and Daamen, LA and de Vos-Geelen, J and van Santvoort, HC and , }, title = {Perspectives of the medical oncologist regarding adjuvant chemotherapy for pancreatic cancer: An international expert survey and case vignette study.}, journal = {European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology}, volume = {51}, number = {3}, pages = {109544}, doi = {10.1016/j.ejso.2024.109544}, pmid = {39689462}, issn = {1532-2157}, mesh = {Humans ; *Pancreatic Neoplasms/drug therapy/surgery ; Chemotherapy, Adjuvant ; *Carcinoma, Pancreatic Ductal/drug therapy/surgery ; *Oncologists ; Male ; Female ; *Practice Patterns, Physicians'/statistics & numerical data ; Surveys and Questionnaires ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Attitude of Health Personnel ; Pancreatectomy ; Oxaliplatin/therapeutic use ; Fluorouracil/therapeutic use ; Aged ; Leucovorin/therapeutic use ; Adult ; Irinotecan ; }, abstract = {INTRODUCTION: Adjuvant chemotherapy improves survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). The decision to initiate chemotherapy involves both patient and physician factors, decision-specific criteria, and contextual considerations. This study aimed to assess medical oncologists' views on adjuvant chemotherapy following pancreatic resection for PDAC.
METHODS: An online survey and case vignette study were distributed to medical oncologists via the Dutch Pancreatic Cancer Group (DPCG), International Hepato-Pancreato-Biliary Association (IHPBA) and related networks.
RESULTS: A total of 91 oncologists from 14 countries participated, 46 % of whom treated more than 40 new PDAC patients annually, with a median experience of 15 years. Significant discrepancies were noted in their recommendations for adjuvant chemotherapy across case vignettes. In patients over 70, 17 % advised against chemotherapy, while 31 % said age was not a factor. Oncologists with less than 10 years of experience and those in non-academic settings were less likely to recommend adjuvant therapy. While 87 % agreed mFOLFIRINOX is the preferred adjuvant treatment, consensus on individual cases was lacking. The recommended interval between surgery and chemotherapy ranged from 3 to 26 weeks, with varying reasons for withholding treatment, primarily due to postoperative recovery and performance status.
CONCLUSIONS: Our study revealed substantial variation among oncologists in counseling on adjuvant chemotherapy after PDAC resection. This emphasizes the need for more patient involvement in decision-making and improving shared decision-making.}, }
@article {pmid39689429, year = {2024}, author = {Hodan, R and Gupta, S and Weiss, JM and Axell, L and Burke, CA and Chen, LM and Chung, DC and Clayback, KM and Felder, S and Foda, Z and Giardiello, FM and Grady, W and Gustafson, S and Hagemann, A and Hall, MJ and Hampel, H and Idos, G and Joseph, N and Kassem, N and Katona, B and Kelly, K and Kieber-Emmons, A and Kupfer, S and Lang, K and Llor, X and Markowitz, AJ and Prats, MM and Niell-Swiller, M and Outlaw, D and Pirzadeh-Miller, S and Samadder, NJ and Shibata, D and Stanich, PP and Swanson, BJ and Szymaniak, BM and Welborn, J and Wiesner, GL and Yurgelun, MB and Dwyer, M and Darlow, S and Diwan, Z}, title = {Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {10}, pages = {695-711}, doi = {10.6004/jnccn.2024.0061}, pmid = {39689429}, issn = {1540-1413}, mesh = {Humans ; Female ; *Endometrial Neoplasms/genetics/diagnosis ; *Genetic Testing/standards/methods ; Risk Assessment/methods ; *Genetic Predisposition to Disease ; Colorectal Neoplasms/genetics/diagnosis ; Stomach Neoplasms/genetics/diagnosis/therapy ; Neoplastic Syndromes, Hereditary/diagnosis/genetics/therapy ; Medical Oncology/standards/methods ; Male ; }, abstract = {Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.}, }
@article {pmid39689352, year = {2024}, author = {Vutien, P and Barnard Giustini, A and Kim, NJ and Moon, AM and Hsu, CN and Mezzacappa, C and Borgerding, JA and Johnson, KM and VoPham, T and Berry, K and Beste, LA and Kaplan, DE and Taddei, TH and Ioannou, GN}, title = {Validation and expansion of Baveno VII criteria for cACLD and CSPH based on liver stiffness and platelet count: Correlation with risk of hepatic decompensation and death.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, pmid = {39689352}, issn = {1527-3350}, abstract = {BACKGROUND AND AIMS: Recently proposed "Rule-of-Five" criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes.
APPROACH AND RESULTS: Patients without prior hepatic decompensation or HCC who underwent LS and platelet measurements (n = 17,076) were categorized as follows: no cACLD (LS: 2.5-9.9 kPa); probable cACLD (LS: 10-14.9 kPa); certain cACLD-no CSPH (LS: 15-19.9 kPa and platelets ≥110,000/µL or LS 20-24.9 kPa and platelets ≥150,000/µL); probable CSPH (LS 15-19.9 kPa and platelets <110,000/µL or LS 20-24.9 and platelets <150,000/µL); and certain CSPH (LS ≥25 kPa), which we further subdivided into 25-49.9 and 50-75 kPa.During a median follow-up of 2.82 years, each increase in the "Rule-of-Five" category was associated linearly with higher risks of death (HR: 1.22, 95% CI: 1.18-1.25) and decompensation (HR: 1.52, 95% CI: 1.46-1.58). Compared to patients with LS 25-49.9 kPa, those with LS 50-75 kPa ("critical" CSPH) had approximately double the risk of decompensation (11.24 vs. 4.20 per 100 patient-years) and death (9.85 vs. 6.98 per 100 patient-years).
CONCLUSIONS: The Baveno VII "Rule-of-Five" criteria provide a valid system for stratifying risks of death and hepatic decompensation and should be used routinely in patients with chronic liver disease. Among patients with CSPH (LS ≥25 kPa), the subgroup with LS 50-75 kPa ("critical" CSPH) has approximately double the risk of death and hepatic decompensation than LS 25-49.9 kPa.}, }
@article {pmid39688693, year = {2024}, author = {Ohlsen, TJD and Hale, MR and Larson, AJ and Jones, SMW and Wilkinson, F and Chow, EJ and Ko, LK and Desai, AD}, title = {Financial toxicity among pediatric oncology families during therapy and early survivorship: a qualitative analysis.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {1}, pages = {36}, pmid = {39688693}, issn = {1433-7339}, mesh = {Humans ; Female ; Male ; *Qualitative Research ; *Neoplasms/psychology/therapy/economics ; Child ; Adult ; *Caregivers/psychology/economics ; Adolescent ; Middle Aged ; Child, Preschool ; Interviews as Topic ; Cost of Illness ; Survivorship ; Family/psychology ; Young Adult ; Cancer Survivors/psychology ; }, abstract = {PURPOSE: Cancer treatment often results in adverse financial consequences-also termed financial toxicity. To build upon limited research in pediatric oncology, we conducted a qualitative study exploring families' lived experiences with financial toxicity and their perspectives on potential mitigation strategies.
METHODS: We conducted in-depth semi-structured interviews with a purposive sample of English- and Spanish-speaking family caregivers, 3-24 months following diagnosis. We performed a thematic analysis focused on elucidating relationships between components/domains of financial toxicity, identifying mitigating and exacerbating factors, eliciting latent constructs for measurement, and querying caregivers' perspectives on interventions. We organized relationships between themes into a framework to compare with prior theoretically derived models.
RESULTS: We interviewed 21 caregivers, diverse with respect to income, age, race and ethnicity, family structure/composition, and patient characteristics. We identified four themes relating to financial toxicity: increased spending on providing care to patients/siblings, reduced income due to challenges in maintaining employment, new or worsened material hardship, and heightened psychological distress regarding finances. We also identified an additional theme pertaining to response behaviors directed at managing financial toxicity, with helpful or harmful downstream effects. Factors that exacerbated or lessened financial toxicity included awareness of resources, geography, and community. Caregivers suggested potential mitigation strategies, including proactive education and resource provision.
CONCLUSION: Pediatric patients and families can experience substantial financial impacts, which may differ from experiences of adults with cancer. These findings suggest a need for careful screening and measurement, as well as family-centered interventions and policies to reduce long-term consequences.}, }
@article {pmid39687983, year = {2024}, author = {Williams, JT and Goodpaster, TA and Haraguchi, M}, title = {Optimizing tissue adherence on glass slides using polyurethane glue: a new slide preparation method.}, journal = {Journal of histotechnology}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/01478885.2024.2440679}, pmid = {39687983}, issn = {2046-0236}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {The application of Clear Gorilla Glue® household adhesive to microscope slides has been found to enhance the mounting and retention of traditionally difficult tissue types, notably bone and tooth specimens. Improvement in end results were observed across H&E staining, immunohistochemistry, and in situ hybridization.}, }
@article {pmid39682018, year = {2025}, author = {Boiko, JR and Hill, GR}, title = {Chronic Graft-versus-host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation.}, journal = {Transplantation}, volume = {109}, number = {6}, pages = {955-966}, pmid = {39682018}, issn = {1534-6080}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; }, abstract = {Chronic graft-versus-host disease (cGVHD) remains a frequent and morbid outcome of allogeneic hematopoietic cell transplantation (HCT), in which the donor-derived immune system attacks healthy recipient tissue. Preceding tissue damage mediated by chemoradiotherapy and alloreactive T cells compromise central and peripheral tolerance mechanisms, leading to aberrant donor T cell and germinal center B cell differentiation, culminating in pathogenic macrophage infiltration and differentiation in target tissue, with ensuant fibrosis. This process results in a heterogeneous clinical syndrome with significant morbidity and mortality, frequently requiring prolonged therapy. In this review, we discuss the processes that interrupt immune tolerance, the subsequent clinical manifestations, and new FDA-approved therapeutic approaches that have been born from a greater understanding of disease pathogenesis in preclinical systems, linking to parallel processes following solid organ transplantation.}, }
@article {pmid39681126, year = {2025}, author = {Velloza, J and Poovan, N and Meisner, A and Ndlovu, N and Ndimande-Khoza, N and Grabow, C and Zwane, P and Mbele, S and Molefe, M and Donnell, D and Baeten, JM and Hosek, S and Celum, C and Delany-Moretlwe, S}, title = {Adaptive HIV pre-exposure prophylaxis adherence interventions for young women in Johannesburg, South Africa: a sequential multiple-assignment randomised trial.}, journal = {The lancet. HIV}, volume = {12}, number = {2}, pages = {e105-e117}, doi = {10.1016/S2352-3018(24)00268-6}, pmid = {39681126}, issn = {2352-3018}, mesh = {Humans ; Female ; *HIV Infections/prevention & control/drug therapy ; *Pre-Exposure Prophylaxis/methods ; South Africa/epidemiology ; Young Adult ; Adult ; Adolescent ; *Medication Adherence ; *Anti-HIV Agents/therapeutic use/administration & dosage ; Tenofovir/therapeutic use/administration & dosage ; Adherence Interventions ; }, abstract = {BACKGROUND: Adherence to daily oral pre-exposure prophylaxis (PrEP) is low among African young women, and layered support strategies are needed to improve PrEP adherence in this population. We aimed to evaluate potentially scalable adherence-support strategies for young women aged 18-25 years who initiated PrEP in Johannesburg, South Africa.
METHODS: We conducted a sequential multiple-assignment randomised trial at Ward 21 of the Wits Reproductive Health and HIV Institute clinical research site, affiliated with University of the Witwatersrand, Johannesburg, South Africa. Participants were eligible if they were assigned female sex at birth, aged 18-25 years, not living with HIV, sexually active, newly initiating PrEP, had regular access to a mobile telephone, and could read. Using sequentially numbered, sealed, opaque envelopes containing group allocation, a staff member assigned enrolled participants (1:1) to receive one of two adherence-support interventions: once per week two-way SMS communication or participation in a WhatsApp peer-support group. Participants assigned to WhatsApp were put into groups with approximately 25 participants, during which they were prompted by staff facilitators to discuss any challenges with PrEP use or other events happening in their lives. The allocation sequence was generated by the data manager using random numbers with variable block sizes between 10 and 14. Only trial investigators were masked to participant intervention assignments; participants, people giving interventions, people assessing outcomes, and people analysing data were not masked to group assignment. All enrolled participants were offered PrEP (ie, co-formulated, once per day oral emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg). The primary outcome was high PrEP adherence at month 9, defined as concentration of tenofovir diphosphate on dried blood sample of 700 fmol per punch or more. At month 3, participants with low PrEP adherence were randomly assigned to a secondary, intensified intervention of issue-focused counselling once per month or drug-level feedback counselling based on PrEP drug concentrations at months 3 and 6. The protocol was registered at ClinicalTrials.gov (NCT04038060) and the trial is complete.
FINDINGS: Participants were enrolled and followed up between May 16, 2019, and Jan 25, 2022. From May 16, 2019, to Jan 29, 2021, 401 participants were screened and 360 were enrolled and initiated PrEP. 180 (50%) were randomly assigned to two-way SMS and 180 (50%) were randomly assigned to WhatsApp support groups. At month 9, 34 (20%) of 174 participants in the two-way SMS arm had tenofovir diphosphate 700 fmol per punch or more, compared with 32 (18%) of 174 in the WhatsApp arm (relative risk 1·06, 95% CI 0·69-1·64; p=0·78). At month 9, four (5%) of 76 participants in the drug-level feedback arm had tenofovir diphosphate 700 fmol per punch or more, compared with three (4%) of 76 participants in the monthly counselling arm (1·33, 0·31-5·76; p=0·70). 22 serious adverse events were reported during the trial, but were all deemed unrelated to the trial.
INTERPRETATION: PrEP adherence did not differ across interventions among young women in Johannesburg, South Africa. Future research is needed on whether and how to scale-up PrEP support for young women in resource-constrained settings.
FUNDING: US National Institutes of Health.}, }
@article {pmid39680601, year = {2024}, author = {Grinde, KE and Browning, BL and Reiner, AP and Thornton, TA and Browning, SR}, title = {Adjusting for principal components can induce collider bias in genome-wide association studies.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011242}, pmid = {39680601}, issn = {1553-7404}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; R01 HG010869/HG/NHGRI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; }, mesh = {Female ; Humans ; Bias ; *Black or African American/genetics ; Genome, Human ; *Genome-Wide Association Study/methods ; *Linkage Disequilibrium ; *Polymorphism, Single Nucleotide ; *Principal Component Analysis ; Pulmonary Disease, Chronic Obstructive/genetics ; }, abstract = {Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.}, }
@article {pmid39680021, year = {2025}, author = {Yamamoto, N and Dobersch, S and Loveless, I and Samraj, AN and Jang, GH and Haraguchi, M and Kang, LI and Ruzinova, MB and Vij, KR and Mudd, JL and Walsh, T and Safyan, RA and Chiorean, EG and Hingorani, SR and Bolton, NM and Li, L and Fields, RC and DeNardo, DG and Notta, F and Crawford, HC and Steele, NG and Kugel, S}, title = {HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {4}, pages = {733-745}, pmid = {39680021}, issn = {1557-3265}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; R01 CA223483/CA/NCI NIH HHS/United States ; R01 CA161112/CA/NCI NIH HHS/United States ; P50 CA285275/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; //Swim Across America (SAA)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; 1R37CA241472//National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *HMGA2 Protein/genetics/metabolism ; *Carcinoma, Pancreatic Ductal/mortality/genetics/pathology/drug therapy/therapy/metabolism ; *Biomarkers, Tumor/genetics/metabolism ; Prognosis ; *Pancreatic Neoplasms/mortality/genetics/pathology/drug therapy/therapy ; Female ; Male ; GATA6 Transcription Factor/genetics/metabolism ; Treatment Outcome ; Gene Expression Regulation, Neoplastic ; Middle Aged ; Aged ; Gemcitabine ; Deoxycytidine/analogs & derivatives/therapeutic use ; }, abstract = {PURPOSE: The purpose of this study was to establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.
EXPERIMENTAL DESIGN: We identified high-mobility group A2 (HMGA2) protein expression in basal PDAC cells in a single-cell RNA sequencing (RNA-seq) atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classic marker GATA-binding factor 6 (GATA6), in a cohort of 580 PDAC samples with multiplex IHC. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNA-seq databases.
RESULTS: We found that expression of HMGA2, but not previously described basal markers cytokeratins 5 or 17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 statuses allowed for the identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n = 94, median survival = 11.2 months after surgery) and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n = 198, median survival = 21.7 months after surgery). HMGA2 was also prognostic for overall survival in RNA-seq from an independent cohort.
CONCLUSIONS: IHC stratification of primary tumors by HMGA2 and GATA6 statuses in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.}, }
@article {pmid39679349, year = {2024}, author = {Follmann, D and Wang, X and Baden, LR and El Sahly, HM and Essink, B and Gilbert, P and Janes, HE and Kelley, CF and Berman, MA and Frank, I and Chu, E and Deng, W and Priddy, F and Dixit, A and Tomassini, JE and Das, R and Miller, J and Zhou, H}, title = {Who to Boost When: The Effect of Age and Dosing Interval on Delta and Omicron COVID-19 Incidence in the Open-label Phase of the COVE Trial.}, journal = {Open forum infectious diseases}, volume = {11}, number = {12}, pages = {ofae689}, pmid = {39679349}, issn = {2328-8957}, abstract = {BACKGROUND: To help inform COVID-19 vaccination recommendations, we evaluated the impact of age and dosing interval on clinical benefit of a third dose of mRNA-1273.
METHODS: Approximately 17 000 participants from the phase 3 Coronavirus Efficacy trial who previously received 2 doses of 100 µg mRNA-1273 were evaluated for COVID-19 between September 2021 and April 2022 during uptake of a third booster dose of 50 µg of mRNA-1273. Cox models assessed booster relative efficacy of a third dose.
RESULTS: Initial booster relative efficacy against Delta COVID-19 was 83% (95% confidence interval, 60-93) 14 days postdose and 83% (67-91) 60 days later. Initial booster efficacy against Omicron COVID-19 was 56% (44-65) at 14 days postdose and 4% (-27 to 28) 120 days later. For those aged ≥65 years, initial booster efficacy against Omicron COVID-19 was 86% (69-93) compared with 50% (36-61) for those <65 years. Placebo crossover to 2 doses of mRNA-1273 induced a median 5-month difference from the second to third dose between the original randomized arms. Postboost, the mRNA-1273 arm had a 24% (16%, 32%) lower risk of Omicron COVID-19 compared to the placebo-mRNA-1273 arm. Modeling predicted a 41% postboost reduction in Omicron COVID-19 for a 15- versus 7-month interval between the second and third doses.
CONCLUSIONS: Boosting reduced Delta COVID-19 risk by 83% through 2 months and reduced Omicron COVID-19 risk by 56% but declined by 4 months. A 15- versus 7-month dosing interval predicted a 41% postboost reduction in Omicron COVID-19 but increased preboost risk.
PRIMARY FUNDING SOURCE: The National Institutes of Health/National Institute of Allergy and Infectious Diseases. Registration for the COVE Trial. ClinicalTrials.gov ID# NCT04470427.}, }
@article {pmid39678499, year = {2024}, author = {Moloney, B and Li, X and Hirano, M and Saad Eddin, A and Lim, JY and Biswas, D and Kazerouni, AS and Tudorica, A and Li, I and Bryant, ML and Wille, C and Pyle, C and Rahbar, H and Hsieh, SK and Rice-Stitt, TL and Dintzis, SM and Bashir, A and Hobbs, E and Zimmer, A and Specht, JM and Phadke, S and Fleege, N and Holmes, JH and Partridge, SC and Huang, W}, title = {Initial experience in implementing quantitative DCE-MRI to predict breast cancer therapy response in a multi-center and multi-vendor platform setting.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1395502}, pmid = {39678499}, issn = {2234-943X}, support = {S10 OD021701/OD/NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; S10 OD018224/OD/NIH HHS/United States ; UM1 TR004403/TR/NCATS NIH HHS/United States ; R01 CA248192/CA/NCI NIH HHS/United States ; R01 CA190299/CA/NCI NIH HHS/United States ; S10 OD025025/OD/NIH HHS/United States ; }, abstract = {Quantitative dynamic contrast-enhanced (DCE) MRI as a promising method for the prediction of breast cancer response to neoadjuvant chemotherapy (NAC) has been demonstrated mostly in single-center and single-vendor platform studies. This preliminary study reports the initial experience in implementing quantitative breast DCE-MRI in multi-center (MC) and multi-vendor platform (MP) settings to predict NAC response. MRI data, including B1 mapping, variable flip angle (VFA) measurements of native tissue R1 (R1,0), and DCE-MRI, were acquired during NAC at three sites using 3T systems with Siemens, Philips, and GE platforms, respectively. High spatiotemporal resolution DCE-MRI was performed using similar vendor product sequences with k-space undersampling during acquisition and view sharing during reconstruction. A breast phantom was used for quality assurance/quality control (QA/QC) across sites. The Tofts model (TM) and shutter-speed model (SSM) were used for pharmacokinetic (PK) analysis of the DCE data. Additionally, tumor region of interest (ROI)- vs. voxel-based analyses in combination with the use of VFA-measured R1,0 vs. fixed, literature-reported R1,0 were investigated to determine the optimal analysis approach. Results from 15 patients who completed the study are reported. Voxel-based PK analysis using fixed R1,0 was deemed the optimal approach, which allowed the inclusion of data from one vendor platform where VFA measurements produced ≥100% overestimation of R1,0. The semi-quantitative signal enhancement ratio (SER) and quantitative PK parameters outperformed the tumor longest diameter (LD) in the prediction of pathologic complete response (pCR) vs. non-pCR after the first NAC cycle, whereas K[trans] consistently provided more accurate predictions than both SER and LD after the first NAC cycle and at the NAC midpoint. Both TM and SSM K[trans] and kep were excellent predictors of response at the NAC midpoint with ROC AUC >0.90, while the SSM parameters (AUC ≥0.80) performed better than their TM counterparts (AUC <0.80) after the first NAC cycle. The initial experience of this ongoing study indicates the importance of QA/QC using a phantom and suggests that deploying voxel-based PK analysis using a fixed R1,0 may mitigate random errors from R1,0 measurements across platforms and potentially eliminate the need for B1 and VFA acquisitions in MC and MP trials.}, }
@article {pmid39678495, year = {2024}, author = {Saini, J and Erickson, DPJ and Vander Stappen, F and Ruth, M and Cui, S and Gorman, V and Rossomme, S and Cao, N and Ford, EC and Meyer, J and Bloch, C and Wong, T and Grassberger, C and Rengan, R and Zeng, J and Schwarz, M}, title = {Commissioning a clinical proton pencil beam scanning beamline for pre-clinical ultra-high dose rate irradiations on a cyclotron-based system.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1460288}, pmid = {39678495}, issn = {2234-943X}, abstract = {BACKGROUND: This manuscript describes modifications to a pencil beam scanning (PBS) proton gantry that enables ultra-high dose rates (UHDR) irradiation, including treatment planning and validation.
METHODS: Beamline modifications consisted of opening the energy slits and setting the degrader to pass-through mode to maximize the dose rate. A range shifter was inserted upstream from the isocenter to enlarge the spot size and make it rotationally symmetric. We measured the beamline transport efficiency and investigated the variation in output due to the recombination of charge in the dose monitoring chamber. The output calibration was performed through a parallel plate chamber (PPC05), and an intercomparison was performed for various detectors. The pre-clinical field for mice irradiation consisted of different dose levels to deliver uniform doses in transmission mode. The field dose rates were determined through log files while scripting in TPS was used to estimate PBS dose rates. The survival experiments consisted of irradiating the full pelvis of the mice at UHDR and conventional dose rates.
RESULTS: The spot size was constant with beam current and had a sigma of 8.5 mm at the isocenter. The beam output increased by 35% at 720 nA compared to 5.6 nA, primarily due to recombination in the dose-monitoring ion chambers. The Faraday Cup and PPC05 agreed within 2%, while other detectors were within 3% of FC for dose rates <60 Gy/s. The pre-clinical fields' PBS dose rate is above 45 Gy/sec for all voxels within the target volume. The average and PBS dose rates decrease as field size increases and approaches 40 Gy/s for a field size of 7x7 cm[2]. All UHDR arms showed better survival than the corresponding conventional dose rate arms.
CONCLUSIONS: We successfully modified a clinical system to perform UHDR pre-clinical experiments. As part of our pre-clinical experiments, we observed the FLASH effect concerning mice survival.}, }
@article {pmid39677796, year = {2024}, author = {Nicoletti, C and Massenet, J and Pintado-Urbanc, AP and Connor, LJ and Nicolau, M and Sundar, S and Xu, M and Schmitt, A and Zhang, W and Fang, Z and Chan, TCI and Tapscott, SJ and Cheung, TH and Simon, MD and Caputo, L and Puri, PL}, title = {E-box independent chromatin recruitment turns MYOD into a transcriptional repressor.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677796}, issn = {2692-8205}, support = {R01 GM134712/GM/NIGMS NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; R01 AR045203/AR/NIAMS NIH HHS/United States ; R01 AR056712/AR/NIAMS NIH HHS/United States ; R01 GM137117/GM/NIGMS NIH HHS/United States ; }, abstract = {MYOD is an E-box sequence-specific basic Helix-Loop-Helix (bHLH) transcriptional activator that, when expressed in non-muscle cells, induces nuclear reprogramming toward skeletal myogenesis by promoting chromatin accessibility at previously silent loci. Here, we report on the identification of a previously unrecognized property of MYOD as repressor of gene expression, via E-box-independent chromatin binding within accessible genomic elements, which invariably leads to reduced chromatin accessibility. MYOD-mediated repression requires the integrity of functional domains previously implicated in MYOD-mediated activation of gene expression. Repression of mitogen- and growth factor-responsive genes occurs through promoter binding and requires a highly conserved domain within the first helix. Repression of cell-of-origin/alternative lineage genes occurs via binding and decommissioning of distal regulatory elements, such as super-enhancers (SE), which requires the N-terminal activation domain as well as two chromatin-remodeling domains and leads to reduced strength of CTCF-mediated chromatin interactions. Surprisingly, MYOD-mediated chromatin compaction and repression of transcription do not associate with reduction of H3K27ac, the conventional histone mark of enhancer or promoter activation, but with reduced levels of the recently discovered histone H4 acetyl-methyl lysine modification (Kacme). These results extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator and reveal a previously unrecognized functional versatility arising from an alternative chromatin recruitment through E-box or non-E-box sequences. The E-box independent repression of gene expression by MYOD might provide a promiscuous mechanism to reduce chromatin accessibility and repress cell-of-origin/alternative lineage and growth factor/mitogen-responsive genes to safeguard the integrity of cell identity during muscle progenitor commitment toward the myogenic lineage.}, }
@article {pmid39677467, year = {2025}, author = {Figgins, MD and Bedford, T}, title = {Frequency dynamics predict viral fitness, antigenic relationships and epidemic growth.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39677467}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {During the COVID-19 pandemic, SARS-CoV-2 variants drove large waves of infections, fueled by increased transmissibility and immune escape. Current models focus on changes in variant frequencies without linking them to underlying transmission mechanisms of intrinsic transmissibility and immune escape. We introduce a framework connecting variant dynamics to these mechanisms, showing how host population immunity interacts with viral transmissibility and immune escape to determine relative variant fitness. We advance a selective pressure metric that provides an early signal of epidemic growth using genetic data alone, crucial with current underreporting of cases. Additionally, we show that a latent immunity space model approximates immunological distances, offering insights into population susceptibility and immune evasion. These insights refine real-time forecasting and lay the groundwork for research into the interplay between viral genetics, immunity, and epidemic growth.}, }
@article {pmid39674548, year = {2025}, author = {Duarte, FB and Garcia, YDO and Hamerschlak, N and Funke, VAM and Moreira, MCR and Paz, AA and Filho, JS and Astigarraga, CC and da Silva, RL and de Molla, VC and Silvério, A and Rocha, VG and Feliciano, JVP and Barros, GMN and Colturato, VAR and Nabhan, SK and Farias, JSH and Maia, ACA and Atalla, Â and Chiattone, R and Macedo, MCMA and Aranha, MAF and Zogbi, YAN and Lener, D and Soares, RDA and Scheinberg, P and Calixto, RF and Teixeira, GM and Colella, MP and Rodrigues, CA and Simione, AJ and da Silva, CC and Martin, PJ and Flowers, ME}, title = {Allogeneic Hematopoietic Cell Transplantation in Elderly Patients in a Latin American Country: Analysis of 11 Year of Data from the Brazilian Registry SBTMO/CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {2}, pages = {79.e1-79.e9}, doi = {10.1016/j.jtct.2024.12.003}, pmid = {39674548}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/mortality ; Middle Aged ; Male ; Female ; Registries ; Brazil/epidemiology ; Aged ; Transplantation, Homologous ; Retrospective Studies ; *Myelodysplastic Syndromes/therapy/mortality ; *Leukemia, Myeloid, Acute/therapy/mortality ; }, abstract = {This study analyzed recent changes in the utilization of allogeneic hematopoietic cell transplantation (HCT) for treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative diseases (MPDs) and the survival of HCT recipients ≥60 years of age in Brazil. This retrospective registry study included patients who received a first allogeneic HCT from any donor between 2012 and 2023. Of the 6657 patients, 444 (7%) were 60 years of age or older who received grafts from human leukocyte antigen (HLA)-matched related (42%) or unrelated (20%) donors or HLA-haploidentical donors (32%). The proportion of HCT recipients 60 years of age or older increased gradually from 3.2% in 2012 to 16% in 2023 mostly due to the increased use of HLA-haploidentical donors since 2018. Overall survival (OS) at day 100 was 77%, and estimated OS at 12 months was 53% (95% CI, 48%-58%). OS at 12 months was higher for transplants during 2015 to 2017 (58%) and 2018 to 2020 (68%) compared with 2012 to 2014 (45%), but it did not differ for those during 2021 to 2023 (49%). Mortality with HLA-haploidentical donors (HR, 2.35; 95% CI, 1.65-3.34 [P < .001]) and cord blood donors (HR, 4.68; 95%,CI, 1.29-16.9 [P = .01]) was higher than with HLA-matched related donors. Mortality was lower for patients with transplants during the 2015 to 2020 period (HR, 0.57; 95% CI, .34-.96 [.037]) than for those during 2012 to 2014.This study revealed a gradual increase in the use of allogeneic HCT in individuals aged 60 years and older in Brazil. While use of haploidentical donors has increased worldwide, its association with increased mortality in the elderly population warrants caution when considering this treatment.}, }
@article {pmid39656951, year = {2025}, author = {Abdou, Y and Barlow, WE and Gralow, JR and Meric-Bernstam, F and Albain, KS and Hayes, DF and Lin, NU and Perez, EA and Goldstein, LJ and Chia, SKL and Dhesy-Thind, S and Rastogi, P and Alba, E and Delaloge, S and Schott, AF and Shak, S and Sharma, P and Lew, DL and Miao, J and Unger, JM and Tripathy, D and Hortobagyi, GN and Pusztai, L and Kalinsky, K}, title = {Race and clinical outcomes in hormone receptor-positive, HER2-negative, node-positive breast cancer in the randomized RxPONDER trial.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {5}, pages = {889-897}, pmid = {39656951}, issn = {1460-2105}, support = {/CA/NCI NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; //Susan G. Komen for the Cure Research Program/ ; //Hope Foundation for Cancer Research/ ; //Breast Cancer Research Foundation/ ; //Genomic Health/ ; //AbbVie/ ; //AstraZeneca/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Antineoplastic Agents, Hormonal/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Black or African American/statistics & numerical data ; *Breast Neoplasms/drug therapy/pathology/ethnology/chemistry/mortality ; Disease-Free Survival ; Hispanic or Latino/statistics & numerical data ; Lymphatic Metastasis ; Neoplasm Recurrence, Local ; *Racial Groups/statistics & numerical data ; *Receptor, ErbB-2/analysis/metabolism ; Receptors, Estrogen/analysis/metabolism ; Receptors, Progesterone/analysis/metabolism ; Treatment Outcome ; White ; }, abstract = {BACKGROUND: The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial.
METHODS: The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment.
RESULTS: A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity.
CONCLUSIONS: NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272037.}, }
@article {pmid39673790, year = {2025}, author = {Chiu, AP and Gowda, GAN and Zhu, W and Arendt-Nielsen, L and Raftery, D and Curatolo, M}, title = {Cerebrospinal fluid metabolomics of pain in patients with spinal muscle atrophy.}, journal = {Pain medicine (Malden, Mass.)}, volume = {26}, number = {5}, pages = {283-286}, pmid = {39673790}, issn = {1526-4637}, support = {//National Institute of Health/ ; //University of Washington Clinical Learning, Evidence And Research/ ; //Center for Musculoskeletal Research/ ; /AR/NIAMS NIH HHS/United States ; P30AR072572/NH/NIH HHS/United States ; //Center for Neuroplasticity and Pain/ ; DNRF121//Danish National Research Foundation/ ; }, }
@article {pmid39673461, year = {2025}, author = {MacInnis, RJ and Jenkins, MA and Milne, RL and John, EM and Daly, MB and Andrulis, IL and Colonna, SV and Phillips, KA and , and Le Marchand, L and Newcomb, PA and Phipps, AI and Schmit, SL and Macrae, FA and Buchanan, DD and Gallinger, S and Pai, RK and Samadder, NJ and Giles, GG and Southey, MC and Hopper, JL and Terry, MB}, title = {Menopausal hormone therapy: assessing associations with breast and colorectal cancers by familial risk.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {1}, pages = {}, pmid = {39673461}, issn = {2515-5091}, support = {U01 CA167551/CA/NCI NIH HHS/United States ; //US government/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/genetics/epidemiology ; Middle Aged ; *Colorectal Neoplasms/genetics/epidemiology ; *Menopause ; *Estrogen Replacement Therapy/adverse effects/statistics & numerical data ; Hormone Replacement Therapy/adverse effects/statistics & numerical data ; Proportional Hazards Models ; Risk Factors ; Aged ; Risk Assessment ; Genetic Predisposition to Disease ; }, abstract = {Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.4 or higher, where 0.4 was equivalent to a 50-year-old woman with 1 parent diagnosed with either breast cancer or CRC at 55 years of age. Of 24 486 women assessed, 1243 and 405 were diagnosed with incident breast cancer and CRC, respectively. For breast cancer, menopausal HRT ever use versus never use hazard ratios were 1.27 (95% CI = 1.11 to 1.45) for a breast cancer familial risk score below 0.4 and 1.01 (95% CI = 0.82 to 1.25) for a breast cancer familial risk score of 0.4 or higher (Pdifference = .08). For CRC, menopausal HRT hazard ratios were 0.63 (95% CI = 0.50 to 0.78) for a CRC familial risk score below 0.4 and 1.21 (95% CI = 0.73 to 2.00) for a CRC familial risk score of 0.4 or higher (Pdifference = .03). Associations with menopausal HRT use that apply to the general population may not hold for women at moderate or strong familial risk of these cancers.}, }
@article {pmid39672634, year = {2025}, author = {Tseng, YD and Mikhaeel, NG}, title = {The seemingly contradictory roles of radiation as focal to systemic therapy in hematologic malignancies.}, journal = {Seminars in radiation oncology}, volume = {35}, number = {1}, pages = {1-3}, doi = {10.1016/j.semradonc.2024.12.001}, pmid = {39672634}, issn = {1532-9461}, }
@article {pmid39672162, year = {2024}, author = {Pasquesi, GIM and Allen, H and Ivancevic, A and Barbachano-Guerrero, A and Joyner, O and Guo, K and Simpson, DM and Gapin, K and Horton, I and Nguyen, LL and Yang, Q and Warren, CJ and Florea, LD and Bitler, BG and Santiago, ML and Sawyer, SL and Chuong, EB}, title = {Regulation of human interferon signaling by transposon exonization.}, journal = {Cell}, volume = {187}, number = {26}, pages = {7621-7636.e19}, pmid = {39672162}, issn = {1097-4172}, support = {R35 GM128822/GM/NIGMS NIH HHS/United States ; R01 CA285446/CA/NCI NIH HHS/United States ; DP1 AI175471/AI/NIAID NIH HHS/United States ; K99 AI151256/AI/NIAID NIH HHS/United States ; K99 GM152820/GM/NIGMS NIH HHS/United States ; R37 CA261987/CA/NCI NIH HHS/United States ; R01 OD034046/OD/NIH HHS/United States ; }, mesh = {Humans ; *Receptor, Interferon alpha-beta/metabolism/genetics ; *Exons/genetics ; *Signal Transduction ; *DNA Transposable Elements/genetics ; *Alternative Splicing/genetics ; Animals ; *SARS-CoV-2/genetics/immunology/metabolism ; Interferons/metabolism ; HEK293 Cells ; COVID-19/immunology/virology/genetics ; Protein Isoforms/metabolism/genetics ; Immunity, Innate/genetics ; }, abstract = {Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.}, }
@article {pmid39671534, year = {2025}, author = {Shroff, RT and King, G and Colby, S and Scott, AJ and Borad, MJ and Goff, L and Matin, K and Mahipal, A and Kalyan, A and Javle, MM and El Dika, I and Tan, B and Cheema, P and Patel, A and Iyer, R and Kelley, RK and Thumar, J and El-Khoueiry, A and Guthrie, KA and Chiorean, EG and Hochster, H and Philip, PA}, title = {SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {5}, pages = {536-544}, pmid = {39671534}, issn = {1527-7755}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Gemcitabine ; Deoxycytidine/analogs & derivatives/administration & dosage/adverse effects ; Cisplatin/administration & dosage/adverse effects ; Male ; Female ; Paclitaxel/administration & dosage/adverse effects ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Albumins/administration & dosage/adverse effects ; Aged ; *Biliary Tract Neoplasms/drug therapy/pathology/mortality ; Adult ; Aged, 80 and over ; }, abstract = {PURPOSE: SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).
METHODS: Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m[2], cisplatin 25 mg/m[2], and nab-paclitaxel 100 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m[2] and cisplatin 25 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle).
RESULTS: Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28).
CONCLUSION: The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.}, }
@article {pmid39671174, year = {2025}, author = {Wilson, GJ and Church, LWP and Kelley, CF and Robinson, ST and Lu, Y and Furch, BD and Fong, Y and Paez, CA and Yacovone, M and Jacobsen, T and Maughan, M and Martik, D and Heptinstall, JR and Zhang, L and Montefiori, DC and Tomaras, GD and Kublin, JG and Corey, L}, title = {HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines.}, journal = {The Journal of infectious diseases}, volume = {231}, number = {4}, pages = {e764-e769}, pmid = {39671174}, issn = {1537-6613}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Disease/ ; //National Institute of Allergy and Infectious Diseases/ ; UM1 AI068614/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Envelope Protein gp120/immunology/genetics ; *AIDS Vaccines/immunology/adverse effects/administration & dosage/genetics ; Female ; HIV Antibodies/blood ; Adult ; Male ; Transfection ; Antibodies, Neutralizing/blood ; *HIV Infections/prevention & control/immunology ; Immunoglobulin G/blood ; Middle Aged ; Young Adult ; Cell Line ; *Immunogenicity, Vaccine ; HIV-1/immunology ; }, abstract = {Utilizing transiently transfected cell lines could significantly reduce manufacturing timelines for protein subunit vaccines. This trial compared safety and immunogenicity of human immunodeficiency virus (HIV) envelope CH505TF gp120 vaccines produced by upstream stable and transient transfection (each admixed with GLA-SE adjuvant, a TL4 agonist). Both vaccines were safe and well tolerated. Serum IgG binding antibody response rates 2 weeks after final injection were 92% in the stable group and 93% in the transient group (P = 1.000). Neutralization response rates against CH505.w4.3 were also equivalent (92% vs 100%, P = .291). These data support transient transfection as an available tool for accelerating HIV vaccine testing and iteration. Clinical Trials Registration. NCT03856996.}, }
@article {pmid39670372, year = {2025}, author = {Ramwala, OA and Lowry, KP and Hippe, DS and Unrath, MPN and Nyflot, MJ and Mooney, SD and Lee, CI}, title = {ClinValAI: A framework for developing Cloud-based infrastructures for the External Clinical Validation of AI in Medical Imaging.}, journal = {Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing}, volume = {30}, number = {}, pages = {215-228}, doi = {10.1142/9789819807024_0016}, pmid = {39670372}, issn = {2335-6936}, mesh = {Humans ; *Cloud Computing ; *Algorithms ; *Computational Biology ; Female ; *Artificial Intelligence ; *Diagnostic Imaging/standards/statistics & numerical data ; Workflow ; Mammography/statistics & numerical data/standards/methods ; Breast Neoplasms/diagnostic imaging ; Validation Studies as Topic ; }, abstract = {Artificial Intelligence (AI) algorithms showcase the potential to steer a paradigm shift in clinical medicine, especially medical imaging. Concerns associated with model generalizability and biases necessitate rigorous external validation of AI algorithms prior to their adoption into clinical workflows. To address the barriers associated with patient privacy, intellectual property, and diverse model requirements, we introduce ClinValAI, a framework for establishing robust cloud-based infrastructures to clinically validate AI algorithms in medical imaging. By featuring dedicated workflows for data ingestion, algorithm scoring, and output processing, we propose an easily customizable method to assess AI models and investigate biases. Our novel orchestration mechanism facilitates utilizing the complete potential of the cloud computing environment. ClinValAI's input auditing and standardization mechanisms ensure that inputs consistent with model prerequisites are provided to the algorithm for a streamlined validation. The scoring workflow comprises multiple steps to facilitate consistent inferencing and systematic troubleshooting. The output processing workflow helps identify and analyze samples with missing results and aggregates final outputs for downstream analysis. We demonstrate the usability of our work by evaluating a state-of-the-art breast cancer risk prediction algorithm on a large and diverse dataset of 2D screening mammograms. We perform comprehensive statistical analysis to study model calibration and evaluate performance on important factors, including breast density, age, and race, to identify latent biases. ClinValAI provides a holistic framework to validate medical imaging models and has the potential to advance the development of generalizable AI models in clinical medicine and promote health equity.}, }
@article {pmid39669607, year = {2024}, author = {Tumulak, MJR and Padilla, CD and Ongchangco, JCE and Laurino, MY and Lagarde, JBB and Regalado, ES and Legaspi, AV and Ventura, ER}, title = {Living with a child with MSUD: Psychosocial issues of Filipino parents with a child with maple syrup urine disease.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101847}, pmid = {39669607}, issn = {2949-7744}, abstract = {PURPOSE: Maple syrup urine disease (MSUD) is a common inborn error of metabolism diagnosed in the Philippines. A family may experience stress, anxiety, sorrow, or feelings of helplessness when a child is diagnosed to have a genetic disorder, which can lead to chronic care and disability. This study aims to explore the psychosocial issues experienced by Filipino parents with children having MSUD.
METHODS: This is a descriptive and qualitative study. One-to-one interviews using a semi-structured set of questions were done between the months of November 2015 to March 2016. A total of 12 parents were interviewed. Thematic analysis was used.
RESULTS: The diagnosis of MSUD in a child is, indeed, a stressful event for the family. Parents experienced fear, confusion, and hurt, among other emotions. Having a child with MSUD had a negative impact on their families, especially in terms of financial burden, dietary restriction, and marital conflicts leading to separation. However, some parents reported positive effects, such as increased confidence in one's abilities to care for the affected child and closer relationships among family members.
CONCLUSION: A diagnosis of MSUD on the child places considerable caregiver burden on the parents. Findings have important implications for genetic counselors.}, }
@article {pmid39669077, year = {2024}, author = {Schnuck, JO and Chauhan, SSB and Sham, JG}, title = {Surrogate endpoints in clinical trials: when is good...good enough?.}, journal = {Hepatobiliary surgery and nutrition}, volume = {13}, number = {6}, pages = {1062-1064}, pmid = {39669077}, issn = {2304-3881}, }
@article {pmid39668236, year = {2025}, author = {Orvain, C and Milano, F and Rodríguez-Arbolí, E and Othus, M and Petersdorf, EW and Sandmaier, BM and Appelbaum, FR and Walter, RB}, title = {Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia.}, journal = {Leukemia}, volume = {39}, number = {2}, pages = {381-390}, pmid = {39668236}, issn = {1476-5551}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/mortality/pathology ; *Neoplasm, Residual ; Adult ; Female ; Male ; Middle Aged ; *Hematopoietic Stem Cell Transplantation/methods ; Retrospective Studies ; Transplantation Conditioning/methods ; Aged ; Young Adult ; Transplantation, Homologous ; *Tissue Donors ; Adolescent ; Unrelated Donors ; Prognosis ; Graft vs Host Disease/etiology ; Survival Rate ; Follow-Up Studies ; }, abstract = {Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.}, }
@article {pmid39668099, year = {2025}, author = {Robichaux, K and Billings, T and Termini, CM}, title = {Inventories invite independence.}, journal = {Trends in biochemical sciences}, volume = {50}, number = {1}, pages = {1-3}, pmid = {39668099}, issn = {0968-0004}, support = {K01 DK126989/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Antibodies ; *Laboratories/organization & administration ; }, abstract = {In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.}, }
@article {pmid39667756, year = {2025}, author = {Biernacki, MA and Bleakley, M}, title = {Clinical trials, challenges, and changes in TCR-based therapeutics for hematologic malignancies.}, journal = {Expert review of hematology}, volume = {18}, number = {1}, pages = {21-31}, doi = {10.1080/17474086.2024.2441962}, pmid = {39667756}, issn = {1747-4094}, mesh = {Humans ; *Hematologic Neoplasms/therapy/immunology/metabolism ; *Receptors, Antigen, T-Cell/genetics/immunology/metabolism ; *Immunotherapy, Adoptive/methods/adverse effects ; Clinical Trials as Topic ; *Receptors, Chimeric Antigen/genetics/immunology ; Antigens, Neoplasm/immunology ; Animals ; }, abstract = {INTRODUCTION: T cells engineered to express antigen-specific T cell receptors (TCR; TCR-T) are a promising class of immunotherapeutic for patients with hematologic malignancies. Like chimeric antigen receptor-engineered T cells (CAR-T), TCR-T are cell products with defined specificity and composition. Unlike CAR-T, TCR-T can recognize targets arising both from intracellular and cell surface proteins and leverage the sensitivity of natural TCR signaling machinery. A growing number of TCR-T targeting various antigens in different hematologic malignancies are in early-phase clinical trials, and more are in preclinical development.
AREAS COVERED: This review covers results from early-phase TCR-T clinical trials for hematologic malignancies. Challenges in the field are reviewed, including identifying optimal targets, engaging CD4[+] help for CD8[+] T cells, and overcoming tumor-induced suppression; recent innovations to overcome these challenges are also highlighted.
EXPERT OPINION: In the future, TCR-T's promise for hematologic malignancies will be borne out in later-phase clinical trials and approvals for clinical use. Improved antigen discovery methods will help build the toolbox of targets needed for broadly applicable TCR-T. Rationally designed TCR-T modifications including incorporation of accessory receptors and gene editing will enhance TCR-T function. New hybrid receptors combining features of TCR and CAR will enter the clinic.}, }
@article {pmid39667379, year = {2025}, author = {Edupuganti, S and Hurt, CB and Stephenson, KE and Huang, Y and Paez, CA and Yu, C and Yen, C and Hanscom, B and He, Z and Miner, MD and Gamble, T and Heptinstall, J and Seaton, KE and Domin, E and Lin, BC and McKee, K and Doria-Rose, N and Regenold, S and Spiegel, H and Anderson, M and McClosky, N and Zhang, L and Piwowar-Manning, E and Ackerman, ME and Pensiero, M and Dye, BJ and Landovitz, RJ and Mayer, K and Siegel, M and Sobieszczyk, M and Walsh, SR and Gama, L and Barouch, DH and Montefiori, DC and Tomaras, GD and , }, title = {Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial.}, journal = {The lancet. HIV}, volume = {12}, number = {1}, pages = {e13-e25}, pmid = {39667379}, issn = {2352-3018}, support = {UM1 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Adult ; *HIV-1/drug effects/immunology ; *HIV Antibodies/administration & dosage/adverse effects ; *HIV Infections/drug therapy/immunology ; *Antibodies, Neutralizing ; Middle Aged ; *Antibodies, Monoclonal/pharmacokinetics/administration & dosage/adverse effects ; United States ; Broadly Neutralizing Antibodies ; Young Adult ; Antibodies, Monoclonal, Humanized/pharmacokinetics/administration & dosage/adverse effects ; }, abstract = {BACKGROUND: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults.
METHODS: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed.
FINDINGS: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups.
INTERPRETATION: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention.
FUNDING: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.}, }
@article {pmid39666929, year = {2024}, author = {Gien, LT and Song, Z and Poklepovic, A and Collisson, EA and Zwiebel, JA and Gray, RJ and Wang, V and McShane, LM and Rubinstein, LV and Patton, DR and Williams, PM and Hamilton, SR and Tricoli, JV and Conley, BA and Arteaga, CL and Harris, LN and O'Dwyer, PJ and Chen, AP and Flaherty, KT}, title = {Phase II Study of Sunitinib in Tumors With c-KIT Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400514}, pmid = {39666929}, issn = {2473-4284}, support = {UG1 CA189869/CA/NCI NIH HHS/United States ; UG1 CA233341/CA/NCI NIH HHS/United States ; UG1 CA233302/CA/NCI NIH HHS/United States ; UG1 CA233180/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180794/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Sunitinib/therapeutic use ; Middle Aged ; *Proto-Oncogene Proteins c-kit/genetics ; Male ; Female ; Adult ; Aged ; *Mutation ; *Antineoplastic Agents/therapeutic use/adverse effects ; Neoplasms/drug therapy/genetics ; }, abstract = {PURPOSE: The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring c-KIT mutations.
METHODS: EAY131-V, is an open-label, single-arm, phase II study. Eligible patients had malignancies containing somatic c-KIT mutation on exons 9, 11, 13, or 14. Exclusions were mutations on exons 17 and 18, gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Patients received sunitinib 50 mg orally once daily for 4 weeks with 2-week rest per cycle, until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS) at 6 months, PFS, overall survival, and toxicities.
RESULTS: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled and nine were eligible and started treatment. The median age was 62 years (range, 30-76), 77.8% received two previous lines of systemic therapy, and 22.2% received >3 lines. The most common histology was melanoma (44%) and then squamous cell carcinoma of the lung or thymus (33%). There were two partial responses with an ORR of 22.2% (90% CI, 4.1 to 55) and stable disease in 44%. All patients demonstrated tumor shrinkage of target lesions. The estimated 6-month PFS was 33.3% (90% CI, 15.4 to 72.4). Grade 3-4 toxicities occurred in five patients (55.6%). This arm was closed in 2022 on the basis of low accrual. Prevalence of eligible c-KIT mutations after screening 5,540 patients was 0.45%.
CONCLUSION: Sunitinib for c-KIT mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible c-KIT mutations was low, affecting accrual to this arm.}, }
@article {pmid39666350, year = {2025}, author = {Goss, LB and Liu, M and Zheng, Y and Guo, B and Conti, DV and Haiman, CA and Kachuri, L and Catalona, WJ and Witte, JS and Lin, DW and Newcomb, LF and Darst, BF}, title = {Polygenic Risk Score and Upgrading in Patients With Prostate Cancer Receiving Active Surveillance.}, journal = {JAMA oncology}, volume = {11}, number = {2}, pages = {168-171}, pmid = {39666350}, issn = {2374-2445}, support = {U01 CA261339/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology/therapy/blood ; Aged ; *Watchful Waiting ; Middle Aged ; Neoplasm Grading ; Prospective Studies ; Risk Assessment ; Risk Factors ; Prostate-Specific Antigen/blood ; *Multifactorial Inheritance ; Genetic Risk Score ; }, abstract = {IMPORTANCE: Active surveillance is the preferred management strategy for patients with low- or favorable intermediate-risk prostate cancer (PCa); however, frequent health care visits can be costly and burdensome to patients. Identifying patients who may benefit from intensive vs passive surveillance could reduce these burdens.
OBJECTIVE: To investigate associations between a polygenic risk score (PRS) and risk of upgrading and other prostate tumor features in patients receiving active surveillance.
This prospective multicenter cohort study across 10 US sites included 1220 patients from the Canary Prostate Active Surveillance Study (PASS) enrolled from July 2008 to November 2017, with follow-up (median, 5.3 years) through August 2022. Participants were those with clinically localized PCa (cT1-T2) receiving active surveillance. Analyses took place from January 2023 to April 2024.
EXPOSURE: Multi-ancestry PRS of 451 PCa risk variants (PRS-451) and 400 PCa risk variants (PRS-400) after excluding prostate-specific antigen (PSA)-associated variants.
MAIN OUTCOMES AND MEASURES: The primary outcome was PCa upgrading (any Gleason grade increase) vs no upgrading. Secondary outcomes included prostate volume, PSA, PSA density, percentage of biopsy cores with cancer, and Gleason grade group at diagnosis.
RESULTS: The median (IQR) age at diagnosis of the 1220 patients receiving active surveillance was 63 (58-67) years. During follow-up, 470 patients upgraded; the 2- and 5-year risks of upgrading were 17.7% (95% CI, 15.5%-19.9%) and 33.3% (95% CI, 30.5%-36.3%), respectively. Each 1-SD unit increase in PRS-451 was associated with 23% increased hazard of upgrading (95% CI, 1.11-1.35; P < .001), whereas PRS-400 was associated with 27% increased hazard (95% CI, 1.15-1.39; P < .001) at any point in time during follow-up. Except for PSA, associations with remaining outcomes were similar or stronger using PRS-400. Higher PRS-400 was associated with smaller prostate volume, a higher percentage of biopsy cores with cancer, and higher PSA density. A model with clinical risk factors had a C-index of 0.64 (95% CI, 0.62-0.67); adding PRS-400 led to a C-index of 0.65 (95% CI, 0.63-0.68).
CONCLUSIONS AND RELEVANCE: In this cohort study, among patients receiving active surveillance, high PRS was associated with risk of upgrading and possibly tumor multifocality. Excluding PSA variants from the PRS revealed an association with smaller prostate size, which has been previously associated with more aggressive tumors. Although PRS may inform active surveillance, it is yet to be seen whether they improve clinical decisions.}, }
@article {pmid39660994, year = {2025}, author = {Livingston, JA and Blay, JY and Trent, J and Valverde, C and Agulnik, M and Gounder, M and Le Cesne, A and McKean, M and Wagner, MJ and Stacchiotti, S and Agresta, S and Quintás-Cardama, A and Reilly, SA and Healy, K and Hickman, D and Zhao, T and Ballesteros-Perez, A and Khalil, A and Collins, MP and Piel, J and Horrigan, K and Lefkovith, A and Innis, S and Lazar, AJ and Cote, GM and Wagner, AJ}, title = {A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {4}, pages = {628-638}, doi = {10.1158/1078-0432.CCR-24-2583}, pmid = {39660994}, issn = {1557-3265}, support = {//Foghorn Therapeutics Inc. (Foghorn)/ ; }, mesh = {Humans ; *Sarcoma, Synovial/drug therapy/pathology/genetics/metabolism ; Female ; Male ; Middle Aged ; Adult ; *SMARCB1 Protein/deficiency/genetics ; Aged ; *Transcription Factors/genetics ; Maximum Tolerated Dose ; Treatment Outcome ; Young Adult ; *Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics/therapeutic use ; Bromodomain Containing Proteins ; }, abstract = {PURPOSE: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.
PATIENTS AND METHODS: In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).
RESULTS: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.
CONCLUSIONS: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.}, }
@article {pmid39660025, year = {2024}, author = {Lubwama, M and Holte, SE and Zhang, Y and Mubiru, KR and Katende, G and Orem, J and Kateete, DP and Bwanga, F and Phipps, W}, title = {Etiology, Risk Factors, and Outcomes of Bacteremia in Patients With Hematologic Malignancies and Febrile Neutropenia in Uganda.}, journal = {Open forum infectious diseases}, volume = {11}, number = {12}, pages = {ofae682}, pmid = {39660025}, issn = {2328-8957}, support = {D43 TW009759/TW/FIC NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: We determined the etiology, risk factors, and outcomes associated with bacteremia in patients with hematologic malignancies and febrile neutropenia (FN) at the Uganda Cancer Institute (UCI).
METHODS: UCI adult and pediatric inpatients with hematologic malignancies and FN were prospectively enrolled and followed up to determine 30-day mortality. Blood drawn from participants with FN was cultured in the BACTEC 9120 blood culture system. Antimicrobial susceptibility testing was performed with the disk diffusion method on identified bacteria. Logistic regression and Cox proportional hazards regression were applied to estimate associations between participant characteristics and FN, bacteremia, and mortality.
RESULTS: Of 495 participants, the majority (n = 306 [62%]) were male. Median age was 23 years (interquartile range, 11-42 years). Of the 132 participants who experienced FN, 43 (33%) had bacteremia. Participants with younger age (odds ratio [OR], 0.98; P = .05), severe neutropenia (OR, 2.9; P = .01), hypotension (OR, 2.46; P = .04), mucositis (OR, 2.77; P = .01), and receipt of chemotherapy (OR, 2.25; P = .03) were more likely to have bacteremia. Fifty (78%) bacteria isolated were gram negative. Escherichia coli (n = 25 [50%]) was predominant. Thirty-seven of 43 (86%) episodes were caused by multidrug-resistant (MDR) bacteria. Thirty-day overall survival for participants with bacteremia was significantly lower than that for participants with no bacteremia (P = .05). MDR bacteremia (hazard ratio, 1.84; P = .05) was associated with increased risk of death.
CONCLUSIONS: Bacteremia was frequent in patients with hematologic cancer and FN and was associated with poor survival. MDR bacteria were the main cause of bacteremia and mortality. There is a need for robust infection control and antimicrobial stewardship programs in cancer centers in sub-Saharan Africa.}, }
@article {pmid39653676, year = {2024}, author = {Gati Mirembe, B and Donnell, D and Krows, M and Zwane, Z and Bukusi, E and Panchia, R and Louw, C and Mwelase, N and Selepe, P and Senne, M and Naidoo, L and Chihana, R and Kasaro, M and Nuwagaba-Biribonwoha, H and Kotze, P and Gill, K and MacDonald, P and vanHeerden, A and Bosman, S and Jaggernath, M and du Preez, P and Ward, A and Peters, RPH and Delany-Moretlwe, S and Peacock, S and Johnson, R and Caucutt, J and Morrison, S and Wang, G and Gandhi, M and Velloza, J and Heffron, R and Celum, C and , }, title = {High recent PrEP adherence with point-of-care urine tenofovir testing and adherence counselling among young African women: results from the INSIGHT cohort.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {12}, pages = {e26389}, pmid = {39653676}, issn = {1758-2652}, support = {R01 AI143340/AI/NIAID NIH HHS/United States ; R37 AI098472/AI/NIAID NIH HHS/United States ; INV-004743/GATES/Bill & Melinda Gates Foundation/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Young Adult ; *Anti-HIV Agents/therapeutic use ; Cohort Studies ; *Counseling ; *HIV Infections/prevention & control/drug therapy ; Point-of-Care Systems ; Point-of-Care Testing ; *Pre-Exposure Prophylaxis/methods/statistics & numerical data ; *Tenofovir/therapeutic use/urine ; *Assessment of Medication Adherence ; }, abstract = {INTRODUCTION: Adolescent girls and young women (AGYW) account for two-thirds of new HIV infections in Africa. African AGYW have had high uptake of oral HIV pre-exposure prophylaxis (PrEP) but low adherence, which might be improved by point-of-care adherence monitoring with tailored counselling.
METHODS: From August 2022 to July 2023, we conducted a PrEP demonstration project with sexually active AGYW ages 16-30 years from 20 sites in South Africa, Eswatini, Kenya, Malawi, Uganda and Zambia. Participants were offered oral tenofovir-based PrEP at enrolment and followed up at 1, 3 and 6 months. PrEP adherence was assessed by a point-of-care qualitative lateral flow urine tenofovir (TFV) assay indicating PrEP use in the prior 4 days, which accompanied real-time adherence counselling that incorporated urine TFV results when testing was available (70.8% of month 1, 35.3% of month 3 and 83.9% of month 6 visits). We estimated overall adherence, correcting for missing test results, and analysed the association of having received urine TFV results at month 1 or 3 with subsequent urine TFV test positivity, using modified Poisson regression.
RESULTS: Of the 3087 AGYW enrolled, the median age was 24 years (interquartile range 21-27), 75.7% were from South Africa, 2878 (93.2%) initiated PrEP at enrolment and 107 (3.5%) after enrolment. Visit retention was 92.0-96.2% for months 1, 3 and 6, and 2518 (90.1%) exited the study with a PrEP refill. Adherence, based on the point-of-care urine tenofovir test positivity rate, was estimated as 72%, 71% and 65% at months 1, 3 and 6, respectively. Women who received one prior urine TFV test had a 42% higher likelihood of a subsequent positive urine TFV test (adjusted odds ratio, OR = 1.42, 95% confidence interval, CI 1.27-1.60), and those having received two prior tests had a 67% higher likelihood (adjusted OR = 1.67; 95% CI 1.41-1.98). Observed HIV incidence was 1.38/100 person-years (95% CI 0.97-2.08).
CONCLUSIONS: Oral PrEP uptake, recent adherence and persistence were high in a multisite cohort of young African women over 6 months of follow-up. The use of a novel point-of-care tenofovir assay with tailored real-time adherence counselling was associated with increased adherence to PrEP at subsequent visits, warranting further study.
CLINICAL TRIALS REGISTRATION: clinicaltrials.gov NCT05746065.}, }
@article {pmid39653279, year = {2025}, author = {Santos, PMG and Silverwood, S and Suneja, G and Ford, EC and Thaker, NG and Ostroff, JS and Weiner, BJ and Gillespie, EF}, title = {Dissemination and Implementation-A Primer for Accelerating "Time to Translation" in Radiation Oncology.}, journal = {International journal of radiation oncology, biology, physics}, volume = {121}, number = {5}, pages = {1102-1114}, doi = {10.1016/j.ijrobp.2024.11.101}, pmid = {39653279}, issn = {1879-355X}, mesh = {*Radiation Oncology/standards ; Humans ; *Translational Research, Biomedical ; *Implementation Science ; *Information Dissemination ; Quality Improvement ; }, abstract = {The field of radiation oncology has achieved significant technological and scientific advancements in the 21st century. Yet uptake of new evidence-based practices has been heterogeneous, even in the presence of national and international guidelines. Addressing barriers to practice change requires a deliberate focus on developing and testing strategies tailored to improving care delivery and quality, especially for vulnerable patient populations. Implementation science provides a systematic approach to developing and testing strategies, though applications in radiation oncology remain limited. In this critical review, we aim to (1) assess the time from first evidence to widespread adoption, or "time to translation," across multiple evidence-based practices involving radiation therapy, and (2) provide a primer on the application of implementation science to radiation oncology. Specifically, we discuss potential targets for implementation research in radiation oncology, including both evidence-based practices and quality metrics, and highlight examples of studies evaluating implementation strategies. We also define key concepts and frameworks in the field of implementation science, review common study designs, including hybrid trials and cluster randomization, and discuss the interaction with related disciplines such as quality improvement and behavioral economics. Ultimately, this review aims to illustrate how a comprehensive understanding of implementation science could be used to promote equity and quality in cancer care through the development of effective, scalable, and sustainable care delivery solutions.}, }
@article {pmid39652675, year = {2025}, author = {Dimopoulos, MA and Voorhees, PM and Schjesvold, F and Cohen, YC and Hungria, V and Sandhu, I and Lindsay, J and Baker, RI and Suzuki, K and Kosugi, H and Levin, MD and Beksac, M and Stockerl-Goldstein, K and Oriol, A and Mikala, G and Garate, G and Theunissen, K and Spicka, I and Mylin, AK and Bringhen, S and Uttervall, K and Pula, B and Medvedova, E and Cowan, AJ and Moreau, P and Mateos, MV and Goldschmidt, H and Ahmadi, T and Sha, L and Cortoos, A and Katz, EG and Rousseau, E and Li, L and Dennis, RM and Carson, R and Rajkumar, SV and , }, title = {Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.}, journal = {The New England journal of medicine}, volume = {392}, number = {18}, pages = {1777-1788}, doi = {10.1056/NEJMoa2409029}, pmid = {39652675}, issn = {1533-4406}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Antibodies, Monoclonal/administration & dosage/adverse effects ; *Antineoplastic Agents/administration & dosage/adverse effects ; Disease Progression ; Injections, Subcutaneous ; Kaplan-Meier Estimate ; *Multiple Myeloma/diagnosis/epidemiology/prevention & control ; Progression-Free Survival ; *Smoldering Multiple Myeloma/diagnosis/mortality/therapy ; *Watchful Waiting/statistics & numerical data ; }, abstract = {BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.
METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.
RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.
CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).}, }
@article {pmid39652470, year = {2025}, author = {Chesner, LN and Polesso, F and Graff, JN and Hawley, JE and Smith, AK and Lundberg, A and Das, R and Shenoy, T and Sjöström, M and Zhao, F and Hu, YM and Linder, S and Chen, WS and Hawkins, RM and Shrestha, R and Zhu, X and Foye, A and Li, H and Kim, LM and Bhalla, M and O'loughlin, T and Kuzuoglu-Ozturk, D and Hua, JT and Badura, ML and Wilkinson, S and Trostel, SY and Bergman, AM and Ruggero, D and Drake, CG and Sowalsky, AG and Fong, L and Cooperberg, MR and Zwart, W and Guan, X and Ashworth, A and Xia, Z and Quigley, DA and Gilbert, LA and Feng, FY and Moran, AE}, title = {Androgen Receptor Inhibition Increases MHC Class I Expression and Improves Immune Response in Prostate Cancer.}, journal = {Cancer discovery}, volume = {15}, number = {3}, pages = {481-494}, pmid = {39652470}, issn = {2159-8290}, support = {HT9425-24-1-0506//U.S. Department of Defense (DOD)/ ; P50 CA275741/CA/NCI NIH HHS/United States ; R01 CA227025/CA/NCI NIH HHS/United States ; OT2CA278665//Cancer Research UK (CRUK)/ ; 2019YIA//Conquer Cancer Foundation (CCF)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; T32CA203703//National Cancer Institute (NCI)/ ; OT2 CA278665/CA/NCI NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; R01 GM147365/GM/NIGMS NIH HHS/United States ; W81XWH-22-1-0833//U.S. Department of Defense (DOD)/ ; R35 CA242986/CA/NCI NIH HHS/United States ; 5R01CA227025//National Cancer Institute (NCI)/ ; DP2 CA239597/CA/NCI NIH HHS/United States ; T90 DE030859/DE/NIDCR NIH HHS/United States ; R35CA253175//National Cancer Institute (NCI)/ ; RP-19-, 181-, 01-RMC//American Cancer Society (ACS)/ ; P30 CA082103/CA/NCI NIH HHS/United States ; W81XWH2110046//U.S. Department of Defense (DOD)/ ; 1P50CA275741//National Cancer Institute (NCI)/ ; R01GM147365//National Cancer Institute (NCI)/ ; W81XWH2110539//U.S. Department of Defense (DOD)/ ; R35CA242986//National Cancer Institute (NCI)/ ; T32 CA203703/CA/NCI NIH HHS/United States ; //Prostate Cancer Foundation (PCF)/ ; W81XWH1910712//U.S. Department of Defense (DOD)/ ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/immunology/drug therapy/metabolism ; *Androgen Receptor Antagonists/pharmacology/therapeutic use ; Animals ; Mice ; *Receptors, Androgen/metabolism ; *Histocompatibility Antigens Class I/metabolism/genetics/immunology ; Cell Line, Tumor ; }, abstract = {Immunotherapy options for immune cold tumors, like prostate cancer, are limited. We show that AR downregulates MHCI expression/antigen presentation and that AR inhibition improves T-cell responses and tumor control. This suggests that treatments combining AR inhibitors and checkpoint blockade may improve tumor immune surveillance and antitumor immunity in patients.}, }
@article {pmid39652116, year = {2025}, author = {Azhideh, A and Pouramini, A and Haseli, S and Abbaspour, E and Karande, G and Kafi, F and Chalian, M}, title = {Radiological assessment of extremity bone involvement in Erdheim-Chester disease: a systematic review of case reports.}, journal = {Skeletal radiology}, volume = {54}, number = {7}, pages = {1441-1455}, pmid = {39652116}, issn = {1432-2161}, mesh = {Humans ; *Erdheim-Chester Disease/diagnostic imaging/pathology ; *Extremities/diagnostic imaging ; *Radiography/methods ; }, abstract = {OBJECTIVE: To describe the clinical presentations and radiological manifestations of Erdheim-Chester disease (ECD) in the extremities, with particular emphasis on radiologic findings, as radiographs are typically the initial imaging modality used in clinical practice.
METHODS: Following the PRISMA guidelines, a comprehensive systematic search was performed across Scopus, PubMed, Web of Science, and Embase databases, covering case reports from inception until August 1, 2024. Included were studies with pathologically confirmed ECD (CD68 positive and CD1a negative) that were evaluated with at least one imaging modality and provided detailed descriptions of radiological findings.
RESULTS: Out of 401 identified articles, 20 articles comprising 20 histologically confirmed cases of ECD met the inclusion criteria following screening and full-text review. Pathological reports were assessed for the presence of lipid-laden cells and Touton giant cells, which were identified in 84.2% and 75% of cases, respectively. Upper extremities were affected in 65% of cases and lower extremities in all cases. Symmetric involvement was observed in 84.6% of upper extremity cases and 84.2% of lower extremity cases. Radiological findings were categorized as pure sclerosis (53.3%) and cortical thickening (42.8%) identified as the most common findings. Clinical manifestations were assessed, with pain and swelling in the extremities being the most common symptoms, occurring in 70% of cases.
CONCLUSION: The hallmark of ECD is bilateral, symmetric diaphyseal and/or metaphyseal osteosclerosis in the long tubular bones of the lower extremities. Epiphyseal sparing is observed in more than half of the patients.}, }
@article {pmid39651955, year = {2025}, author = {von Itzstein, MS and Burns, TF and Dowell, JE and Horn, L and Camidge, DR and York, SJ and Eaton, KD and Kyle, K and Fattah, F and Liu, J and Mu-Mosley, H and Gupta, A and Nadeem, U and Gao, A and Zhang, S and Gerber, DE}, title = {Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant Non-Small Cell Lung Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {4}, pages = {639-648}, pmid = {39651955}, issn = {1557-3265}, support = {P30 CA142543/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; 1P30 CA 142543-03//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; P50CA070907-21//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; }, mesh = {Humans ; Female ; Hydrazines/administration & dosage/adverse effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/mortality ; *Proto-Oncogene Proteins p21(ras)/genetics ; Docetaxel/administration & dosage ; Aged ; Male ; Triazoles/administration & dosage/adverse effects ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration & dosage ; *Mutation ; Exportin 1 Protein ; *Lung Neoplasms/drug therapy/genetics/pathology/mortality ; *Karyopherins/antagonists & inhibitors ; Adult ; Aged, 80 and over ; Treatment Outcome ; Maximum Tolerated Dose ; Neoplasm Staging ; }, abstract = {PURPOSE: Patients with Kirsten rat sarcoma viral oncogene (KRAS)-mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on the activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated, advanced KRAS-mutant NSCLC.
PATIENTS AND METHODS: The primary outcomes of this multicenter phase I/II dose-escalation trial of selinexor plus docetaxel were safety and tolerability. Selinexor was started 1 week before docetaxel to permit monotherapy pharmacodynamic assessment.
RESULTS: Among 40 enrolled patients, the median age was 66 years, 55% were female, and 85% were White. The MTD was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every 3 weeks. The most common adverse events were nausea (73%, 8% grade ≥3), fatigue (70%, 5% grade ≥3), neutropenia (65%, 60% grade ≥3), and diarrhea (58%, 10% grade ≥3). Of 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild-type TP53 (42%), including response and disease control rates (27% and 80% vs. 9% and 27%, respectively; P = 0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% confidence interval, 0.07-0.67; P = 0.003). After selinexor initiation and prior to docetaxel administration, serum lactate dehydrogenase levels increased an average of 51 U/L in TP53-altered cases and decreased an average of 48 U/L in TP53 wild-type cases (P = 0.06).
CONCLUSIONS: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS-mutant NSCLC. The regimen has promising efficacy in TP53 wild-type cases, in which selinexor monotherapy may also have activity.}, }
@article {pmid39651886, year = {2025}, author = {Painter, H and Larsen, SE and Williams, BD and Abdelaal, HFM and Baldwin, SL and Fletcher, HA and Fiore-Gartland, A and Coler, RN}, title = {Backtranslation of human RNA biosignatures of tuberculosis disease risk into the preclinical pipeline is condition dependent.}, journal = {mSphere}, volume = {10}, number = {1}, pages = {e0086424}, pmid = {39651886}, issn = {2379-5042}, support = {75N93021C00029/AI/NIAID NIH HHS/United States ; R01 AI125160/AI/NIAID NIH HHS/United States ; R01 AI168023/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Tuberculosis/genetics ; Mycobacterium tuberculosis ; Tuberculosis Vaccines ; *RNA/genetics ; Transcriptome ; Disease Progression ; }, abstract = {UNLABELLED: It is unclear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with Mycobacterium tuberculosis or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk of progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, the characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (replacement, reduction, and refinement) approach we reanalyzed heterogeneous publicly available transcriptional data sets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3, and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes and have been carefully evaluated across several clinical cohorts. These data suggest that in certain experimental designs and in several tissue types, human COR signatures correlate with disease progression as measured by the bacterial burden in the preclinical TB model pipeline. We observed the best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations.
IMPORTANCE: Understanding the strengths or limitations of back-translating human-derived correlate of risk (COR) RNA signatures into the preclinical pipeline may help streamline down-selection of therapeutic vaccine and drug candidates and better align preclinical models with proposed clinical trial efficacy endpoints.}, }
@article {pmid39651791, year = {2025}, author = {Gupta, S and Rau, RE and Kairalla, JA and Rabin, KR and Wang, C and Angiolillo, AL and Alexander, S and Carroll, AJ and Conway, S and Gore, L and Kirsch, I and Kubaney, HR and Li, AM and McNeer, JL and Militano, O and Miller, TP and Moyer, Y and O'Brien, MM and Okada, M and Reshmi, SC and Shago, M and Wagner, E and Winick, N and Wood, BL and Haworth-Wright, T and Zaman, F and Zugmaier, G and Zupanec, S and Devidas, M and Hunger, SP and Teachey, DT and Raetz, EA and Loh, ML}, title = {Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.}, journal = {The New England journal of medicine}, volume = {392}, number = {9}, pages = {875-891}, pmid = {39651791}, issn = {1533-4406}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; U10CA180899/CA/NCI NIH HHS/United States ; U20CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, mesh = {Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *Antibodies, Bispecific/administration & dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects ; Disease-Free Survival ; Kaplan-Meier Estimate ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality ; *Antineoplastic Agents, Immunological/administration & dosage/adverse effects ; Follow-Up Studies ; *Neoplasm Recurrence, Local/epidemiology/prevention & control ; Cytokine Release Syndrome/chemically induced/epidemiology/immunology ; Seizures/chemically induced/epidemiology/immunology ; Sepsis/chemically induced/epidemiology/immunology ; Incidence ; Treatment Outcome ; }, abstract = {BACKGROUND: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.
METHODS: We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival.
RESULTS: The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a higher relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone.
CONCLUSIONS: Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).}, }
@article {pmid39651227, year = {2024}, author = {Liu, B and Greenwood, NF and Bonzanini, JE and Motmaen, A and Sharp, J and Wang, C and Visani, GM and Vafeados, DK and Roullier, N and Nourmohammad, A and Garcia, KC and Baker, D}, title = {Design of high specificity binders for peptide-MHC-I complexes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39651227}, issn = {2692-8205}, support = {CGCATF-2023/100001/CRUK_/Cancer Research UK/United Kingdom ; R01 AI103867/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to denovo design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.}, }
@article {pmid39649604, year = {2024}, author = {Unsworth, M and Fabens, I and Setswe, G and Moyo, K and Pienaar, J and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Sardini, M and Dong, T and Sharma, M and Tweya, H and Ndebele, F and Holec, M and Feldacker, C}, title = {What does it cost to expand two-way texting for post-operative follow-up? A cost analysis in routine voluntary medical male circumcision settings in South Africa.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39649604}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, abstract = {Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa (SSA) region, yet all clients in South Africa (SA) are still required to attend in-person reviews, creating added work for providers and barriers for clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with support from VMMC nurse-led telehealth and that 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this costing activity were to assess the additive cost of 2wT vs. SoC during a stepped wedge design (SWD) expansion trial; costing an augmentation of 2wT with dedicated personnel during peak VMMC periods; and estimate the cost savings of 2wT from the payer perspective if scaled in routine VMMC settings. Data was collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods; sensitivity analysis estimated 2wT costs at scale. We included data from 6,842 males, with 2,586 (38%) opting for 2wT. 2wT participants attended an average of zero visits; SoC males had an average of 2 visits. Under 2wT, quality care markers improved and AE ascertainment increased while loss to follow-up (LTFU) decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When implemented at scale, 2wT appears to significantly reduce costs to the healthcare system while improving the quality of post-operative care and requiring no additional client costs. 2wT should be expanded for eligible males across VMMC and other post-operative contexts in South Africa.}, }
@article {pmid39647999, year = {2025}, author = {Shadman, M and Munir, T and Robak, T and Brown, JR and Kahl, BS and Ghia, P and Giannopoulos, K and Šimkovič, M and Österborg, A and Laurenti, L and Walker, PA and Opat, SS and Ciepluch, H and Greil, R and Hanna, M and Tani, M and Trněný, M and Brander, D and Flinn, IW and Grosicki, S and Verner, E and Tedeschi, A and de Guibert, S and Tumyan, G and Laribi, K and García-Marco, JA and Li, JY and Tian, T and Liu, Y and Korolkiewicz, R and Szeto, A and Tam, CS and Jurczak, W}, title = {Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {7}, pages = {780-787}, pmid = {39647999}, issn = {1527-7755}, mesh = {Humans ; *Bendamustine Hydrochloride/administration & dosage/adverse effects/therapeutic use ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics/mortality ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Female ; Male ; *Pyrimidines/administration & dosage/therapeutic use/adverse effects ; *Rituximab/administration & dosage/adverse effects/therapeutic use ; Middle Aged ; Aged ; *Pyrazoles/administration & dosage/therapeutic use/adverse effects ; *Piperidines/administration & dosage/adverse effects/therapeutic use ; Follow-Up Studies ; Adult ; Aged, 80 and over ; Progression-Free Survival ; }, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.}, }
@article {pmid39645377, year = {2024}, author = {, }, title = {Burden of disease scenarios by state in the USA, 2022-50: a forecasting analysis for the Global Burden of Disease Study 2021.}, journal = {Lancet (London, England)}, volume = {404}, number = {10469}, pages = {2341-2370}, pmid = {39645377}, issn = {1474-547X}, support = {75N94023C00004/HD/NICHD NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Cause of Death/trends ; Disability-Adjusted Life Years/trends ; *Forecasting ; *Life Expectancy/trends ; Risk Factors ; United States/epidemiology ; *Cost of Illness ; *Population Health ; }, abstract = {BACKGROUND: The capacity to anticipate future health issues is important for both policy makers and practitioners in the USA, as such insights can facilitate effective planning, investment, and implementation strategies. Forecasting trends in disease and injury burden is not only crucial for policy makers but also garners substantial interest from the general populace and leads to a better-informed public. Through the integration of new data sources, the refinement of methodologies, and the inclusion of additional causes, we have improved our previous forecasting efforts within the scope of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to produce forecasts at the state and national levels for the USA under various possible scenarios.
METHODS: We developed a comprehensive framework for forecasting life expectancy, healthy life expectancy (HALE), cause-specific mortality, and disability-adjusted life-years (DALYs) due to 359 causes of disease and injury burden from 2022 to 2050 for the USA and all 50 states and Washington, DC. Using the GBD 2021 Future Health Scenarios modelling framework, we forecasted drivers of disease, demographic drivers, risk factors, temperature and particulate matter, mortality and years of life lost (YLL), population, and non-fatal burden. In addition to a reference scenario (representing the most probable future trajectory), we explored various future scenarios and their potential impacts over the next several decades on human health. These alternative scenarios comprised four risk elimination scenarios (including safer environment, improved behavioural and metabolic risks, improved childhood nutrition and vaccination, and a combined scenario) and three USA-specific scenarios based on risk exposure or attributable burden in the best-performing US states (improved high adult BMI and high fasting plasma glucose [FPG], improved smoking, and improved drug use [encompassing opioids, cocaine, amphetamine, and others]).
FINDINGS: Life expectancy in the USA is projected to increase from 78·3 years (95% uncertainty interval 78·1-78·5) in 2022 to 79·9 years (79·5-80·2) in 2035, and to 80·4 years (79·8-81·0) in 2050 for all sexes combined. This increase is forecasted to be modest compared with that in other countries around the world, resulting in the USA declining in global rank over the 2022-50 forecasted period among the 204 countries and territories in GBD, from 49th to 66th. There is projected to be a decline in female life expectancy in West Virginia between 1990 and 2050, and little change in Arkansas and Oklahoma. Additionally, after 2023, we projected almost no change in female life expectancy in many states, notably in Oklahoma, South Dakota, Utah, Iowa, Maine, and Wisconsin. Female HALE is projected to decline between 1990 and 2050 in 20 states and to remain unchanged in three others. Drug use disorders and low back pain are projected to be the leading Level 3 causes of age-standardised DALYs in 2050. The age-standardised DALY rate due to drug use disorders is projected to increase considerably between 2022 and 2050 (19·5% [6·9-34·1]). Our combined risk elimination scenario shows that the USA could gain 3·8 additional years (3·6-4·0) of life expectancy and 4·1 additional years (3·9-4·3) of HALE in 2050 versus the reference scenario. Using our USA-specific scenarios, we forecasted that the USA could gain 0·4 additional years (0·3-0·6) of life expectancy and 0·6 additional years (0·5-0·8) of HALE in 2050 under the improved drug use scenario relative to the reference scenario. Life expectancy and HALE are likewise projected to be 0·4-0·5 years higher in 2050 under the improved adult BMI and FPG and improved smoking scenarios compared with the reference scenario. However, the increases in these scenarios would not substantially improve the USA's global ranking in 2050 (from 66th of 204 in life expectancy in the reference scenario to 63rd-64th in each of the three USA-specific scenarios), indicating that the USA's best-performing states are still lagging behind other countries in their rank throughout the forecasted period. Regardless, an estimated 12·4 million (11·3-13·5) deaths could be averted between 2022 and 2050 if the USA were to follow the combined scenario trajectory rather than the reference scenario. There would also be 1·4 million (0·7-2·2) fewer deaths over the 28-year forecasted period with improved adult BMI and FPG, 2·1 million (1·3-2·9) fewer deaths with improved exposure to smoking, and 1·2 million (0·9-1·5) fewer deaths with lower rates of drug use deaths.
INTERPRETATION: Our findings highlight the alarming trajectory of health challenges in the USA, which, if left unaddressed, could lead to a reversal of the health progress made over the past three decades for some US states and a decline in global health standing for all states. The evidence from our alternative scenarios along with other published studies suggests that through collaborative, evidence-based strategies, there are opportunities to change the trajectory of health outcomes in the USA, such as by investing in scientific innovation, health-care access, preventive health care, risk exposure reduction, and education. Our forecasts clearly show that the time to act is now, as the future of the country's health and wellbeing-as well as its prosperity and leadership position in science and innovation-are at stake.
FUNDING: Bill & Melinda Gates Foundation.}, }
@article {pmid39644910, year = {2025}, author = {Goya, S and Greninger, AL}, title = {Pneumovirus genome misassemblies associated with duplications in glycoprotein genes.}, journal = {The Lancet. Infectious diseases}, volume = {25}, number = {2}, pages = {e60}, doi = {10.1016/S1473-3099(24)00801-6}, pmid = {39644910}, issn = {1474-4457}, }
@article {pmid39644492, year = {2024}, author = {Chao, CW and Sprouse, KR and Miranda, MC and Catanzaro, NJ and Hubbard, ML and Addetia, A and Stewart, C and Brown, JT and Dosey, A and Valdez, A and Ravichandran, R and Hendricks, GG and Ahlrichs, M and Dobbins, C and Hand, A and McGowan, J and Simmons, B and Treichel, C and Willoughby, I and Walls, AC and McGuire, AT and Leaf, EM and Baric, RS and Schäfer, A and Veesler, D and King, NP}, title = {Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115036}, doi = {10.1016/j.celrep.2024.115036}, pmid = {39644492}, issn = {2211-1247}, support = {P01 AI167966/AI/NIAID NIH HHS/United States ; 75N93022C00036/AI/NIAID NIH HHS/United States ; S10 OD030220/OD/NIH HHS/United States ; }, mesh = {*Middle East Respiratory Syndrome Coronavirus/immunology ; Animals ; *Antibodies, Neutralizing/immunology ; *Nanoparticles/chemistry ; Mice ; Humans ; *Viral Vaccines/immunology ; *Spike Glycoprotein, Coronavirus/immunology ; *Antibodies, Viral/immunology ; Coronavirus Infections/immunology/prevention & control/virology ; Mice, Inbred BALB C ; Female ; Epitopes/immunology ; Nanovaccines ; }, abstract = {Middle East respiratory syndrome coronavirus (MERS-CoV) is a betacoronavirus that causes severe respiratory illness in humans. There are no licensed vaccines against MERS-CoV and only a few candidates in phase I clinical trials. Here, we develop MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two-component nanoparticles displaying spike (S)-derived antigens induce neutralizing responses and protect mice against challenge with mouse-adapted MERS-CoV. Epitope mapping reveals the dominant responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle elicits antibodies targeting multiple non-overlapping epitopes in the RBD. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.}, }
@article {pmid39644022, year = {2024}, author = {Radich, J}, title = {Mutations and MRD: clinical implications of clonal ontogeny.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2024}, number = {1}, pages = {150-157}, pmid = {39644022}, issn = {1520-4383}, mesh = {Humans ; *Neoplasm, Residual ; *Leukemia, Myeloid, Acute/genetics/pathology ; *Mutation ; Recurrence ; }, abstract = {Measurable residual disease (MRD) is a strong but imprecise predictor of relapse in acute myeloid leukemia. Many patients fall into the outlier categories of MRD positivity without relapse or MRD negativity with relapse. Why? We will discuss these states in the context of "clonal ontogeny" examining how mutations, clonal structure, and Darwinian rules impact response, resistance, and relapse.}, }
@article {pmid39643988, year = {2024}, author = {Kuczmarski, TM and Lynch, RC}, title = {Has PD-1 blockade changed the standard of care for cHL?.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2024}, number = {1}, pages = {505-510}, pmid = {39643988}, issn = {1520-4383}, mesh = {Humans ; *Hodgkin Disease/drug therapy/therapy ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors ; *Standard of Care ; Immune Checkpoint Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Nivolumab/therapeutic use ; }, abstract = {The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.}, }
@article {pmid39643004, year = {2025}, author = {El Kalach, N and Julceus, EF and Rudisill, AC and Malik, FS and Flory, K and Frongillo, EA and Sauder, KA and Mendoza, JA and Liese, AD}, title = {Association Between Food Insecurity and Inability to Obtain Provider-Recommended Medications, Multidisciplinary Services, and Technology in Youth and Young Adults With Diabetes: A Cross-Sectional Study.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {298-305}, pmid = {39643004}, issn = {1530-891X}, support = {R01 DK117461/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Cross-Sectional Studies ; *Food Insecurity ; Male ; Female ; Adolescent ; Young Adult ; *Diabetes Mellitus, Type 1/therapy/drug therapy/epidemiology ; *Diabetes Mellitus, Type 2/therapy/drug therapy/epidemiology ; Adult ; *Hypoglycemic Agents/therapeutic use ; *Health Services Accessibility/statistics & numerical data ; }, abstract = {OBJECTIVE: We assessed if food insecurity (FI) is associated with not obtaining recommended diabetes medications, technology, and multidisciplinary services, and explored the most common reasons for not obtaining recommended treatments in youth and young adults (YYA) with diabetes.
METHODS: In this cross-sectional study, among 911 YYA with type 1 diabetes (T1D) and 144 with type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study Follow-up 1 (2018-2021), FI (≥ 3 items affirmed from the 18-item Household Food Security Survey module), and inability to obtain recommended treatments were self-reported.
RESULTS: Almost 30% of YYA with T1D and FI and 20% of YYA with T2D and FI did not obtain 1 or more recommended treatments. Participants with T1D who reported FI had higher odds of not obtaining insulin (OR 3.2, 95% CI 1.2-8.4), mental health counseling (OR 3.3, 95% CI 1.3-8.2), diabetes education (OR 3.6, 95% CI 1.4-9.3), an insulin pump (OR 2.2, 95% CI 1.2-4.4), and a continuous glucose monitor (OR 2.5, 95% CI 1.5-4.4) compared to those who reported food security. Among participants with T2D, FI was related to not obtaining dietician services (OR 8.1, 95% CI 1.2-53.8). Participants with T1D and FI reported more financial reasons for not obtaining a continuous glucose monitor compared to food secure participants.
CONCLUSION: YYA with diabetes and FI face constraints in obtaining medications, diabetes technology, and multidisciplinary services, largely due to financial and structural reasons. New strategies are needed to bridge the gap between medical care required vs obtained by YYA with diabetes.}, }
@article {pmid39642888, year = {2025}, author = {Qiu, Y and Su, Y and Xie, E and Cheng, H and Du, J and Xu, Y and Pan, X and Wang, Z and Chen, DG and Zhu, H and Greenberg, PD and Li, G}, title = {Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.}, journal = {Cancer cell}, volume = {43}, number = {1}, pages = {103-121.e8}, pmid = {39642888}, issn = {1878-3686}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Cell Differentiation/immunology ; *Mannose/metabolism/pharmacology ; Mice ; Humans ; N-Acetylglucosaminyltransferases/metabolism ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; Mice, Inbred C57BL ; *Neoplasms/immunology/therapy/metabolism ; beta Catenin/metabolism ; Cell Proliferation ; Immunotherapy, Adoptive/methods ; Cell Line, Tumor ; Lymphocyte Activation ; }, abstract = {Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8[+] T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.}, }
@article {pmid39642637, year = {2024}, author = {Rosenberg, JE and Galsky, MD and Powles, T and Petrylak, DP and Bellmunt, J and Loriot, Y and Necchi, A and Hoffman-Censits, J and Perez-Gracia, JL and van der Heijden, MS and Dreicer, R and Durán, I and Castellano, D and Drakaki, A and Retz, M and Sridhar, SS and Grivas, P and Yu, EY and O'Donnell, PH and Burris, HA and Mariathasan, S and Shi, Y and Goluboff, E and Bajorin, D}, title = {Atezolizumab monotherapy for metastatic urothelial carcinoma: final analysis from the phase II IMvigor210 trial.}, journal = {ESMO open}, volume = {9}, number = {12}, pages = {103972}, pmid = {39642637}, issn = {2059-7029}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Carcinoma, Transitional Cell/drug therapy ; Urologic Neoplasms/drug therapy/pathology ; Adult ; B7-H1 Antigen/metabolism/antagonists & inhibitors ; Treatment Outcome ; }, abstract = {BACKGROUND: The IMvigor210 trial demonstrated clinical benefit and manageable toxicity with atezolizumab monotherapy [anti-programmed death-ligand 1 (PD-L1)] in patients with metastatic urothelial carcinoma (UC) in primary analyses. Final efficacy and safety results after long-term follow-up are reported.
PATIENTS AND METHODS: This phase II single-arm trial of atezolizumab monotherapy in patients with advanced UC included two cohorts: untreated patients ineligible for cisplatin-based chemotherapy (cohort 1; n = 119) and those previously treated with platinum-based chemotherapy (cohort 2; n = 310). Atezolizumab was administered i.v. (1200 mg every 21 days) until progression or unacceptable toxicity. Primary endpoints were independent review facility-assessed confirmed objective response rate (ORR) per RECIST 1.1 in cohort 1 and independent review facility-assessed ORR per RECIST 1.1 and investigator-assessed modified (m)RECIST in cohort 2. Overall survival (OS), efficacy by PD-L1 status, and safety were also assessed.
RESULTS: At data cut-off (1 June 2023), the median survival follow-up was 96.4 months (range, 0.2-103.4 months) in cohort 1 and 46.2 months [0.2 (censored)-54.9 months] in cohort 2. In cohort 1, the ORR [95% confidence interval (CI)] was 23.5% (16.2% to 32.2%) in all patients and 28.1% (13.8% to 46.8%) in the PD-L1 tumor-infiltrating immune cell (IC)2/3 subgroup. Median OS (95% CI) was 16.3 months (10.4-24.5 months) overall and 12.3 months (6.0-49.8 months) in the PD-L1 IC2/3 subgroup. In cohort 2, the ORR (95% CI) was 16.5% (12.5% to 21.1%) per RECIST 1.1 and 19.7% (95% CI 15.4% to 24.6%) per mRECIST in all patients and 27.0% (18.6% to 36.8%) and 28.0% (19.5% to 37.9%), respectively, in the PD-L1 IC2/3 subgroup. Median OS (95% CI) was 7.9 months (6.7-9.3 months) in all patients and 11.9 months (9.0-22.8 months) in the IC2/3 subgroup. Treatment-related grade 3/4 adverse events occurred in 21.8% (cohort 1) and 18.7% (cohort 2); one treatment-related death occurred in cohort 1.
CONCLUSIONS: With long-term follow-up, atezolizumab monotherapy demonstrated clinically meaningful efficacy with durable responses in a subset of patients with metastatic UC; there were no new safety signals.}, }
@article {pmid39642635, year = {2024}, author = {Choueiri, TK and Kuzel, TM and Tykodi, SS and Verzoni, E and Kluger, H and Nair, S and Perets, R and George, S and Gurney, H and Pachynski, RK and Folefac, E and Castonguay, V and Lee, CH and Vaishampayan, U and Miller, WH and Bhagavatheeswaran, P and Wang, Y and Gupta, S and DeSilva, H and Lee, CW and Escudier, B and Motzer, RJ}, title = {Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial.}, journal = {ESMO open}, volume = {9}, number = {12}, pages = {104073}, pmid = {39642635}, issn = {2059-7029}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Nivolumab/therapeutic use/pharmacology/administration & dosage ; *Carcinoma, Renal Cell/drug therapy/mortality ; Male ; Female ; *Ipilimumab/therapeutic use/pharmacology/administration & dosage ; Middle Aged ; *Kidney Neoplasms/drug therapy/mortality/pathology ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.
METHODS: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.
RESULTS: FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments.
CONCLUSIONS: Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.}, }
@article {pmid39640936, year = {2024}, author = {Hawwash, NK and Sperrin, M and Martin, GP and Sinha, R and Matthews, CE and Ricceri, F and Tjønneland, A and Heath, AK and Neuhouser, ML and Joshu, CE and Platz, EA and Freisling, H and Gunter, MJ and Renehan, AG}, title = {Excess weight by degree and duration and cancer risk (ABACus2 consortium): a cohort study and individual participant data meta-analysis.}, journal = {EClinicalMedicine}, volume = {78}, number = {}, pages = {102921}, pmid = {39640936}, issn = {2589-5370}, support = {001/WHO_/World Health Organization/International ; }, abstract = {BACKGROUND: Elevated body mass index (BMI) ≥25 kg/m[2] is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m[2,] and cancer incidence, and compare this with single BMI.
METHODS: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m[2]) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270.
FINDINGS: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I[2]: 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I[2]: 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I[2]: 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I[2]: 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I[2]: 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I[2]: 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I[2]: 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I[2]: 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women.
INTERPRETATION: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure.
FUNDING: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council.}, }
@article {pmid39638730, year = {2025}, author = {Barata, PC and Zarrabi, KK and Bex, A and Grivas, P and Hermann, K and Hofman, MS and Li, R and Lopez-Beltran, A and Padani, AR and Powles, T and Taplin, ME and Loriot, Y}, title = {Novel Methods to Assess Tumor Burden and Minimal Residual Disease in Genitourinary Cancers.}, journal = {European urology}, volume = {87}, number = {4}, pages = {412-423}, doi = {10.1016/j.eururo.2024.11.011}, pmid = {39638730}, issn = {1873-7560}, mesh = {Humans ; Neoplasm, Residual ; *Urogenital Neoplasms/pathology/diagnostic imaging/genetics/therapy ; *Tumor Burden ; Male ; }, abstract = {BACKGROUND AND OBJECTIVE: Advances in molecular diagnostics have ushered in a new era for patients with prostate, renal, and urothelial cancers, with novel radiographic and molecular modalities for the assessment of disease burden and minimal residual disease (MRD). Conventional imaging has a limited threshold for disease detection and is often unable to discern clinically occult disease with varying risks of false-negative or false-positive findings depending on the disease state and type of imaging.
METHODS: We provide an overview of emerging radiographic and molecular tools in development within the genitourinary (GU) disease space. A literature review of contemporary basic, translational, and clinical research studies was performed, covering the timeframe of 1980-2024 through the MEDLINE (via PubMed) and Scopus databases. We highlight select examples of emerging technologies and biomarker-informed clinical trials, which aim to quantify disease at lower thresholds and have the potential for integrating MRD in clinical practice for GU patients.
KEY FINDINGS AND LIMITATIONS: The development of novel radiotracers, such as prostate-specific membrane antigen or carbonic anhydrase IX, is being evaluated in both clinical practice and trial setting, aiming to change the management of these tumors. Molecular tools including circulating tumor cells and byproducts such as plasma and urine cell-free circulating tumor DNA provide the opportunity for MRD detection. MRD capture on single-cell or cellular byproducts can serve as a conduit for genomic and transcriptomic analyses, providing insight into the molecular underpinnings and clonal evolution of disease.
While the full potential for MRD applications has yet to be realized, we are witnessing the emergence of novel techniques aimed at MRD detection and the rapid development of elegantly designed studies implementing iterative detection of MRD as means to provide biological rationale and tailor therapeutic options in GU tumors.}, }
@article {pmid39638687, year = {2025}, author = {Zacchi, F and Abida, W and Antonarakis, ES and Bryce, AH and Castro, E and Cheng, HH and Shandhu, S and Mateo, J}, title = {Recent and Future Developments in the Use of Poly (ADP-ribose) Polymerase Inhibitors for Prostate Cancer.}, journal = {European urology oncology}, volume = {8}, number = {3}, pages = {818-828}, doi = {10.1016/j.euo.2024.11.011}, pmid = {39638687}, issn = {2588-9311}, mesh = {Humans ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/pharmacology ; Male ; *Prostatic Neoplasms/drug therapy/genetics ; }, abstract = {BACKGROUND AND OBJECTIVE: Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies.
METHODS: This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy.
KEY FINDINGS AND LIMITATIONS: Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble.
PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations. There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.
PATIENT SUMMARY: Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.}, }
@article {pmid39636638, year = {2024}, author = {Back, AL and Freeman-Young, TK and Morgan, L and Sethi, T and Baker, KK and Myers, S and McGregor, BA and Harvey, K and Tai, M and Kollefrath, A and Thomas, BJ and Sorta, D and Kaelen, M and Kelmendi, B and Gooley, TA}, title = {Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {7}, number = {12}, pages = {e2449026}, pmid = {39636638}, issn = {2574-3805}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Burnout, Professional/drug therapy ; *COVID-19/psychology ; *Depression/drug therapy ; Double-Blind Method ; Hallucinogens/therapeutic use ; Pandemics ; *Psilocybin/therapeutic use ; *Stress Disorders, Post-Traumatic/drug therapy ; Treatment Outcome ; }, abstract = {IMPORTANCE: The psychological morbidity experienced by physicians, advanced practice practitioners (APPs), and nurses from working during the COVID-19 pandemic includes burnout, depression, and posttraumatic stress disorder (PTSD).
OBJECTIVE: To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic.
This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no prepandemic mental health diagnoses but had moderate or severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle.
INTERVENTION: One intervention episode consisted of 2 preparation visits, 1 medication session, and 3 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally.
MAIN OUTCOME AND MEASURES: The primary outcome was a change from baseline (preparation 1 session) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. The secondary outcomes were a change in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]).
RESULTS: A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) participated, of whom 15 were randomly assigned to receive psilocybin and 15 to receive niacin. The mean change in symptoms of depression (MADRS scores) from preparation 1 session to day 28 was -21.33 (7.84) in the psilocybin arm compared with -9.33 (7.32) in the niacin arm, with a mean difference between arms of -12.00 (95% CI, -17.67 to -6.33; P < .001), a decrease in MADRS scores indicating improvement. The mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger improvement in symptoms of burnout in the psilocybin compared with the niacin arm (-6.40 [5.00] vs -2.33 [5.97]; P = .05) but was not statistically significant. Since the SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (-16.67 [15.04] vs -6.73 [10.69]), but this difference was not statistically tested.
CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that psilocybin therapy resulted in a significant, sustained reduction in symptoms of depression experienced by clinicians after frontline work during the COVID-19 pandemic. The findings establish psilocybin therapy as a new paradigm of treatment for this postpandemic condition.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05163496.}, }
@article {pmid39636625, year = {2025}, author = {Goddard, KAB and Feuer, EJ and Mandelblatt, JS and Meza, R and Holford, TR and Jeon, J and Lansdorp-Vogelaar, I and Gulati, R and Stout, NK and Howlader, N and Knudsen, AB and Miller, D and Caswell-Jin, JL and Schechter, CB and Etzioni, R and Trentham-Dietz, A and Kurian, AW and Plevritis, SK and Hampton, JM and Stein, S and Sun, LP and Umar, A and Castle, PE}, title = {Estimation of Cancer Deaths Averted From Prevention, Screening, and Treatment Efforts, 1975-2020.}, journal = {JAMA oncology}, volume = {11}, number = {2}, pages = {162-167}, pmid = {39636625}, issn = {2374-2445}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; U01 CA253915/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Neoplasms/mortality/prevention & control/therapy/diagnosis ; *Early Detection of Cancer ; United States/epidemiology ; Colorectal Neoplasms/mortality/therapy/diagnosis/prevention & control ; Middle Aged ; Incidence ; Aged ; Lung Neoplasms/mortality/therapy/prevention & control/diagnosis ; Risk Factors ; Uterine Cervical Neoplasms/mortality/therapy/diagnosis/prevention & control ; Mass Screening ; Prostatic Neoplasms/mortality/therapy/diagnosis/prevention & control ; }, abstract = {IMPORTANCE: Cancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites.
OBJECTIVE: To quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers.
In this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020. Model inputs were based on national data on risk factors, cancer incidence, cancer survival, and mortality due to other causes, and dissemination and effects of prevention, screening (for interception and early detection), and treatment. Simulated or modeled data using parameters derived from multiple birth cohorts of the US population were used.
INTERVENTIONS: Primary prevention via smoking reduction (lung), screening for interception (cervix and colorectal) or early detection (breast, cervix, colorectal, and prostate), and therapy (breast, colorectal, lung, and prostate).
MAIN OUTCOMES AND MEASURES: The estimated cumulative number of cancer deaths averted with interventions vs no advances.
RESULTS: An estimated 5.94 million cancer deaths were averted for breast, cervical, colorectal, lung, and prostate cancers combined. Cancer prevention and screening efforts averted 8 of 10 of these deaths (4.75 million averted deaths). The contribution of each intervention varied by cancer site. Screening accounted for 25% of breast cancer deaths averted. Averted cervical cancer deaths were nearly completely averted through screening and removal of cancer precursors as treatment advances were modest during the study period. Averted colorectal cancer deaths were averted because of screening and removal of precancerous polyps or early detection in 79% and treatment advances in 21%. Most lung cancer deaths were avoided by smoking reduction (98%) because screening uptake was low and treatment largely palliative before 2014. Screening contributed to 56% of averted prostate cancer deaths.
CONCLUSIONS AND RELEVANCE: Over the past 45 years, cancer prevention and screening accounted for most cancer deaths averted for these causes; however, their contribution varied by cancer site according to these models using population-level cancer mortality data. Despite progress, efforts to reduce the US cancer burden will require increased dissemination of effective interventions and new technologies and discoveries.}, }
@article {pmid39634680, year = {2024}, author = {Alamin, T and Lin-Martore, M and Kornblith, AE and O'Donnell, A and Gragalia, S}, title = {Piloting a Diagnostic Foot and Ankle Fracture Sonographic Algorithm with Rural and Adolescent Patients.}, journal = {POCUS journal}, volume = {9}, number = {2}, pages = {102-108}, pmid = {39634680}, issn = {2369-8543}, abstract = {Background: Foot and ankle injuries are a common presenting complaint to the Emergency Department (ED) and are often assessed with plain radiography. Rural environments may not have access to radiography mandating the referral or transfer patients to regional centers for definitive diagnosis. The Ottawa Foot and Ankle Rules (OFAR) is a clinical decision rule that can assist in ruling out fractures. Point of care ultrasound (POCUS) can augment this decision rule. The objective of this study was to assess both the feasibility and test characteristics of a previously described POCUS augmented clinical assessment, OFAR-POCUS, for adolescent and adult patients with foot and ankle pain in a rural environment. Methods: This was a prospective cohort study from June to August 2022 including patients with chief complaint of foot or ankle injury presenting to a rural clinic. Patients were included if they had positive finding(s) on the OFAR Test and required radiographic imaging. Patients were excluded if they did not consent, speak English, were unable to be scanned, had obvious joint deformities, had altered mental status, were not physiologically stable, had other injuries preventing sonography, were pregnant, or had previous injury with internal fixation, osteomyelitis, or rheumatoid arthritis. POCUS was performed before transport for radiography. POCUS examiners were POCUS novices who underwent a one and a half to two-hour, standardized foot and ankle POCUS training session. All POCUS studies were reviewed by two emergency medicine ultrasound fellowship trained faculty for quality assurance. Standard test characteristics were calculated for bedside clinician and expert POCUS interpretations compared to the radiographic control. Results: Thirteen POCUS examiners performed exams on 20 patients included in analysis; four patients had fractures on radiograph (20%). The bedside clinician POCUS interpretation had sensitivity (SN) = 100% (95% Cl, 40%-100%), specificity (SP) =94% (95% Cl, 70%-100%), and negative likelihood ratio (-LR) = 16.00 (95% Cl, 2.40-106.73). Expert POCUS interpretation had SN=75% (95% Cl, 19%-99%), SP=75% (95% Cl, 48%-93%), and -LR=0.33 (95% Cl, 0.06-1.86). Conclusion: A POCUS enhanced clinical strategy for clinically significant foot and ankle fractures in adolescent and adult patients in a rural setting is feasible. Larger studies are required to further characterize test characteristics and use of foot and ankle POCUS where plain radiography is unavailable.}, }
@article {pmid39633050, year = {2025}, author = {Lyu, A and Fan, Z and Clark, M and Lea, A and Luong, D and Setayesh, A and Starzinski, A and Wolters, R and Arias-Badia, M and Allaire, K and Wu, K and Gurunathan, V and Valderrábano, L and Wei, XX and Miller, RA and Van Allen, EM and Fong, L}, title = {Evolution of myeloid-mediated immunotherapy resistance in prostate cancer.}, journal = {Nature}, volume = {637}, number = {8048}, pages = {1207-1217}, pmid = {39633050}, issn = {1476-4687}, support = {P30 DK063720/DK/NIDDK NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; S10 OD021822/OD/NIH HHS/United States ; U01 CA233100/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Animals ; Humans ; Mice ; *Prostatic Neoplasms, Castration-Resistant/immunology/pathology/drug therapy/therapy ; *Drug Resistance, Neoplasm/immunology/drug effects ; *Immunotherapy ; CD8-Positive T-Lymphocytes/immunology ; Osteopontin/genetics/metabolism ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Tumor-Associated Macrophages/immunology/drug effects/metabolism ; Single-Cell Analysis ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors/immunology ; Disease Progression ; B7-H1 Antigen/antagonists & inhibitors/immunology ; Signal Transduction/drug effects ; *Myeloid Cells/immunology/drug effects ; Disease Models, Animal ; }, abstract = {Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)[1,2], partly because there are immunosuppressive myeloid cells in tumours[3,4]. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1[hi]-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8[+] T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1[hi]-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1[hi]-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1[hi]-TAM-mediated immunosuppression in CD8[+] T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1[hi]-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1[hi]-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.}, }
@article {pmid39632080, year = {2025}, author = {Alamdarloo, SM and Hashemi, A and Hessami, K and Askary, E and Barzegar, H and Haseli, S and Abbaspour, E}, title = {Gross hematuria and placenta percreta: Report of two cases and literature review.}, journal = {The journal of obstetrics and gynaecology research}, volume = {51}, number = {1}, pages = {e16177}, doi = {10.1111/jog.16177}, pmid = {39632080}, issn = {1447-0756}, mesh = {Humans ; Female ; *Placenta Accreta/surgery/diagnosis ; Pregnancy ; *Hematuria/etiology ; Adult ; *Hysterectomy ; Cesarean Section ; }, abstract = {Placenta percreta, a rare variant of placenta accreta spectrum (PAS) disorders, poses a significant risk of life-threatening hemorrhage associated with the adherent placenta. Bladder involvement signifies an even rarer incidence and may sometimes present solely with gross hematuria. Therefore, it is imperative to consider both microscopic and gross hematuria during pregnancy as alarming signs. Among 342 cases of PAS admitted to our hospital between 2016 and 2023, 48 patients were diagnosed with placenta percreta. Two patients, one at 18 weeks and the other at 25 weeks of pregnancy, were referred to our tertiary care center due to severe gross hematuria. Following thorough preoperative evaluation, both pregnancies were terminated due to their unstable conditions. The first case underwent an elective supracervical cesarean hysterectomy at the 19th week of gestation, while the second case underwent an emergency total cesarean hysterectomy due to lack of response to blood transfusions. Both procedures included bilateral internal iliac artery ligation. Postoperatively, patients recovered without any complications; however, the fetuses did not survive. Placenta percreta, protruding into the bladder, can lead to severe hematuria at any stage of pregnancy, increasing the risk of life-threatening hemorrhage. Therefore, both microscopic and macroscopic hematuria during pregnancy should be considered alarming signs that require immediate attention. Early involvement of a urologist and a multidisciplinary medical team is also essential in suspected or confirmed cases of placenta percreta, as immediate surgical intervention may be necessary to ensure patient safety.}, }
@article {pmid39626349, year = {2025}, author = {Liang, EC and Huang, JJ and Portuguese, AJ and Ortiz-Maldonado, V and Albittar, A and Wuliji, N and Basom, R and Jeon, Y and Wu, Q and Torkelson, A and Kirchmeier, D and Chutnik, A and Pender, B and Sorror, M and Hill, JA and Kopmar, NE and Banerjee, R and Cowan, AJ and Green, D and Gopal, AK and Poh, C and Shadman, M and Hirayama, AV and Till, BG and Kimble, EL and Iovino, L and Chapuis, AG and Otegbeye, F and Cassaday, RD and Milano, F and Turtle, CJ and Maloney, DG and Gauthier, J}, title = {Development and validation of predictive models of early immune effector cell-associated hematotoxicity.}, journal = {Blood advances}, volume = {9}, number = {3}, pages = {606-616}, pmid = {39626349}, issn = {2473-9537}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; Biomarkers ; *Immunotherapy, Adoptive/adverse effects/methods ; Aged ; *Hematologic Neoplasms/therapy ; Adolescent ; Young Adult ; }, abstract = {Immune effector cell-associated hematotoxicity (ICAHT) is associated with morbidity and mortality after chimeric antigen receptor (CAR) T-cell therapy. To date, the factors associated with ICAHT are poorly characterized, and there is no validated predictive model of ICAHT as defined by current consensus criteria. Therefore, we performed comprehensive univariate analyses to identify factors associated with severe (grade 3-4) early ICAHT (eICAHT) in 691 patients who received commercial or investigational CAR T-cell therapy for hematologic malignancies. In univariate logistic regression, preinfusion factors associated with severe eICAHT included disease type (acute lymphoblastic leukemia), prelymphodepletion (pre-LD) blood counts including absolute neutrophil count (ANC), lactate dehydrogenase (LDH), and inflammatory (C-reactive protein [CRP], ferritin, and interleukin-6 [IL-6]) and coagulopathy biomarkers (D-dimer). Postinfusion laboratory markers associated with severe eICAHT included early and peak levels of inflammatory biomarkers (CRP, ferritin, and IL-6), coagulopathy biomarkers (D-dimer), peak cytokine release syndrome grade, and peak neurotoxicity grade. We trained (n = 483) and validated (n = 208) 2 eICAHT prediction models (eIPMs): eIPMPre including preinfusion factors only (disease type and pre-LD ANC, platelet count, LDH, and ferritin) and eIPMPost containing both preinfusion (disease type and pre-LD ANC, platelet count, and LDH) and early postinfusion (day +3 ferritin) factors. Both models generated calibrated predictions and high discrimination (area under the receiver operating characteristic curve in test set, 0.87 for eIPMPre and 0.88 for eIPMPost), with higher net benefit in decision curve analysis for eIPMPost. Individualized predictions of severe eICAHT can be generated from both eIPMs using our online tool (available at https://eipm.fredhutch.org).}, }
@article {pmid39626158, year = {2024}, author = {Crupi, E and Costa de Padua, T and Marandino, L and Fallara, G and Pederzoli, F and Cimadamore, A and Goetz, EC and Cigliola, A and Patané, DA and Mercinelli, C and Tateo, V and Salonia, A and Briganti, A and Montorsi, F and Meeks, JJ and Spiess, PE and Alhalabi, O and Gao, J and Kamat, AM and Grivas, P and Necchi, A and Raggi, D}, title = {Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400470}, doi = {10.1200/PO-24-00470}, pmid = {39626158}, issn = {2473-4284}, mesh = {Humans ; *Urogenital Neoplasms/pathology/metabolism ; *Cell Adhesion Molecules/analysis ; Urinary Bladder Neoplasms/pathology/metabolism ; Male ; Nectins ; }, abstract = {PURPOSE: Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially in urothelial carcinoma of the bladder (UBC). Limited data on N4 positivity in nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate N4 positivity among GU malignancies.
METHODS: A systematic literature review was performed on March 2023 using PubMed, MEDLINE, and Embase databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Protocol was amended to incorporate a new updated search on March 2024.
RESULTS: Twenty-five studies evaluating N4 positivity in GU tumors were included, 14 on UBC, three on upper tract urothelial carcinoma (UTUC), six on histologic subtypes (HS) and divergent histology of the bladder, one on papillary renal cell carcinoma (pRCC), one in chromophobe RCC (chRCC), two on penile cancer, one in prostate cancer (PCa). Among UBC, stratifying per stage N4 positivity was higher in metastatic (weighted mean [WM], 90.8; range, 59.6-100) and in non-muscle-invasive (WM, 87.4; range, 86.7-88.3) than in muscle-invasive UC (WM, 83.1; range, 68.2-100). The N4 positivity of UBC was higher than UTUC (WM, 62.9; range, 44.4-65.7). Immunohistochemistry N4 positivity was reported to be lower in non-UC malignancies, including pRCC (WM, 44.1; range, 44.1-44.1), HS (WM, 63.5; range, 0-100), PCa (WM0; range, 0-0), chRCC (WM, 18.5; range, 18.5-18.5), and penile cancer (WM, 86.5; range, 61.4-98.3), compared with UBC overall (WM, 87.1; range, 59.6-100).
CONCLUSION: Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.}, }
@article {pmid39625477, year = {2024}, author = {Sinnott-Armstrong, N and Fields, S and Roth, F and Starita, LM and Trapnell, C and Villen, J and Fowler, DM and Queitsch, C}, title = {Understanding genetic variants in context.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39625477}, issn = {2050-084X}, support = {5RM1HG010461/NH/NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; NIGMS R35GM139532/NH/NIH HHS/United States ; Creativity Award//Bruce G. Cochener Foundation/ ; R35 GM139532/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Genetic Variation ; Genomics/methods ; Genetic Predisposition to Disease ; Animals ; Phenotype ; }, abstract = {Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes - most notably functional regulatory elements - in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants - at all scales, from other genetic variants and gene regulation to cell biology to organismal environment - are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.}, }
@article {pmid39624798, year = {2024}, author = {Liu, WL and Kampouri, E and Bui, JK and Sekhon, MK and Tercero, A and Finlay, D and Asghedom, LH and Romasanta, GR and Rice, NT and Ranjbaran, F and Stoltzman, C and Cook, J and Blake, J and Delaney, CS and Hill, JA}, title = {Off-the-shelf allogeneic natural killer cells for the treatment of COVID-19.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {4}, pages = {101361}, pmid = {39624798}, issn = {2329-0501}, support = {T32 AI007140/AI/NIAID NIH HHS/United States ; }, abstract = {Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 10[6], 300 × 10[6], or 900 × 10[6] cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy.}, }
@article {pmid39624744, year = {2024}, author = {Mittal, V and So, JY and Li, S and Swetter, SM and Linos, E and Van Horn, L and Neuhouser, ML and Stefanick, ML and Tang, JY}, title = {Associations between dietary and supplemental vitamin A intake and melanoma and non-melanoma skin cancer.}, journal = {Skin health and disease}, volume = {4}, number = {6}, pages = {e462}, pmid = {39624744}, issn = {2690-442X}, abstract = {BACKGROUND: Cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) are rising in postmenopausal women. Although high doses of oral vitamin A reduce NMSC risk in high-risk patients, the role of vitamin A in preventing skin cancer in this group remains unexplored.
OBJECTIVES: To determine the association between total (dietary and supplemental) vitamin A and risk of CM and NMSC in postmenopausal women.
METHODS: This retrospective cohort study included 52 877 White women from the Women's Health Initiative cohort, spanning from 1993 to 2019. Exposures were intake of total vitamin A, retinol and provitamin A carotenoids. Cox proportional hazard models estimated hazard ratios for overall CM incidence, whereas logistic regression determined odds ratios (ORs) for melanoma subtypes and NMSC.
RESULTS: 1154 cases of CM and 9085 cases of NMSC were identified over an average follow-up period of 17.8 years (SD 6.7). No associations were identified between total vitamin A intake and melanoma risk. Higher dietary vitamin A intake was associated with higher risk of NMSC (OR of 3rd vs. 1st tertile of dietary intake = 1.12, 95% confidence interval [CI] [1.06, 1.18]), as was dietary beta-cryptoxanthin, a provitamin A carotenoid (OR of 3rd vs. 1st tertile of dietary intake = 1.22, 95% CI [1.15, 1.29]); these results were consistent across both age- and fully adjusted regression models.
CONCLUSIONS: Total vitamin A intake was not associated with lower risk of CM or NMSC. Dietary vitamin A and beta-cryptoxanthin intake were associated with a slightly higher risk of NMSC in postmenopausal women.}, }
@article {pmid39624634, year = {2024}, author = {Huang, Y and Dasgupta, S}, title = {Biomarker Panel Development Using Logic Regression in the Presence of Missing Data.}, journal = {The New England Journal of Statistics in Data Science}, volume = {2}, number = {1}, pages = {3-14}, pmid = {39624634}, issn = {2693-7166}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {We consider the problem of developing flexible and parsimonious biomarker combinations for cancer early detection in the presence of variable missingness at random. Motivated by the need to develop biomarker panels in a cross-institute pancreatic cyst biomarker validation study, we propose logic-regression based methods for feature selection and construction of logic rules under a multiple imputation framework. We generate ensemble trees for classification decision, and further select a single decision tree for simplicity and interpretability. We demonstrate superior performance of the proposed methods compared to alternative methods based on complete-case data or single imputation. The methods are applied to the pancreatic cyst data to estimate biomarker panels for pancreatic cysts subtype classification and malignant potential prediction.}, }
@article {pmid39624016, year = {2025}, author = {Georges, GE and Khanna, D and Wener, MH and Mei, MG and Mayes, MD and Simms, RW and Sanchorawala, V and Hosing, C and Kafaja, S and Pawarode, A and Holmberg, LA and Kolfenbach, J and Furst, DE and Sullivan, KM and Huang, S and Gooley, T and Nash, RA}, title = {Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation for Diffuse Cutaneous Systemic Sclerosis: Identifying Disease Risk Factors for Toxicity and Long-Term Outcomes in a Prospective, Single-Arm Trial.}, journal = {Arthritis & rheumatology (Hoboken, N.J.)}, volume = {77}, number = {5}, pages = {571-581}, pmid = {39624016}, issn = {2326-5205}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Prospective Studies ; Mycophenolic Acid/therapeutic use ; Cyclophosphamide/therapeutic use ; Adult ; Transplantation, Autologous ; *Scleroderma, Diffuse/therapy/mortality ; *Immunosuppressive Agents/therapeutic use ; Antilymphocyte Serum/therapeutic use ; Risk Factors ; Treatment Outcome ; Aged ; }, abstract = {OBJECTIVE: Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSCs) compared with monthly cyclophosphamide (CY). We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of a CD34+ selected graft, could provide comparable AHSCT outcomes.
METHODS: Twenty patients with high-risk SSc were enrolled in a prospective, single-arm trial with CY 200 mg/kg and horse antithymocyte globulin (ATG; CY200/ATG), followed by unmanipulated autologous PBSC, and then MMF maintenance starting at 2 months after AHSCT.
RESULTS: Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% confidence interval [CI] 60.4%-94.9%) and 75% (95% CI 50%-88.7%), respectively. Median follow-up was 7.5 years (range 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in two patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of nine patients with anti-RNA polymerase III antibodies had prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) on study entry; all four patients developed prolonged organ failure/death early after transplant.
CONCLUSION: We observed favorable OS and EFS after AHSCT for patients with SSc, using CY200/ATG, unmanipulated PBSCs, and MMF posttransplant maintenance, which was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcomes after AHSCT.}, }
@article {pmid39621969, year = {2025}, author = {Tregnago, C and Benetton, M and Ries, RE and Peplinski, JH and Alonzo, TA and Stirewalt, D and Othus, M and Duployez, N and Sonneveld, E and Abrahamsson, J and Fogelstrand, L and von Neuhoff, N and Hasle, H and Reinhardt, D and Meshinchi, S and Locatelli, F and Pigazzi, M}, title = {Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {8}, pages = {972-984}, doi = {10.1200/JCO-24-01715}, pmid = {39621969}, issn = {1527-7755}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Nucleophosmin ; *Leukemia, Myeloid, Acute/genetics/mortality/drug therapy ; *Nuclear Proteins/genetics ; Male ; Adult ; Female ; Genotype ; Child ; Mutation ; Adolescent ; Middle Aged ; Young Adult ; Prognosis ; Child, Preschool ; Aged ; }, abstract = {PURPOSE: Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.
MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied.
RESULTS: Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.
CONCLUSION: The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.}, }
@article {pmid39621968, year = {2025}, author = {Pusztai, L and Hoag, JR and Albain, KS and Barlow, WE and Stemmer, SM and Meisner, A and Hortobagyi, GN and Shak, S and Rae, JM and Baehner, R and Sharma, P and Kalinsky, KM}, title = {Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor-Positive, Node-Positive Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {8}, pages = {919-928}, pmid = {39621968}, issn = {1527-7755}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/chemistry/genetics ; Middle Aged ; Receptors, Estrogen/analysis/metabolism ; Prognosis ; Adult ; Receptor, ErbB-2/analysis ; Aged ; Receptors, Progesterone/analysis ; Disease-Free Survival ; Lymphatic Metastasis ; Neoplasm Recurrence, Local ; Proportional Hazards Models ; Biomarkers, Tumor/analysis ; Antineoplastic Agents, Hormonal/therapeutic use ; Risk Assessment ; }, abstract = {PURPOSE: Clinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence risk and chemotherapy benefit predictions by menopausal status for patients with HR+/human epidermal growth factor receptor 2-negative, lymph node-positive breast cancer by integrating the RS result with clinicopathological factors (grade, tumor size, age).
METHODS: We used patient-level data from 5,283 patients treated with chemoendocrine therapy (CET) versus endocrine therapy alone (ET) in the S1007 (N = 4,916) and S8814 (N = 367) trials to develop the tool. Cox proportional hazards regression models stratified by trial were used to estimate 5-year invasive disease-free survival for pre- and postmenopausal woman, respectively. The integrated RSClinN+ model was compared with RS alone and clinicopathological models using likelihood ratio tests. Absolute CET benefit was estimated as the difference between ET and CET risk estimates. Validation of RSClinN+ was performed in 592 patients with node-positive disease in the Clalit Health Services registry.
RESULTS: RSClinN+ provides better prognostic information than RS model alone (premenopausal P = .034; postmenopausal P < .001) or clinicopathological model alone (premenopausal P = .002; postmenopausal, P < .001). In postmenopausal women, RS showed interaction with CET benefit (P = .016), with RSClinN+ absolute CET benefit ranging from <0.1% to 21.5% over RS ranges 0-50. In premenopausal patients with RS ≤25, there was no significant interaction between RS and CET benefit. In external validation, RSClinN+ risk estimates were prognostic (hazard ratio, 1.75 [95% CI, 1.38 to 2.20]) and concordant with observed risk (Lin's concordance, 0.92).
CONCLUSION: RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.}, }
@article {pmid39621930, year = {2024}, author = {Zanders, SE and Smith, GR}, title = {Killer meiotic drive executed by two alternative conformations of a single protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2420620121}, pmid = {39621930}, issn = {1091-6490}, support = {R35 GM118120/GM/NIGMS NIH HHS/United States ; R35 GM151982/GM/NIGMS NIH HHS/United States ; GM118120//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, }
@article {pmid39621322, year = {2024}, author = {Terry, KL and Harris, HR and Missmer, SA}, title = {Endometriosis and Ovarian Cancer.}, journal = {JAMA}, volume = {332}, number = {24}, pages = {2116-2117}, doi = {10.1001/jama.2024.21905}, pmid = {39621322}, issn = {1538-3598}, }
@article {pmid39619675, year = {2024}, author = {Little, A and Deek, RA and Zhang, A and Zhao, N and Ling, W and Wu, MC}, title = {Enhanced visualization of microbiome data in repeated measures designs.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1480972}, pmid = {39619675}, issn = {1664-8021}, abstract = {INTRODUCTION: Repeated measures microbiome studies, including longitudinal and clustered designs, offer valuable insights into the dynamics of microbial communities and their associations with various health outcomes. However, visualizing such multivariate data poses significant challenges, particularly in distinguishing meaningful biological patterns from noise introduced by covariates and the complexities of repeated measures.
METHODS: In this study, we propose a framework to enhance the visualization of repeated measures microbiome data using Principal Coordinates Analysis (PCoA) adjusted for covariates through linear mixed models (LMM). Our method adjusts for confounding variables and accounts for the repeated measures structure of the data, enabling clearer identification of microbial community variations across time points or clusters.
RESULTS: We demonstrate the utility of our approach through simulated scenarios and real datasets, showing that it effectively mitigates the influence of nuisance covariates and highlights key axes of microbiome variation.
DISCUSSION: This refined visualization technique provides a robust tool for researchers to explore and understand microbial community dynamics in repeated measures microbiome studies.}, }
@article {pmid39619274, year = {2024}, author = {Tsao, AS and Hsieh, MH and Koczywas, M and Tu, J and Riess, J and Tanvetyanon, T and Ma, BT and Zhao, YQ and Redman, MW and Edelman, MJ and Gandara, DR and Gray, JE and Kelly, KL}, title = {S1701, A Randomized Phase 2 Trial of Carboplatin-Paclitaxel With and Without Ramucirumab in Patients With Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma.}, journal = {JTO clinical and research reports}, volume = {5}, number = {12}, pages = {100738}, pmid = {39619274}, issn = {2666-3643}, abstract = {INTRODUCTION: Thymic carcinoma is a rare and aggressive malignancy with few treatment options. Preclinical studies suggested that targeting the angiogenic pathway may be beneficial in this disease.
METHODS: This randomized phase 2 trial enrolled patients with unresectable, locally advanced, recurrent, or metastatic thymic carcinoma. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab. The primary end point was progression-free survival (PFS) and secondary end points included response by Response Evaluation Criteria in Solid Tumors, disease control, toxicity, and overall survival. The primary analysis was done using a one-sided 10%-level log-rank test. Target sample size was 66 patients.
RESULTS: Between 2018 and 2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n = 8) and to the control arm (carboplatin-paclitaxel [CP], n = 13) with one patient on CP not meeting eligibility criteria. Owing to slow accrual, the study was terminated early by the Data and Safety Monitoring Board. Of the 20 eligible patients, eight on RCP and nine on CP received protocol treatment. PFS was not statistically different (hazard ratio = 0.51, 80% confidence interval [CI]: 0.24-1.09, p = 0.13). There were no grade 4 or higher treatment-related adverse events with RCP, although 50% experienced grade 3 adverse events, in which one patient had a grade 3 thromboembolic event. Among nine assessable patients for toxicity on CP, one patient (11%) encountered grade 4 neutropenia and one patient (11%) reported grade 3 thromboembolic events. Response rates favored the RCP arm, with an 88% (seven of eight, 80% CI: 59%-99%) response rate compared with 40% (four of 10, 80% CI: 19%-65%) on CP arm (p = 0.04). Disease control rate was higher in the RCP arm (100% versus 70%, p = 0.09). At the time of analysis, as only one death has been reported, overall survival remains immature.
CONCLUSIONS: Accrual to this population is challenging, and the study was closed early because of feasibility. Although PFS was not statistically better with RCP, the hazard ratio was 0.51 and the lack of significance was likely due to small sample sizes. Notably, addition of ramucirumab to CP led to higher response rates than CP alone. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies such as thymic carcinoma.}, }
@article {pmid39617269, year = {2025}, author = {Franić, D and Pravica, M and Zubčić, K and Miles, S and Bedalov, A and Boban, M}, title = {Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy, and nucleus-vacuole junctions.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {1}, pages = {108045}, pmid = {39617269}, issn = {1083-351X}, support = {R01 GM117446/GM/NIGMS NIH HHS/United States ; }, mesh = {*Proteasome Endopeptidase Complex/metabolism/genetics ; *Autophagy ; *Saccharomyces cerevisiae/metabolism/genetics/cytology ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Proteolysis ; *Vacuoles/metabolism/genetics ; *Cell Nucleus/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; Protein Folding ; Glucose/metabolism ; }, abstract = {Many cells spend a major part of their life in quiescence, a reversible state characterized by a distinct cellular organization and metabolism. In glucose-depleted quiescent yeast cells, there is a metabolic shift from glycolysis to mitochondrial respiration, and a large fraction of proteasomes are reorganized into cytoplasmic granules containing disassembled particles. Given these changes, the operation of protein quality control (PQC) in quiescent cells, in particular the reliance on degradation-mediated PQC and the specific pathways involved, remains unclear. By examining model misfolded proteins expressed in glucose-depleted quiescent yeast cells, we found that misfolded proteins are targeted for selective degradation requiring functional 26S proteasomes. This indicates that a significant pool of proteasomes remains active in degrading quality control substrates. Misfolded proteins were degraded in a manner dependent on the E3 ubiquitin ligases Ubr1 and San1, with Ubr1 playing a dominant role. In contrast to exponentially growing cells, the efficient clearance of certain misfolded proteins additionally required intact nucleus-vacuole junctions (NVJ) and Cue5-independent selective autophagy. Our findings suggest that proteasome activity, autophagy, and NVJ-dependent degradation operate in parallel. Together, the data demonstrate that quiescent cells maintain active PQC that relies primarily on selective protein degradation. The necessity of multiple degradation pathways for the removal of misfolded proteins during quiescence underscores the importance of misfolded protein clearance in this cellular state.}, }
@article {pmid39617028, year = {2024}, author = {Bender Ignacio, RA and Shapiro, AE and Montaño, MA and Titanji, BK}, title = {An urgent call to address the intersection of mpox and HIV in Africa.}, journal = {Lancet (London, England)}, volume = {404}, number = {10470}, pages = {2417-2419}, pmid = {39617028}, issn = {1474-547X}, support = {K01 MH132505/MH/NIMH NIH HHS/United States ; K23 AI140918/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; }, }
@article {pmid39616600, year = {2025}, author = {Hatlen, TJ and Bender Ignacio, R and Daar, ES}, title = {Advances in Treatment and Prevention of HIV.}, journal = {JAMA}, volume = {333}, number = {7}, pages = {576-578}, doi = {10.1001/jama.2024.24027}, pmid = {39616600}, issn = {1538-3598}, }
@article {pmid39616467, year = {2025}, author = {Bryce, AH and Agarwal, N and Beltran, H and Hussain, MH and Sartor, O and Shore, N and Antonarakis, ES and Armstrong, AJ and Calais, J and Carducci, MA and Dorff, TB and Efstathiou, JA and Gleave, M and Gomella, LG and Higano, C and Hope, TA and Iagaru, A and Morgans, AK and Morris, DS and Morris, MJ and Petrylak, DP and Reiter, RE and Rettig, MB and Ryan, CJ and Sellinger, SB and Spratt, DE and Srinivas, S and Tagawa, ST and Taplin, ME and Yu, EY and Zhang, T and McKay, RR and Koo, PJ and Crawford, ED}, title = {Implementing evidence-based strategies for men with biochemically recurrent and advanced prostate cancer: Consensus recommendations from the US Prostate Cancer Conference 2024.}, journal = {Cancer}, volume = {131}, number = {1}, pages = {e35612}, pmid = {39616467}, issn = {1097-0142}, support = {P30 CA077598/CA/NCI NIH HHS/United States ; R37 CA241486/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/therapy/pathology ; *Neoplasm Recurrence, Local ; Consensus ; Evidence-Based Medicine/standards ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms, Castration-Resistant/therapy/pathology ; United States ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Practice Guidelines as Topic ; }, abstract = {Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high-level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day-to-day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US-focused expert clinical decision-making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration-sensitive prostate cancer; poly [ADP-ribose] polymerase inhibitors; prostate-specific membrane antigen radioligand therapy; and metastatic, castration-resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.}, }
@article {pmid39616411, year = {2025}, author = {Newton, H and Colla, CH and Busch, SH and Tomaino, M and Hardy, B and Brunette, MF and Agravat, D and Meara, E}, title = {Medicare Accountable Care Organization Treatment of Serious Mental Illness: Associations Between Behavioral Health Integration Activities and Outcomes.}, journal = {Medical care}, volume = {63}, number = {2}, pages = {123-132}, pmid = {39616411}, issn = {1537-1948}, support = {R01 MH109531/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Accountable Care Organizations/statistics & numerical data ; United States ; *Medicare/statistics & numerical data ; *Mental Disorders/therapy ; Male ; Female ; Cross-Sectional Studies ; Aged ; Delivery of Health Care, Integrated/organization & administration ; Fee-for-Service Plans ; Middle Aged ; Mental Health Services/statistics & numerical data/organization & administration ; Quality of Health Care/statistics & numerical data ; }, abstract = {OBJECTIVE: Characterize the association between Medicare Accountable Care Organizations' (ACOs) behavioral health integration capability and quality and utilization among adults with serious mental illness (SMI).
BACKGROUND: Controlled research supports the efficacy of integrating physical and mental health care for adults with SMI, yet little is known about the organizations integrating care and associations between integration capability and quality.
METHODS: We surveyed Medicare ACOs (2017-2018 National Survey of ACOs, response rate 69%) and linked responses to 2016-2017 fee-for-service Medicare claims for beneficiaries with SMI. We examined the cross-sectional association between ACO-reported integration capability (tertiles of a 14-item index) and 7 patient-level quality and utilization outcomes. We fit generalized linear models for each outcome as a function of ACO integration capability, adjusting for ACO and beneficiary characteristics.
RESULTS: Study sample included 274,928 beneficiary years (199,910 unique beneficiaries) attributed to 265 Medicare ACOs. ACOs with high behavioral health integration capability (top-tertile) served more dual-eligible beneficiaries (67.8%) than bottom-tertile (63.7%) and middle-tertile ACOs (63.3%). Most beneficiaries received follow-up 30 days after mental health hospitalization and chronic disease monitoring-exceeding national quality benchmarks-but beneficiaries receiving care from top-tertile (vs bottom-tertile) ACOs were modestly less likely to receive follow-up [-2.17 percentage points (pp), P < 0.05], diabetes monitoring (-2.19 pp, P < 0.05), and cardiovascular disease monitoring (-6.07 pp, P < 0.05). Integration capability was not correlated with utilization.
CONCLUSIONS: ACOs serving adults with substantial physical and mental health needs were more likely to report comprehensive integration capability but were not yet meeting the primary care needs of many adults with SMI.}, }
@article {pmid39616199, year = {2024}, author = {Vadathya, AK and Garza, T and Alam, U and Ho, A and Musaad, SMA and Beltran, A and Moreno, JP and Baranowski, T and Haidar, N and Hughes, SO and Mendoza, JA and Veeraraghavan, A and Young, J and Sano, A and O'Connor, TM}, title = {Validation studies of the FLASH-TV system to passively measure children's TV viewing.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {29805}, pmid = {39616199}, issn = {2045-2322}, support = {R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Humans ; *Television ; Female ; Male ; Child ; Screen Time ; Machine Learning ; Child, Preschool ; }, abstract = {TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children's TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff at 5-second epochs for whenever the child watched TV. For the combined sample with valid data (n = 59), FLASH-TV 3.0 provided a mean 85% (SD 8%) accuracy, 80% (SD 17%) sensitivity, 86% (SD 8%) specificity, and 0.71 (SD 0.15) kappa, compared to gold-standard. The mean intra-class correlation (ICC) of child's TV viewing durations of FLASH-TV 3.0 to gold-standard was 0.86. Overall, FLASH-TV 3.0 correlated well with the gold standard across a diverse sample of children, but with higher variability among Black children than others. FLASH-TV provides a tool to estimate children's TV viewing and increase the precision of research on TV viewing's impact on children's health.}, }
@article {pmid39612623, year = {2025}, author = {Lee, MJ and Litchford, ML and Vendrame, E and Vergara, R and Ranganath, T and Fish, CS and Chebet, D and Langat, A and Mburu, C and Neary, J and Benki, S and Wamalwa, D and John-Stewart, G and Lehman, DA and Blish, CA}, title = {Distinct immune profiles in children living with HIV based on timing and duration of suppressive antiretroviral treatment.}, journal = {Virology}, volume = {602}, number = {}, pages = {110318}, pmid = {39612623}, issn = {1096-0341}, support = {T32 AI007290/AI/NIAID NIH HHS/United States ; R01 HD094718/HD/NICHD NIH HHS/United States ; F31 AI172319/AI/NIAID NIH HHS/United States ; DP1 DA046089/DA/NIDA NIH HHS/United States ; R01 HD023412/HD/NICHD NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; T32 AI00729037/NH/NIH HHS/United States ; F31 AI172311-01/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/immunology/virology ; Child ; Male ; Female ; Kenya ; *Viral Load ; Child, Preschool ; Killer Cells, Natural/immunology/drug effects ; Anti-HIV Agents/therapeutic use ; Cohort Studies ; Leukocytes, Mononuclear/immunology ; HIV-1/immunology/drug effects ; Adolescent ; CD4 Lymphocyte Count ; Time Factors ; Anti-Retroviral Agents/therapeutic use ; CD4-Positive T-Lymphocytes/immunology ; Antiretroviral Therapy, Highly Active ; }, abstract = {Timely initiation of antiretroviral therapy (ART) remains a major challenge in the effort to treat children living with HIV ("CLH") and little is known regarding the dynamics of immune normalization following ART in CLH with varying times to and durations of ART. Here, we leveraged two cohorts of virally-suppressed CLH from Nairobi, Kenya to examine differences in the peripheral immune systems between two cohorts of age-matched children (to control for immune changes with age): one group which initiated ART during early HIV infection and had been on ART for 5-6 years at evaluation (early, long-term treated; "ELT" cohort), and one group which initiated ART later and had been on ART for approximately 9 months at evaluation (delayed, short-term treated; "DST" cohort). We profiled PBMC and purified NK cells from these two cohorts by mass cytometry time-of-flight (CyTOF). Although both groups of CLH had undetectable viral RNA load at evaluation, there were marked differences in both immune composition and immune phenotype between the ELT cohort and the DST cohort. DST donors had reduced CD4 T cell percentages, decreased naive to effector memory T cell ratios, and markedly higher expression of stress-induced markers. Conversely, ELT donors had higher naive to effector memory T cell ratios, low expression of stress-induced markers, and increased expression of markers associated with an effective antiviral response and resolution of inflammation. Collectively, our results demonstrate key differences in the immune systems of virally-suppressed CLH with different ages at ART initiation and durations of treatment and provide further rationale for emphasizing early onset of ART.}, }
@article {pmid39612163, year = {2024}, author = {Swensen, SN and Figuracion, KCF and Venur, VA and Emerson, S and Tseng, YD and Lo, SS and Ermoian, RP and Halasz, LM}, title = {Treatment Options for IDH-Mutant Malignant Gliomas.}, journal = {Current treatment options in oncology}, volume = {25}, number = {12}, pages = {1594-1604}, pmid = {39612163}, issn = {1534-6277}, mesh = {Humans ; *Isocitrate Dehydrogenase/genetics ; *Glioma/therapy/diagnosis/genetics/pathology ; *Mutation ; *Brain Neoplasms/therapy/diagnosis/genetics/pathology ; Combined Modality Therapy ; Neoplasm Grading ; Disease Management ; Treatment Outcome ; Prognosis ; Clinical Decision-Making ; }, abstract = {As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.}, }
@article {pmid39610699, year = {2024}, author = {Wu, P and Barros-Becker, F and Ogelman, R and Camci, ED and Linbo, TH and Simon, JA and Rubel, EW and Raible, DW}, title = {Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1480435}, pmid = {39610699}, issn = {1664-2295}, support = {R01 DC005987/DC/NIDCD NIH HHS/United States ; }, abstract = {Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 h of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 h for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.}, }
@article {pmid39610652, year = {2024}, author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J}, title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae087}, pmid = {39610652}, issn = {2057-1577}, abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis, multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.}, }
@article {pmid39609636, year = {2025}, author = {Thomas, CE and Peters, U}, title = {Genomic landscape of cancer in racially and ethnically diverse populations.}, journal = {Nature reviews. Genetics}, volume = {26}, number = {5}, pages = {336-349}, pmid = {39609636}, issn = {1471-0064}, mesh = {Humans ; *Neoplasms/genetics/ethnology ; *Ethnicity/genetics ; *Genomics/methods ; Genetic Predisposition to Disease ; *Racial Groups/genetics ; Genome, Human ; }, abstract = {Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.}, }
@article {pmid39609400, year = {2024}, author = {Lemos, MP and Astronomo, RD and Huang, Y and Narpala, S and Prabhakaran, M and Mann, P and Paez, CA and Lu, Y and Mize, GJ and Glantz, H and Westerberg, K and Colegrove, H and Smythe, KS and Lin, M and Pierce, RH and Hutter, J and Frank, I and Mascola, JR and McDermott, AB and Bekker, LG and McElrath, MJ}, title = {Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10332}, pmid = {39609400}, issn = {2041-1723}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV-1/immunology ; *Rectum/virology ; *HIV Antibodies/immunology ; Adult ; Male ; *HIV Infections/immunology/prevention & control/virology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/pharmacokinetics/immunology/administration & dosage ; Tissue Distribution ; Mucous Membrane/immunology/virology/metabolism ; Antibodies, Neutralizing/immunology ; Middle Aged ; Vagina/virology/immunology ; Young Adult ; Half-Life ; Intestinal Mucosa/metabolism/immunology ; }, abstract = {To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues, <3% are in seminal and rectal secretions. Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1.}, }
@article {pmid39607987, year = {2025}, author = {Weiss, NS}, title = {Gauging the efficacy of multicancer screening: the road ahead may be long and bumpy.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {2}, pages = {212-213}, pmid = {39607987}, issn = {1460-2105}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; #R35 CA274442/CA/NCI NIH HHS/United States ; }, }
@article {pmid39607599, year = {2025}, author = {Ondeng'e, K and Guo, X and Mbeda, C and Schnabel, D and Panchia, R and Dominguez, K and Dadabhai, S and Hamilton, EL and Sandfort, TGM}, title = {Bisexuality among Men who have Sex with Men in Sub-Saharan Africa: Findings from the HPTN 075 Study.}, journal = {AIDS and behavior}, volume = {29}, number = {3}, pages = {747-759}, pmid = {39607599}, issn = {1573-3254}, support = {R21 MH130217/MH/NIMH NIH HHS/United States ; R21-MH130217//National Institute of Mental Health and Neurosciences/ ; P30 MH043520/MH/NIMH NIH HHS/United States ; UM1-AI068613//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; P30-MH43520/MH/NIMH NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1-AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; Adult ; *Homosexuality, Male/statistics & numerical data/psychology ; Africa South of the Sahara/epidemiology ; *HIV Infections/prevention & control/epidemiology ; Young Adult ; *Bisexuality/statistics & numerical data/psychology ; Adolescent ; Sexual Partners ; *Sexual Behavior/statistics & numerical data/psychology ; Female ; Risk-Taking ; *Sexual and Gender Minorities/psychology/statistics & numerical data ; Condoms/statistics & numerical data ; }, abstract = {Studies among men who have sex with men (MSM) in sub-Saharan Africa (SSA) focus mainly on HIV epidemiology, revealing little about the diversity within this population. We utilized data from the HIV Prevention Trials Network (HPTN) 075 study, to explore demographic and psychosexual characteristics of MSM in SSA who also have sex with women. Persons included in the analyses were aged 18-44 years and assigned male sex at birth and identified as male, reported anal sex with a man in the past 3 months, and had enrolled at one of four study sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Nearly a quarter of the participants had recently engaged in sex with both men and women (MSMW). These men differed in terms of demographic and psychosexual characteristics, and sexual behavior from men who only had had sex with men (MSME). Compared to the latter, MSMW were more likely to prefer the insertive sexual role, reported more sexual partners in the past three months, and had more instances of condomless insertive anal intercourse with a man. These findings suggest that men who have sex with both men and women have specific characteristics and need tailored interventions that take their specific needs into account.}, }
@article {pmid39606729, year = {2024}, author = {Jennings-Shaffer, C and Rich, DH and Macaulay, M and Karcher, MD and Ganapathy, T and Kiami, S and Kooperberg, A and Zhang, C and Suchard, MA and Matsen, FA}, title = {Finding high posterior density phylogenies by systematically extending a directed acyclic graph.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39606729}, issn = {2331-8422}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Bayesian phylogenetics typically estimates a posterior distribution, or aspects thereof, using Markov chain Monte Carlo methods. These methods integrate over tree space by applying local rearrangements to move a tree through its space as a random walk. Previous work explored the possibility of replacing this random walk with a systematic search, but was quickly overwhelmed by the large number of probable trees in the posterior distribution. In this paper we develop methods to sidestep this problem using a recently introduced structure called the subsplit directed acyclic graph (sDAG). This structure can represent many trees at once, and local rearrangements of trees translate to methods of enlarging the sDAG. Here we propose two methods of introducing, ranking, and selecting local rearrangements on sDAGs to produce a collection of trees with high posterior density. One of these methods successfully recovers the set of high posterior density trees across a range of data sets. However, we find that a simpler strategy of aggregating trees into an sDAG in fact is computationally faster and returns a higher fraction of probable trees.}, }
@article {pmid39606437, year = {2024}, author = {Vo, P and Sandmaier, B and Othus, M and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Davis, C and Basom, R and Storb, R and Walter, R}, title = {Relationship Between Age, Conditioning Intensity, and Outcome After Allografting in Adults Age ≥60 Years with AML.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606437}, issn = {2693-5015}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥ 70 (n = 122) who underwent allogeneic HCT for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥ 70 years had a higher risk of non-relapse mortality (NRM) than those aged ≥ 60-64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Age ≥ 70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no association was found with nonmyeloablative conditioning. Conversely, patients aged 60-64 and 65-69, not those aged ≥ 70, had a significantly lower risk of relapse with RIC, but NRM risk increased with age. Our findings support allogeneic HCT for adults with AML in remission even if aged beyond 70, especially with nonmyeloablative conditioning.}, }
@article {pmid39605726, year = {2024}, author = {Rominger, MC and Gupta, S and Moorthi, S and McSharry, M and Kamlapurkar, S and O'Brien, S and Waldum, A and Lo, A and Duke, F and Lowe, AR and Cromwell, E and Glabman, R and Koehne, A and Berger, AH}, title = {Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605726}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA228944/CA/NCI NIH HHS/United States ; R00 CA197762/CA/NCI NIH HHS/United States ; R37 CA252050/CA/NCI NIH HHS/United States ; }, abstract = {The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the "Ras-like in all tissues" (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1[M90I] variant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1[M90I] in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1[M90I] and inactivation of Nf2 drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1's oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer.}, }
@article {pmid39605711, year = {2024}, author = {Wu, E and Bieniosek, M and Wu, Z and Thakkar, N and Charville, GW and Makky, A and Schürch, C and Huyghe, JR and Peters, U and Li, CI and Li, L and Giba, H and Behera, V and Raman, A and Trevino, AE and Mayer, AT and Zou, J}, title = {ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605711}, issn = {2692-8205}, support = {P20 CA252733/CA/NCI NIH HHS/United States ; P50 CA285275/CA/NCI NIH HHS/United States ; R01 CA280639/CA/NCI NIH HHS/United States ; }, abstract = {Hematoxylin and eosin (H&E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&E images. Our model is trained on a dataset of over 1000 paired and aligned H&E and multiplex immunofluorescence (mIF) samples from 20 tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.}, }
@article {pmid39605495, year = {2024}, author = {Slein, MD and Backes, IM and Kelkar, NS and Garland, CR and Khanwalkar, US and Sholukh, AM and Johnston, CM and Leib, DA and Ackerman, ME}, title = {Improving antibody-mediated protection against HSV infection by eliminating interactions with the viral Fc receptor gE/gI.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605495}, issn = {2692-8205}, support = {R01 AI178284/AI/NIAID NIH HHS/United States ; R01 EY009083/EY/NEI NIH HHS/United States ; P01 AI098681/AI/NIAID NIH HHS/United States ; U19 AI145825/AI/NIAID NIH HHS/United States ; R21 AI147714/AI/NIAID NIH HHS/United States ; R01 AI176646/AI/NIAID NIH HHS/United States ; T32 AI007363/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules, allowing the virus to escape immune clearance. In addition to their role in neuropathogenesis and cell-cell spread, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG and promote evasion of humoral immune responses. While monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of the vFcR on mAb-mediated protection by binding to IgG is unknown. Using HSV-1 with intact and ablated gE-mediated IgG Fc binding, and Fc-engineered antibodies with modified ability to interact with gE/gI, we investigated the role of the vFcR in viral pathogenesis and mAb-mediated protection from nHSV. The gD-specific human mAb HSV8 modified to lack binding to gE exhibited enhanced neutralization and in vivo protection compared to its native IgG1 form. This improved protection by the engineered mAbs was dependent on the presence of the vFcR. Human IgG3 allotypes lacking vFcR binding also exhibited enhanced antiviral activity in vivo, suggesting that vaccines that robustly induce IgG3 responses could show enhanced protection. suggesting the value of vaccination strategies that robustly induce this subclass. Lastly, analysis of longitudinal responses to acute primary genital infection in humans raised the possibility that unlike most viruses, HSV may exhibited slow induction of IgG3. In summary, this study demonstrates that mAbs lacking the ability to interact with the vFcR can exhibit improved protection from HSV-offering new prospects for antibody-based interventions.}, }
@article {pmid39605329, year = {2024}, author = {Nolan, CT and Campbell, I and Farrell-Sherman, A and Ortiz, BAB and Naish, KA and Stilio, VD and Kaldy, JE and Donoghue, C and Ruesink, JL and Imaizumi, T}, title = {Florigen and antiflorigen gene expression correlates with reproductive state in a marine angiosperm, Zostera marina.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605329}, issn = {2692-8205}, support = {R01 GM079712/GM/NIGMS NIH HHS/United States ; }, abstract = {• Florigen and antiflorigen genes within the phosphatidylethanolamine-binding protein (PEBP) family regulate flowering in angiosperms. In eelgrass (Zostera marina), a marine foundation species threatened by climate change, flowering and seed production are crucial for population resilience. Yet, the molecular mechanism underpinning flowering remains unknown. • Using phylogenetic analysis and functional assays in Arabidopsis, we identified thirteen PEBP genes in Z. marina (ZmaPEBP) and showed that four genes altered flowering phenotypes when overexpressed. We used quantitative RT-PCR on Z. marina shoots from perennial and annual populations in Willapa Bay, USA to assess expression of these four genes in different tissue and expression changes throughout the growth season. • We demonstrated that ZmaFT2 and ZmaFT4 promote flowering, and ZmaFT9 and ZmaTFL1a repress flowering in Arabidopsis. Across five natural sites exhibiting different degrees of population genetic structure, ZmaFT2 and ZmaFT4 were expressed in leaves of vegetative and reproductive shoots and in stems and rhizomes of reproductive shoots. ZmaFT9 was distinctively expressed in leaves of vegetative and juvenile shoots, while ZmaTFL1a levels increased after flowering shoots emerged. • Our results suggest that ZmaFT2 and ZmaFT4 may promote flowering, while ZmaFT9 may inhibit a floral transition in eelgrass. We speculate that ZmaTFL1a may be involved in flowering shoot architecture.}, }
@article {pmid39605281, year = {2024}, author = {Zheng, C and Furukawa, C and Liu, J and Sankaran, S and Lin, H and Munugeti, N and Wang, M and Smith, GR}, title = {Debunking the dogma that RecBCD nuclease destroys phage.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyae199}, pmid = {39605281}, issn = {1943-2631}, support = {R35 GM118120/GM/NIGMS NIH HHS/United States ; }, abstract = {For decades, it has been repeatedly claimed that the potent bacterial helicase-nuclease RecBCD (exonuclease V) destroys foreign (non-self) DNA, such as that of phages, but repairs and recombines cellular (self) DNA. While this would constitute a strong host-survival mechanism, no phage destroyed by RecBCD is ever specified in those claims. To determine which phages are destroyed by RecBCD, we searched for phage isolates that grow on Escherichia coli ΔrecBCD but not on recBCD+. In contrast to the prevailing claim, we found none among >80 new isolates from nature and >80 from previous collections. Based on these and previous observations, we conclude that RecBCD repairs broken DNA that can recombine but destroys DNA that cannot recombine and recycles the nucleotides.}, }
@article {pmid39604409, year = {2024}, author = {Holmes, S and Li, H and Shen, X and Martin, M and Tuck, R and Chen, Y and Giorgi, EE and Kirshner, HF and Berry, M and Van Italie, E and Venkatayogi, S and Martin Beem, JS and Edwards, RJ and Mansouri, K and Singh, A and Kuykendall, C and Gurley, T and Anthony Moody, M and DeNayer, N and Demarco, T and Denny, TN and Wang, Y and Evangelous, TD and Clinton, JT and Hora, B and Wagh, K and Seaman, MS and Saunders, KO and Solomotis, N and Misamore, J and Lewis, MG and Wiehe, K and Montefiori, DC and Shaw, GM and Williams, WB}, title = {Neonatal immunity associated with heterologous HIV-1 neutralizing antibody induction in SHIV-infected Rhesus Macaques.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10302}, pmid = {39604409}, issn = {2041-1723}, support = {HHSN272201800004C/AI/NIAID NIH HHS/United States ; AI140897//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160607//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI160607/AI/NIAID NIH HHS/United States ; R01 AI140897/AI/NIAID NIH HHS/United States ; P01 AI131251/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta/immunology ; *HIV-1/immunology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology/blood ; *Animals, Newborn ; Female ; Humans ; Male ; B-Lymphocytes/immunology ; HIV Infections/immunology/virology ; T-Lymphocytes, Regulatory/immunology ; Germinal Center/immunology ; Disease Models, Animal ; Epitopes/immunology ; }, abstract = {The details of the pediatric immune system that supports induction of antibodies capable of neutralizing geographically-diverse or heterologous HIV-1 is currently unclear. Here we explore the pediatric immune environment in neonatal macaque undergoing Simian-HIV infection. Simian-HIV infection of 11 pairs of therapy-naive dams and infant rhesus macaques for 24 months results in heterologous HIV-1 neutralizing antibodies in 64% of young macaques compared to 18% of adult macaques. Heterologous HIV-1 neutralizing antibodies emerge by 12 months post-infection in young macaques, in association with lower expression of immunosuppressive genes, fewer germinal center CD4 + T regulatory cells, and a lower ratio of CD4 + T follicular regulatory to helper cells. Antibodies from peripheral blood B cells in two young macaques following SHIV infection neutralize 13% of 119 heterologous HIV-1 strains and map to regions of canonical broadly neutralizing antibody epitopes on the envelope surface protein. Here we show that pediatric immunity to SHIV infection in a macaque model may inform vaccine strategies to induce effective HIV-1 neutralizing antibodies in infants and children prior to viral exposure.}, }
@article {pmid39604364, year = {2024}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Minot, SS and Dean, DR and Rashidi, A}, title = {A sex-dependent salivary bacterium influences oral mucositis severity after allogeneic hematopoietic cell transplantation.}, journal = {NPJ biofilms and microbiomes}, volume = {10}, number = {1}, pages = {140}, pmid = {39604364}, issn = {2055-5008}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; resident research award//American Academy of Oral Medicine Research Advancement Committee/ ; Dr. Douglass L. Morell Dentistry Research Fund//Research Advisory Committee of the University of Washington School of Dentistry/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; *Stomatitis/etiology/microbiology ; *Saliva/microbiology ; Middle Aged ; Adult ; *Transplantation, Homologous/adverse effects ; Sex Factors ; Microbiota ; Severity of Illness Index ; Uric Acid/analysis ; Aged ; }, abstract = {The success of allogeneic hematopoietic cell transplantation (alloHCT) in curing hematologic disorders is limited by its short- and long-term toxicities. One such toxicity is oral mucositis (OM), causing pain, speech/swallowing difficulty, and prolonged hospitalization. Although conditioning chemoradiotherapy is the direct cause of OM, potential host-intrinsic mediators of mucosal injury remain elusive. We hypothesized that the oral microbiota may influence OM severity. We used a validated comprehensive scoring system based on specialized Oral Medicine examinations to longitudinally quantify OM severity in alloHCT recipients. High-throughput multi-site profiling of the oral microbiota was performed in parallel. We identify a sex-dependent commensal bacterium, Oribacterium asaccharolyticum, whose presence in saliva before transplantation is associated with more severe OM 14 days after transplantation. The sex predilection of this species correlated with higher uric acid levels in men. Our findings represent the first sex-dependent microbiota-mediated pathway in OM pathogenesis and introduce novel targets for preventative interventions.}, }
@article {pmid39603592, year = {2025}, author = {Thomson, CA and Arnold, KB and Anderson, G and Sun, V and Secord, AA and Yung, A and Al-Kasspooles, M and Nfonsam, VN and Grant, M and Deutsch, GB and Deneve, JL and Krouse, RS}, title = {Intake and Nutritional Adequacy in Patients With Cancer Diagnosed With Malignant Bowel Obstruction: A Secondary Analysis of a Randomized Trial.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {125}, number = {5}, pages = {654-665.e3}, pmid = {39603592}, issn = {2212-2672}, support = {P30 CA023074/CA/NCI NIH HHS/United States ; R01 HS021491/HS/AHRQ HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Diet/statistics & numerical data ; *Eating ; *Intestinal Obstruction/etiology/therapy ; *Neoplasms/complications ; Nutrition Assessment ; *Nutritional Status ; }, abstract = {BACKGROUND: Malignant bowel obstruction (MBO) is experienced by many with advanced cancer. Patients with MBO cannot eat and may have reduced ability to eat once the acute process has resolved. Sparse data exist to describe oral intake capacity and adequacy of nutrition in patients with MBO. These data are critical to developing effective supportive care nutrition therapy for patients with MBO.
OBJECTIVE: The aim of this study was to describe the ability to consume food and liquids orally, estimating nutritional adequacy of diet in a sample of patients who received surgical or nonsurgical treatment for MBO.
DESIGN: A descriptive secondary data analysis of repeated dietary intake measures from S1316, a pragmatic comparative effectiveness trial of surgical and nonsurgical treatment for MBO. Participant enrollment occurred between 2015 and 2020. Ability to eat was assessed through self-reported telephone survey and intake was estimated using telephone-based 24-hour recalls, applying US Department of Agriculture multipass methodology.
PARTICIPANTS/SETTING: The primary trial was conducted within the SWOG Cancer Research Network and included recruitment sites across the United States and Latin America. Eligible participants were diagnosed with, and hospitalized for, MBO.
MAIN OUTCOME MEASURES: The main outcomes measures were self- or caregiver-reported ability to eat, as well as overall nutrient intake.
STATISTICAL ANALYSIS: Descriptive statistics were used to report patient characteristics, intake, and nutrient adequacy. Nutrient intake was presented by tertiles of gastrointestinal symptom severity and assessed.
RESULTS: Two hundred twenty-one participants were registered; 199 were eligible and included. At week 1, 51% of patients with MBO reported consuming some solid food orally; 34% reported no oral intake; and 13% were on enteral feeding only. For patients alive and responsive to recalls at 13 weeks (n = 57), 82% (n = 47) reported consuming solid food. Compared with recommendations, mean reported intake was inadequate for most nutrients.
CONCLUSIONS: Oral intake is reported in more than one-half of patients diagnosed with MBO. Medical nutrition therapy should be tailored to patient's tolerance for eating and with consideration or patient's desire to address nutritional inadequacies.}, }
@article {pmid39600206, year = {2024}, author = {Antin, T and Cartujano-Barrera, F and De Genna, NM and Hinds, JT and Kaner, E and Lee, J and Patterson, JG and Ruiz, RA and Stimatze, T and Tan, ASL and Heffner, JL}, title = {Structural stigma and inequities in tobacco use among sexual and gender minoritized people: Accounting for context and intersectionality.}, journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae280}, pmid = {39600206}, issn = {1469-994X}, }
@article {pmid39599646, year = {2024}, author = {Smith, KS and Gudenkauf, LM and Hoogland, AI and Li, X and Hoobler, R and Playdon, MC and Gigic, B and Small, BJ and Gonzalez, BD and Oswald, LB and Byrd, DA and Greathouse, KL and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Peoples, AR and Siegel, EM and Figueiredo, JC and Jim, HSL and Crowder, SL}, title = {Associations Between Dietary Patterns and Quality of Life in a Longitudinal Cohort of Colorectal Cancer Survivors.}, journal = {Nutrients}, volume = {16}, number = {22}, pages = {}, pmid = {39599646}, issn = {2072-6643}, support = {R01NR018762/NR/NINR NIH HHS/United States ; T32CA009168, R2 U01CA206110, 1A1 R01CA189184, R01CA207371, and T32CA090314/CA/NCI NIH HHS/United States ; P30-CA076292//Cancer Center Support Grant/ ; }, mesh = {Humans ; *Quality of Life ; Female ; Male ; Middle Aged ; *Colorectal Neoplasms/psychology ; *Cancer Survivors/psychology/statistics & numerical data ; Aged ; Longitudinal Studies ; Prospective Studies ; *Diet ; Adult ; Cross-Sectional Studies ; Feeding Behavior/psychology ; United States/epidemiology ; }, abstract = {PURPOSE: To characterize dietary patterns and examine associations with cross-sectional and longitudinal changes in quality of life (QOL) over approximately one year after colorectal cancer (CRC) diagnosis.
METHODS: The ColoCare Study is an international, multi-center, prospective cohort study of newly diagnosed CRC survivors of any stage. A subset of participants with CRC in the United States completed patient-reported outcome measures at 6- and 12-months post-enrollment, including the Food Frequency Questionnaire (FFQ) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Dietary patterns at 6 months (around the time of treatment completion) were identified using Principal Component Analysis (PCA) with varimax rotation. Adherence scores were calculated for participants within each dietary pattern, with higher scores indicating higher adherence. Mixed models were used to examine the effect of each dietary pattern on changes in QOL at 6- and 12-month follow-ups, controlling for cancer stage, biological sex, body mass index (BMI), smoking status, and age.
RESULTS: Participants (N = 174) were, on average, 56 ± 14 years old and were mostly female (51.5%), stage III or IV (51.7%), never smokers (60.2%), non-Hispanic (97.1%), and White (83.3%) with a BMI of 27.9 ± 6.1 kg/m[2]. PCA revealed two emerging dietary patterns: "Western diet", characterized by processed meats, refined grains, and sugars, and "Prudent diet" characterized by lean proteins, fruits, and vegetables. Higher adherence to a Western diet was associated with worse social functioning at 6-month follow-up (FE = -12.6, p = 0.010). Loss of appetite from 6 to 12 months was associated with higher adherence to both the Western and Prudent dietary patterns (FE = 1.5, p = 0.044; FE = 1.3, p = 0.046, respectively). Neither dietary pattern was associated with global QOL score at 6- or 12-month follow-up (p's > 0.05).
CONCLUSIONS: Among CRC survivors in the United States, the Western diet was concurrently associated with worse social functioning. Loss of appetite was reported by CRC survivors following both dietary patterns, suggesting that loss of appetite may be a global experience for CRC survivors during this timeframe. Further research is needed to understand specific social challenges experienced by CRC survivors and develop supportive care interventions to address appetite and nutritional concerns.}, }
@article {pmid39596582, year = {2024}, author = {Ha, ET and Haessler, J and Taylor, KD and Tuftin, B and Briggs, M and Parikh, MA and Peterson, SJ and Gerszten, RE and Wilson, JG and Kelsey, K and Tahir, UA and Seeman, T and Rich, SS and Carson, AP and Post, WS and Kooperberg, C and Rotter, JI and Raffield, LM and Auer, P and Reiner, AP}, title = {The Relationship of Duffy Gene Polymorphism with High-Sensitivity C-Reactive Protein, Mortality, and Cardiovascular Outcomes in Black Individuals.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596582}, issn = {2073-4425}, support = {75N92020D00001/HL/NHLBI NIH HHS/United States ; N01 WH022110/WH/WHI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 HG004790/HG/NHGRI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N02 HL064278/HL/NHLBI NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; U01 HG004801/HG/NHGRI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Black or African American/genetics ; *C-Reactive Protein/genetics/metabolism ; *Cardiovascular Diseases/genetics/mortality ; *Duffy Blood-Group System/genetics ; *Polymorphism, Single Nucleotide ; Receptors, Cell Surface/genetics ; }, abstract = {Background: Black adults have higher incidence of all-cause mortality and worse cardiovascular disease (CVD) outcomes when compared to other U.S. populations. The Duffy chemokine receptor is not expressed on erythrocytes in a large majority of Black adults, but the clinical implications of this are unclear. Methods: Here, we investigated the relationship of Duffy receptor status, high-sensitivity C-reactive protein (hs-CRP), and mortality and incident CVD events (coronary heart disease, stroke, and heart failure) in self-identified Black members of three contemporary, longitudinal cohort studies (the Women's Health Initiative, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis). Data on 14,358 Black participants (9023 Duffy-null and 5335 Duffy-receptor-positive, as defined using single-nucleotide polymorphism (SNP) rs2814778) were included in this analysis. Results: Duffy null was strongly associated with higher hs-CRP (meta-analysis p = 2.62 × 10[-9]), but the association was largely attenuated, though still marginally significant (p = 0.005), after conditioning on known CRP locus alleles in linkage disequilibrium with the Duffy gene. In our discovery cohorts, Duffy-null status appeared to be associated with a higher risk of all-cause mortality and incident stroke, though these associations were attenuated and non-significant following adjustment for traditional risk factors including hs-CRP. Moreover, the association of Duffy-null status with mortality could not be replicated in an independent sample of Black adults from the UK Biobank. Conclusions: These findings suggest that the higher levels of hs-CRP found in Duffy-null individuals may be in part independent of CRP alleles known to influence circulating levels of hs-CRP. During the follow-up of this community-based sample of Black participants, Duffy-null status was not associated with mortality or incident CVD events independently of traditional risk factors including hs-CRP.}, }
@article {pmid39596404, year = {2024}, author = {Wang, Z and Kaplan, RC and Burk, RD and Qi, Q}, title = {The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596404}, issn = {1422-0067}, support = {K01 HL169019/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cardiovascular Diseases/microbiology/immunology/metabolism ; *Mouth/microbiology ; Inflammation/microbiology/metabolism/immunology ; Gastrointestinal Microbiome ; Microbiota ; Animals ; }, abstract = {Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome's role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.}, }
@article {pmid39594840, year = {2024}, author = {Dekker, SE and Deng, L}, title = {Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, pmid = {39594840}, issn = {2072-6694}, abstract = {KRAS mutation is one of the most common oncogenic drivers in non-small cell lung cancer. Since its discovery about four decades ago, drug development targeting KRAS has been met with countless failures. Recently, KRAS G12C, a subvariant of KRAS, became the first druggable KRAS mutation. The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon. Additionally, novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data. We will review the clinical advances and challenges for patients with KRAS-mutated non-small cell lung cancer, with a focus on small molecule inhibitors.}, }
@article {pmid39594810, year = {2024}, author = {Ally, F and Chen, X}, title = {Acute Myeloid Leukemia: Diagnosis and Evaluation by Flow Cytometry.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, pmid = {39594810}, issn = {2072-6694}, abstract = {With recent technological advances and significant progress in understanding the pathogenesis of acute myeloid leukemia (AML), the updated fifth edition WHO Classification (WHO-HAEM5) and the newly introduced International Consensus Classification (ICC), as well as the European LeukemiaNet (ELN) recommendations in 2022, require the integration of immunophenotypic, cytogenetic, and molecular data, alongside clinical and morphologic findings, for accurate diagnosis, prognostication, and guiding therapeutic strategies in AML. Flow cytometry offers rapid and sensitive immunophenotyping through a multiparametric approach and is a pivotal laboratory tool for the classification of AML, identification of therapeutic targets, and monitoring of measurable residual disease (MRD) post therapy. The association of immunophenotypic features and recurrent genetic abnormalities has been recognized and applied in informing further diagnostic evaluation and immediate therapeutic decision-making. Recently, the evolving role of machine learning models in assisting flow cytometric data analysis for the automated diagnosis and prediction of underlying genetic alterations has been illustrated.}, }
@article {pmid39591433, year = {2025}, author = {Peebles, K and Matrajt, L and Baeten, JM and Palanee-Phillips, T and Brown, ER and , }, title = {Understanding the sources of efficacy dilution in a trial of a monthly dapivirine vaginal ring for HIV-1 prevention.}, journal = {International journal of STD & AIDS}, volume = {36}, number = {3}, pages = {195-204}, doi = {10.1177/09564624241300199}, pmid = {39591433}, issn = {1758-1052}, mesh = {Humans ; Female ; *HIV Infections/prevention & control ; *Pyrimidines/administration & dosage ; *Contraceptive Devices, Female ; *HIV-1/drug effects ; *Anti-HIV Agents/administration & dosage ; Adult ; Administration, Intravaginal ; Treatment Outcome ; Sexual Behavior ; }, abstract = {INTRODUCTION: Women-initiated HIV - 1 prevention products are key to reducing women's HIV-1 risk. Clinical trials of vaginal microbicides have shown limited to no efficacy in intention-to-treat (ITT) analyses. It is hypothesized that these negative results are partly due to efficacy dilution.
METHODS: We developed a microsimulation model of MTN-020/ASPIRE, a phase 3 trial that evaluated monthly use of a dapivirine vaginal ring for HIV-1 prevention. We evaluated four sources of efficacy dilution: trial-level factors: (i) an imbalance in the number of monthly sex acts between study arms and (ii) heterogeneity in risk emergent over time; and individual-level factors: (iii) product non-adherence and (iv) receptive anal intercourse.
RESULTS: Assuming 70% per-vaginal exposure efficacy (consistent with the ITT estimate of 27%), heterogeneity in risk accounted for the largest proportion of efficacy dilution, at 42% (90% CrI: 38, 45), followed by non-adherence (33%; 90% CrI: 27, 39), an imbalance in arms (18%; 90% CrI: 16, 21) and lastly, anal intercourse with less than 10% of efficacy dilution.
CONCLUSION: Our results suggest that heterogeneity in risk was the most important source of efficacy dilution in the ASPIRE trial. Future trials of HIV-1 prevention products for women should consider alternative trial designs and analytic approaches that minimize bias introduced by heterogeneity in risk.}, }
@article {pmid39589879, year = {2024}, author = {Varuzhanyan, G and Chen, CC and Freeland, J and He, T and Tran, W and Song, K and Wang, L and Cheng, D and Xu, S and Dibernardo, GA and Esedebe, FN and Bhatia, V and Han, M and Abt, ER and Park, JW and Memarzadeh, S and Shackelford, DB and Lee, JK and Graeber, TG and Shirihai, OS and Witte, ON}, title = {PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2416882121}, pmid = {39589879}, issn = {1091-6490}, support = {01//G. Harold and Leila Y. Mathers Foundation (Mathers Foundation)/ ; I01 BX004651/BX/BLRD VA/United States ; I01BX006019//Veteran Affairs funds/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research predoctoral fellowship/ ; 2 P30 CA016042-44//NIH (NIH)/ ; 1 S10 OD026917-01A1//NIH (NIH)/ ; DP2 CA271301/CA/NCI NIH HHS/United States ; I01 BX006019/BX/BLRD VA/United States ; S10 OD026917/OD/NIH HHS/United States ; 01//Parker Institute for Cancer Immunotherapy (PICI)/ ; P50 CA092131/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; NIH T32 CA-009056//UCLA Tumor Cell Biology Training Program (USHHS) Ruth L. Kirschstein Institutional national Research Service Award/ ; T32 CA009056/CA/NCI NIH HHS/United States ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Hal Gaba Director's Fund for Cancer Stem Cell Research/ ; 01//UCLA Dissertation Year Fellowship/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award/ ; 01//University of California-Historically Black Colleges and Universities (UC-HBCU) Initiative Fellowship provided by University of California Office of the President (UCOP)./ ; R01 CA222877/CA/NCI NIH HHS/United States ; R01CA222877Â//NIH R01 Grant/ ; P50CA092131Â//NIH UCLA SPORE in Prostate Cancer/ ; }, mesh = {Humans ; *Basic Helix-Loop-Helix Transcription Factors/metabolism/genetics ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Mitochondria/metabolism ; Male ; *Oxidative Phosphorylation ; Animals ; Cell Line, Tumor ; *Disease Progression ; Mice ; Prostatic Neoplasms/metabolism/pathology/genetics ; Gene Expression Regulation, Neoplastic ; Neuroendocrine Tumors/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.}, }
@article {pmid39589470, year = {2024}, author = {Udovicich, C and Lo, SS and Guckenberger, M and Sahgal, A}, title = {Shifting the Landscape of Spine and Non-Spine Bone Metastases: A Review of Stereotactic Body Radiotherapy.}, journal = {Cancer journal (Sudbury, Mass.)}, volume = {30}, number = {6}, pages = {385-392}, pmid = {39589470}, issn = {1540-336X}, mesh = {Humans ; *Radiosurgery/methods ; *Spinal Neoplasms/secondary/radiotherapy ; *Bone Neoplasms/secondary/radiotherapy ; Palliative Care/methods ; Treatment Outcome ; }, abstract = {Both spine and nonspine bone metastases are frequent sites of spread from solid organ malignancies. As bone metastases frequently cause significant morbidity for patients, it is critical to offer a treatment that can achieve rapid and durable symptomatic relief and local control, without being associated with serious risks of toxicity. Conventional palliative radiation therapy has a key treatment component in the multidisciplinary management of these patients; however, over the past decade, it has evolved to routinely deliver high biologically effective doses with precision in the form of stereotactic body radiation therapy. This change in paradigm is a result of the shifting landscape in cancer care, such that short-term pain relief is no longer the sole therapeutic aim for selected patients, and durable symptom relief and local tumor control are the goals. This review discusses the randomized prospective evidence, ongoing trials, approach to surveillance imaging, and treatment delivery for stereotactic body radiation therapy, to both spine and nonspine bone metastases, with a specific section on sacral metastases.}, }
@article {pmid39589370, year = {2024}, author = {Lerner, SP and Tangen, C and Svatek, RS and Daneshmand, S and Pohar, KS and Skinner, E and Schuckman, A and Sagalowsky, AI and Smith, ND and Kamat, AM and Kassouf, W and Plets, M and Bangs, R and Koppie, TM and Alva, A and La Rosa, FG and Pal, SK and Kibel, AS and Canter, DJ and Thompson, IM and , }, title = {Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer.}, journal = {The New England journal of medicine}, volume = {391}, number = {13}, pages = {1206-1216}, pmid = {39589370}, issn = {1533-4406}, support = {U10 CA180821/CA/NCI NIH HHS/United States ; 707213//Canadian Cancer Society/ ; U10 CA180863/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10CA180888 U10CA180819, U10CA180820, U10CA180821,/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Chemotherapy, Adjuvant ; *Cystectomy/adverse effects/methods ; Disease-Free Survival ; Kaplan-Meier Estimate ; *Lymph Node Excision/adverse effects/methods ; Lymphatic Metastasis/pathology/therapy ; Neoadjuvant Therapy ; Neoplasm Invasiveness ; Neoplasm Staging ; *Urinary Bladder Neoplasms/mortality/pathology/therapy ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear.
METHODS: We randomly assigned, in a 1:1 ratio, patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2) to undergo bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes. Randomization was performed during surgery and stratified according to the receipt and type of neoadjuvant chemotherapy, tumor stage (T2 vs. T3 or T4a), and a Zubrod's performance-status score (0 or 1 vs. 2; assessed on a 5-point scale, with higher scores indicating greater disability). The primary outcome was disease-free survival. Overall survival and safety were also assessed.
RESULTS: Of 658 patients who were enrolled, 592 eligible patients were randomly assigned to undergo extended lymphadenectomy (292 patients) or standard lymphadenectomy (300). Surgery was performed by 36 surgeons at 27 sites in the United States and Canada. Neoadjuvant chemotherapy had been received by 57% of the patients. At a median follow-up of 6.1 years, recurrence or death had occurred in 130 patients (45%) in the extended-lymphadenectomy group and in 127 (42%) in the standard-lymphadenectomy group, and the estimated 5-year disease-free survival was 56% and 60%, respectively (hazard ratio for recurrence or death, 1.10; 95% confidence interval [CI], 0.86 to 1.40; P = 0.45). Overall survival at 5 years was 59% in the extended-lymphadenectomy group and 63% in the standard-lymphadenectomy group (hazard ratio for death, 1.13; 95% CI, 0.88 to 1.45). Adverse events of grade 3 to 5 occurred in 157 patients (54%) in the extended-lymphadenectomy group and in 132 (44%) in the standard-lymphadenectomy group; death within 90 days after surgery occurred in 19 patients (7%) and 7 patients (2%), respectively.
CONCLUSIONS: As compared with standard lymphadenectomy, extended lymphadenectomy did not result in improved disease-free or overall survival among patients with muscle-invasive bladder cancer undergoing radical cystectomy and was associated with higher perioperative morbidity and mortality. (Funded by the National Cancer Institute and the Canadian Cancer Society; SWOG S1011 ClinicalTrials.gov number, NCT01224665.).}, }
@article {pmid39589343, year = {2025}, author = {Haffner, MC and Morris, MJ and Ding, CC and Sayar, E and Mehra, R and Robinson, B and True, LD and Gleave, M and Lotan, TL and Aggarwal, R and Huang, J and Loda, M and Nelson, PS and Rubin, MA and Beltran, H}, title = {Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {3}, pages = {466-478}, pmid = {39589343}, issn = {1557-3265}, support = {P50CA097186//National Cancer Institute (NCI)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; W81XWH-17-1-0653//U.S. Department of Defense (DOD)/ ; R01 CA234715/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R37CA286450//National Cancer Institute (NCI)/ ; P30CA15704//National Cancer Institute (NCI)/ ; R01 CA266452/CA/NCI NIH HHS/United States ; //the V Foundation/ ; P50CA272390//National Cancer Institute (NCI)/ ; //Brotman Baty Institute for Precision Medicine/ ; P01CA265768//National Cancer Institute (NCI)/ ; W81XWH-20-1-0111//U.S. Department of Defense (DOD)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA272390/CA/NCI NIH HHS/United States ; P01 CA265768/CA/NCI NIH HHS/United States ; //Prostate Cancer Foundation (PCF)/ ; //UW/FHCC Institute for Prostate Cancer Research/ ; R37 CA241486/CA/NCI NIH HHS/United States ; P50CA211024//National Cancer Institute (NCI)/ ; P50 CA211024/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; Grant 2021184//Doris Duke Charitable Foundation (DDCF)/ ; P30CA008748//National Cancer Institute (NCI)/ ; W81XWH-19-1-0566//U.S. Department of Defense (DOD)/ ; R01CA234715-03//National Cancer Institute (NCI)/ ; W81XWH-18-1-0689//U.S. Department of Defense (DOD)/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/pathology/diagnosis/metabolism ; Biomarkers, Tumor ; Biopsy ; Receptors, Androgen/genetics/metabolism ; Prognosis ; Neoplasm Metastasis ; }, abstract = {Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine (NE) prostate cancer (NEPC) occur in up to 15% to 20% of patients with castration-resistant prostate cancer (CRPC) as a mechanism of treatment resistance and are associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of NE lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions, making clinical trial design challenging. In this manuscript, we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and IHC markers with a priority for AR, NK3 homeobox 1, insulinoma-associated protein 1, synaptophysin, and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.}, }
@article {pmid39589272, year = {2025}, author = {Han, YY and Chen, W and Forno, E and Perreira, KM and Oren, E and Daviglus, M and Garcia-Bedoya, O and Kaplan, R and Isasi, CR and Celedón, JC}, title = {Sociocultural Stressors and Asthma among Adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Annals of the American Thoracic Society}, volume = {22}, number = {4}, pages = {549-559}, pmid = {39589272}, issn = {2325-6621}, support = {HL168539//National Heart, Lung, and Blood Institute (National Heart, Lung, and Blood Institute)/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; HL152475//National Heart, Lung, and Blood Institute (National Heart, Lung, and Blood Institute)/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; R01 HL152475/HL/NHLBI NIH HHS/United States ; R01 HL168539/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acculturation ; Anxiety/ethnology ; *Asthma/ethnology/psychology ; Cross-Sectional Studies ; Depression/ethnology ; *Hispanic or Latino/psychology/statistics & numerical data ; Logistic Models ; Residence Characteristics ; *Stress, Psychological/ethnology ; United States/epidemiology ; }, abstract = {Rationale: Hispanic/Latino adults commonly experience high psychosocial stress; yet, little is known about the pathways linking sociocultural stressors and asthma in this population. Objectives: To study whether and how sociocultural stressors are associated with asthma in Hispanic/Latino adults. Methods: We conducted a cross-sectional study of 4,759 adults aged 18 to 74 years who participated in the Sociocultural Ancillary Study of the Hispanic Community Health Study/Study of Latinos. All participants completed a sociocultural assessment, including acculturative stress, perceived ethnic discrimination, neighborhood problems, neighborhood social cohesion, and a cumulative measure of all sociocultural stressors. Weighted multivariable logistic regression accounting for sampling design was used for the analysis of sociocultural stressors and current asthma or current asthma symptoms. A mediation analysis was conducted to estimate the contributions of depressive symptoms and anxiety to the cumulative sociocultural stressors-asthma association. Results: Acculturative stress and neighborhood problems were associated with 1.4 to 2.1 times higher odds of current asthma or current asthma symptoms, and perceived ethnic discrimination was associated with 1.4 times higher odds of current asthma symptoms. Neighborhood social cohesion was associated with 0.6 times lower odds of asthma. Cumulative sociocultural stressors were associated with 1.6 times higher odds of current asthma symptoms (odds ratio for below the median versus greater than or equal to the median value, 1.60; 95% confidence interval, 1.29, 1.99). Depressive symptoms and anxiety explained 26% and 22%, respectively, of the association between cumulative sociocultural stressors and asthma symptoms. Conclusions: Among Hispanic/Latino adults, sociocultural stressors were associated with current asthma or asthma symptoms. Depressive symptoms and anxiety partly mediated this association. Clinicians caring for Hispanic/Latino adults with asthma should be aware of potential stressors and comorbidities such as depression and anxiety.}, }
@article {pmid39587707, year = {2024}, author = {Ilozumba, MN and Lin, T and Hardikar, S and Byrd, DA and Round, JL and Stephens, WZ and Holowatyj, AN and Warby, CA and Damerell, V and Li, CI and Figueiredo, JC and Toriola, AT and Shibata, D and Fillmore, GC and Pickron, B and Siegel, EM and Kahlert, C and Florou, V and Gigic, B and Ose, J and Ulrich, CM}, title = {Fusobacterium nucleatum Abundance is Associated with Cachexia in Colorectal Cancer Patients: The ColoCare Study.}, journal = {Cancer medicine}, volume = {13}, number = {22}, pages = {e70431}, pmid = {39587707}, issn = {2045-7634}, support = {R01 CA207371/CA/NCI NIH HHS/United States ; //the German Ministry of Education and Research project PerMiCCion (01KD2101D)/ ; //German Cancer Research Center/ ; R01 CA254108/CA/NCI NIH HHS/United States ; //Huntsman Cancer Foundation/ ; R01 CA189184/CA/NCI NIH HHS/United States ; R01 AG083580/AG/NIA NIH HHS/United States ; //ERA-NET (European Research Area Network) on Translational Cancer Research (TRANSCAN) project/ ; U01 CA206110/CA/NCI NIH HHS/United States ; //the Rahel-Goitein-Straus-Program, Medical Faculty Heidelberg University/ ; //Stiftung LebensBlicke, Matthias Lackas Stiftung, Claussen-Simon Stiftung/ ; K07 CA222060/CA/NCI NIH HHS/United States ; //the German Consortium of Translational Cancer Research, (DKTK)/ ; R01 CA211705/CA/NCI NIH HHS/United States ; //University of Utah Immunology, Inflammation, and Infectious Disease Initiative/ ; //Cancer Control and Population Health Sciences (CCPS) at the University of Utah/ ; }, mesh = {Humans ; *Colorectal Neoplasms/complications/microbiology ; Male ; *Cachexia/etiology/microbiology ; *Fusobacterium nucleatum/isolation & purification ; Female ; Aged ; Middle Aged ; *Feces/microbiology ; Fusobacterium Infections/complications/microbiology ; Neoplasm Staging ; Risk Factors ; }, abstract = {BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established.
METHODS: We evaluated the association between Fn abundance in pre-surgical stool samples and onset of cachexia at 6 months post-surgery in n = 87 patients with stages I-III CRC in the ColoCare Study.
RESULTS: High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4-fold increased risk of cachexia onset at 6 months post-surgery (OR = 4.82, 95% CI = 1.15, 20.10, p = 0.03).
CONCLUSION: Our findings suggest that high fecal Fn abundance was associated with an increased risk of cachexia at 6 months post-surgery in CRC patients. This is the first study to link Fn abundance with cachexia in CRC patients, offering novel insights into biological mechanisms and potential management of cancer cachexia. Due to the small sample size, our results should be interpreted with caution. Future studies with larger sample sizes are needed to validate these findings.}, }
@article {pmid39587448, year = {2025}, author = {Papadimitriou, N and Murphy, N and Jenab, M and Chen, Z and Brenner, H and Kweon, SS and Le Marchand, L and Moreno, V and Platz, EA and van Duijnhoven, FJB and Cheng, I and Pai, RK and Phipps, AI and Peters, U and Zheng, W and Hughes, DJ}, title = {Body mass index at birth and early life and colorectal cancer: A two-sample Mendelian randomization analysis in European and East Asian genetic similarity populations.}, journal = {Pediatric obesity}, volume = {20}, number = {1}, pages = {e13186}, pmid = {39587448}, issn = {2047-6310}, support = {R01 CA188214/CA/NCI NIH HHS/United States ; R01CA188214/NH/NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; 31312020//International Health Cohorts Consortium/Global Genomic Medicine Collaborative/ ; 001/WHO_/World Health Organization/International ; }, mesh = {Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Asia, Eastern/epidemiology ; *Body Mass Index ; *Colorectal Neoplasms/genetics/epidemiology ; *East Asian People/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Norway/epidemiology ; Polymorphism, Single Nucleotide ; Risk Factors ; *White People/genetics ; }, abstract = {BACKGROUND: Varying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.
OBJECTIVES: We conducted a two-sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8 years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.
METHODS: Summary data were obtained from genome-wide association study (GWAS) of BMI in 28 681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102 893 cases and 485 083 non-cases).
RESULTS: There were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1-standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1-SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer-site-specific analyses.
CONCLUSIONS: We found little evidence of any associations between early life adiposity on later life CRC risk.}, }
@article {pmid39586191, year = {2025}, author = {Dean, NE and Halloran, ME and Zarnitsyna, VI}, title = {Poor vaccine responders mask the true trend in vaccine effectiveness against progression to severe disease.}, journal = {Vaccine}, volume = {43}, number = {Pt 2}, pages = {126516}, pmid = {39586191}, issn = {1873-2518}, support = {R01 AI139761/AI/NIAID NIH HHS/United States ; U01 AI150747/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/prevention & control/immunology ; *Disease Progression ; *COVID-19 Vaccines/immunology/administration & dosage ; *SARS-CoV-2/immunology ; *Vaccine Efficacy ; Models, Theoretical ; Vaccination/methods ; }, abstract = {Vaccines can reduce an individual's risk of infection and their risk of progression to severe disease given infection. The latter effect is less commonly estimated but is relevant for vaccine impact modeling and cost-effectiveness calculations. Using a motivating example from the COVID-19 literature, we note how vaccine effectiveness against progression to severe disease can appear to increase from below 0 % to over 70 % within 8 months. With true biological strengthening of this magnitude being unlikely, we use a mathematical modeling framework to identify parameter combinations where this phenomenon can occur. Fundamental features are an immunocompetent population with high initial protection against infection, contrasted with a vulnerable subpopulation with poor vaccine response against infection and progression. As a result, the earliest infections are among those with the weakest protection against severe disease. This work highlights methodological challenges in isolating a vaccine's effect on progression to severe disease after infection, and it signals the need for refined analytical methods to adjust for differences between the vaccinated infected and the unvaccinated infected populations.}, }
@article {pmid39586040, year = {2025}, author = {LeBlanc, ML}, title = {Using Cure Models for Trial Analysis and Design.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {8}, pages = {903-906}, doi = {10.1200/JCO-24-01918}, pmid = {39586040}, issn = {1527-7755}, }
@article {pmid39584453, year = {2024}, author = {Colasurdo, M and Ferrer-Font, L and Middlebrook, A and Konecny, AJ and Prlic, M and Spidlen, J}, title = {SingletSeeker: an unsupervised clustering approach for automated singlet discrimination in cytometry.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {}, number = {}, pages = {}, pmid = {39584453}, issn = {1552-4957}, support = {R56 DE032009/NH/NIH HHS/United States ; R01 AI123323/AI/NIAID NIH HHS/United States ; //Emerson Collective/ ; R01 AI123323/NH/NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; }, abstract = {Flow cytometry is a high-throughput, high-dimensional technique that generates large sets of single-cell data. Prior to analyzing this data, it is common to exclude any events that contain two or more cells, multiplets, to ensure downstream analysis and quantification is of single-cell events, singlets, only. The process of singlet discrimination is critical yet fundamentally subjective and time-consuming; it is performed manually by the user, where the proper exclusion of multiplets depends on the user's expertise and often varies from experiment to experiment. To address this problem, we have developed an algorithm to automatically discriminate singlets from other unwanted events such as multiplets and debris. Using parameters derived from imaging, the algorithm first identifies high-density clusters of events using a density-based clustering algorithm, and then classifies the clusters based on their properties. Multiplets are discarded in the first step, while singlets are distinguished from debris in the second step. The algorithm can use different strategies on imaging feature selection-based user's preferences and imaging features available. In addition, the relative importance of singlets precision vs. sensitivity can be further tweaked via a density coefficient adjustment. Twenty-two datasets from various sites and of various cell types acquired on the BD FACSDiscover™ S8 Cell Sorter with CellView™ Image Technology were used to develop and validate the algorithm across multiple imaging feature sets. A consistent singlets precision >97% with a solid >88% sensitivity has been demonstrated with a LightLoss feature set and the default density coefficient. This work yields a high-precision, high-sensitivity algorithm capable of objective and automated singlet discrimination across multiple cell types using various imaging-derived parameters. A free FlowJo™ Software plugin implementation is available for simple and reproducible singlet discrimination for use at the beginning of any user's workflow.}, }
@article {pmid39582620, year = {2024}, author = {Isacchini, G and Quiniou, V and Barennes, P and Mhanna, V and Vantomme, H and Stys, P and Mariotti-Ferrandiz, E and Klatzmann, D and Walczak, AM and Mora, T and Nourmohammad, A}, title = {Local and Global Variability in Developing Human T-Cell Repertoires.}, journal = {PRX life}, volume = {2}, number = {1}, pages = {}, pmid = {39582620}, issn = {2835-8279}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.}, }
@article {pmid39581232, year = {2025}, author = {Setia, M and Suvas, PK and Rana, M and Chakraborty, A and Suvas, S}, title = {Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas.}, journal = {Mucosal immunology}, volume = {18}, number = {1}, pages = {188-204}, pmid = {39581232}, issn = {1935-3456}, support = {P30 CA046592/CA/NCI NIH HHS/United States ; P30 EY004068/EY/NEI NIH HHS/United States ; R01 EY029690/EY/NEI NIH HHS/United States ; R01 EY030129/EY/NEI NIH HHS/United States ; }, mesh = {*Herpesvirus 1, Human/immunology/physiology ; *Keratitis, Herpetic/immunology/virology ; Animals ; Mice ; *Memory T Cells/immunology/metabolism ; Immunologic Memory ; *Cornea/immunology/virology ; Humans ; Disease Models, Animal ; *CD8-Positive T-Lymphocytes/immunology ; Mice, Inbred C57BL ; Female ; *CD4-Positive T-Lymphocytes/immunology ; }, abstract = {The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (TRM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of TRM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 TRM cells than HSK corneas. The TRM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of TRM cells in HSV-1 infected corneas that did or did not develop HSK.}, }
@article {pmid39580580, year = {2025}, author = {Chan, WC and Liu, L and Bouras, E and Zuber, V and Wen, W and Long, J and Gill, D and Murphy, N and Gunter, MJ and Assimes, TL and Bujanda, L and Gruber, SB and Küry, S and Lynch, BM and Qu, C and Thomas, M and White, E and Woods, MO and Peters, U and Li, CI and Chan, AT and Brenner, H and Tsilidis, KK and Zheng, W}, title = {Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study.}, journal = {British journal of cancer}, volume = {132}, number = {1}, pages = {103-110}, pmid = {39580580}, issn = {1532-1827}, support = {001/WHO_/World Health Organization/International ; 29019/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Colorectal Neoplasms/blood/genetics/epidemiology ; Mendelian Randomization Analysis ; *Cholesterol, LDL/blood ; Male ; Proprotein Convertase 9/genetics ; Female ; Triglycerides/blood ; Middle Aged ; Risk Factors ; Cholesterol, HDL/blood ; Polymorphism, Single Nucleotide ; *Lipids/blood ; Hydroxymethylglutaryl CoA Reductases/genetics ; Membrane Proteins/genetics ; Aged ; Case-Control Studies ; Membrane Transport Proteins ; }, abstract = {BACKGROUND: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear.
METHODS: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed.
RESULTS: Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets.
CONCLUSIONS: We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.}, }
@article {pmid39579334, year = {2024}, author = {Clement, ME and Hanscom, B and Haines, D and Bazan, JA and Chotirosniramit, N and Kofron, R and Mannheimer, S and Mayer, KH and Torres Silva, MS and Soto-Torres, L and Rinehart, AR and Rooney, JF and Jennings, A and Gomez-Feliciano, K and McCauley, M and Grinsztejn, B and Landovitz, RJ and , }, title = {Cabotegravir Maintains Protective Efficacy in the Setting of Bacterial STIs: A Secondary Analysis of HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae572}, pmid = {39579334}, issn = {1537-6591}, abstract = {BACKGROUND: Sexually transmitted infections (STIs) have been shown to facilitate HIV transmission and acquisition. HPTN 083, a global clinical trial, demonstrated superiority of long-acting cabotegravir (CAB-LA) versus daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention among transgender women and cisgender men who have sex with men. This analysis assessed whether CAB-LA maintained protective efficacy when bacterial STIs (syphilis, rectal/urethral gonorrhea and chlamydia) were present.
METHODS: STI events per 100 person-years (PY) were calculated, including by subgroups (age, race/ethnicity, gender, education, treatment arm, drug use, alcohol use, region/country, condom usage, partner number, marital status, baseline STI). Association between baseline factors and STI incidence was modeled using Poisson regression. Cox proportional hazards modeling with STI status as a time-varying covariate was used to evaluate potential interactions between STI status and the relative efficacy of CAB-LA vs. TDF/FTC.
FINDINGS: Among 3,859 participants, overall STI incidence rate was 50.7 infections/100PY. STIs were diagnosed in 1,562 (40.5%) participants; 79% of STIs occurred in 25% of the participants. STI incidence was not different by PrEP arm. In the final multivariable model, age, region, race, education level, marital status, and baseline STI were associated with incident STI (p<0.05). HIV incidence was lower with CAB-LA vs. TDF/FTC with or without STIs (hazard ratios 0.37 and 0.31, respectively), with no significant interaction between STIs and the HR for HIV incidence (p = 0.75).
CONCLUSION: In a large PrEP trial with high STI incidence, CAB-LA maintained robust protective efficacy relative to TDF/FTC in the setting of bacterial STIs.}, }
@article {pmid39577421, year = {2024}, author = {Hamidi, H and Senbabaoglu, Y and Beig, N and Roels, J and Manuel, C and Guan, X and Koeppen, H and Assaf, ZJ and Nabet, BY and Waddell, A and Yuen, K and Maund, S and Sokol, E and Giltnane, JM and Schedlbauer, A and Fuentes, E and Cowan, JD and Kadel, EE and Degaonkar, V and Andreev-Drakhlin, A and Williams, P and Carter, C and Gupta, S and Steinberg, E and Loriot, Y and Bellmunt, J and Grivas, P and Rosenberg, J and van der Heijden, MS and Galsky, MD and Powles, T and Mariathasan, S and Banchereau, R}, title = {Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade.}, journal = {Cancer cell}, volume = {42}, number = {12}, pages = {2098-2112.e4}, doi = {10.1016/j.ccell.2024.10.016}, pmid = {39577421}, issn = {1878-3686}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *B7-H1 Antigen/antagonists & inhibitors/genetics/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Urinary Bladder Neoplasms/drug therapy/genetics/pathology ; Carcinoma, Transitional Cell/drug therapy/genetics/pathology ; Male ; Female ; Biomarkers, Tumor/genetics/metabolism ; Genetic Heterogeneity ; Aged ; }, abstract = {Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology. Machine learning identifies four transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care is observed in immune and basal tumors, through different response mechanisms. A self-supervised digital pathology approach can classify molecular subtypes from H&E slides with high accuracy, which could accelerate tumor molecular profiling. This study represents a large integration of UC molecular and clinical data in randomized trials, paving the way for clinical studies tailoring treatment to specific molecular subtypes in UC and other indications.}, }
@article {pmid39576958, year = {2025}, author = {Adams, RC and MacDonald, KPA and Hill, GR}, title = {The contribution of the monocyte-macrophage lineage to immunotherapy outcomes.}, journal = {Blood}, volume = {145}, number = {10}, pages = {1010-1021}, doi = {10.1182/blood.2024025680}, pmid = {39576958}, issn = {1528-0020}, mesh = {Humans ; *Macrophages/immunology/pathology/metabolism ; *Monocytes/immunology/pathology/cytology ; *Immunotherapy/methods ; Animals ; *Graft vs Host Disease/therapy/immunology/pathology/etiology ; Hematopoietic Stem Cell Transplantation/adverse effects ; *Cell Lineage ; Macrophage Colony-Stimulating Factor ; }, abstract = {Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.}, }
@article {pmid39576815, year = {2024}, author = {Weissman, JL and Chappell, CR and Francesco Rodrigues de Oliveira, B and Evans, N and Fagre, AC and Forsythe, D and Frese, SA and Gregor, R and Ishaq, SL and Johnston, J and K R, B and Matsuda, SB and McCarren, S and Ortiz Alvarez de la Campa, M and Roepke, TA and Sinnott-Armstrong, N and Stobie, CS and Talluto, L and Vargas-Muñiz, JM and , }, title = {Queer- and trans-inclusive faculty hiring-A call for change.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002919}, pmid = {39576815}, issn = {1545-7885}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; }, mesh = {*Faculty ; Humans ; *Personnel Selection/methods ; *Sexual and Gender Minorities ; Universities ; }, abstract = {As queer and trans scientists, we face varied and systemic barriers to our professional success, resulting in our relative absence from faculty ranks at many institutions. In this Perspective, we call for a change in faculty hiring practices and present concrete guidance to make it a more inclusive process.}, }
@article {pmid39576760, year = {2024}, author = {Correa-Medero, RL and Pai, R and Ebare, K and Buchanan, DD and Jenkins, MA and Phipps, AI and Newcomb, PA and Gallinger, S and Grant, R and Le Marchand, L and Banerjee, I}, title = {Causal debiasing for unknown bias in histopathology-A colon cancer use case.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0303415}, pmid = {39576760}, issn = {1932-6203}, support = {U01 CA167551/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colonic Neoplasms/pathology ; Proportional Hazards Models ; Bias ; Prognosis ; Female ; Male ; Disease-Free Survival ; }, abstract = {Advancement of AI has opened new possibility for accurate diagnosis and prognosis using digital histopathology slides which not only saves hours of expert effort but also makes the estimation more standardized and accurate. However, preserving the AI model performance on the external sites is an extremely challenging problem in the histopathology domain which is primarily due to the difference in data acquisition and/or sampling bias. Although, AI models can also learn spurious correlation, they provide unequal performance across validation population. While it is crucial to detect and remove the bias from the AI model before the clinical application, the cause of the bias is often unknown. We proposed a Causal Survival model that can reduce the effect of unknown bias by leveraging the causal reasoning framework. We use the model to predict recurrence-free survival for the colorectal cancer patients using quantitative histopathology features from seven geographically distributed sites and achieve equalized performance compared to the baseline traditional Cox Proportional Hazards and DeepSurvival model. Through ablation study, we demonstrated benefit of novel addition of latent probability adjustment and auxiliary losses. Although detection of cause of unknown bias is unsolved, we proposed a causal debiasing solution to reduce the bias and improve the AI model generalizibility on the histopathology domain across sites. Open-source codebase for the model training can be accessed from https://github.com/ramon349/fair_survival.git.}, }
@article {pmid39576210, year = {2025}, author = {Sweis, RF and Chatta, GS and Jain, RK and Moon, H and Delacroix, SE and Fang, A and D'Amico, L and Kask, AS and Cheever, MA and Fling, S and Sharon, E and Lacroix, A and Kaiser, JC and Pachynski, RK and Yu, EY}, title = {A Phase II Open-Label, Randomized Clinical Trial of Atezolizumab with or without Human Recombinant IL-7 (CYT107) in Advanced Urothelial Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {2}, pages = {299-307}, pmid = {39576210}, issn = {1557-3265}, support = {K08CA234392//National Cancer Institute (NCI)/ ; K08 CA234392/CA/NCI NIH HHS/United States ; UM1 CA154967/CA/NCI NIH HHS/United States ; U01 CA154967/CA/NCI NIH HHS/United States ; U01 CA243075/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; Aged ; Middle Aged ; *Interleukin-7/administration & dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged, 80 and over ; Adult ; Recombinant Proteins/administration & dosage ; *Urologic Neoplasms/drug therapy/pathology ; Treatment Outcome ; }, abstract = {PURPOSE: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (Cancer Immunotherapy Trials Network-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.
PATIENTS AND METHODS: Patients with urothelial cancer after platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by the objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.
RESULTS: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities and lower grade 3 to 4 treatment-related adverse events compared with atezolizumab monotherapy. The ORR was 26.3% for the combination therapy versus 23.8% for atezolizumab alone (P = 0.428). The complete response rate was 10.5% for the combination therapy versus 4.8% for monotherapy. Three patients on combination therapy had responses >21 months versus one with monotherapy. CD4+ and CD8+ T-lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cells. Patients who responded to treatment exhibited elevated baseline levels of CCL4 and reduced levels of VEGFA and TNF.
CONCLUSIONS: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the complete response rate, and durable responses exceeding 2 years. However, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.}, }
@article {pmid39575237, year = {2024}, author = {Byrne, C and Schiffer, JT}, title = {Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1426016}, pmid = {39575237}, issn = {1664-3224}, mesh = {Animals ; *Macaca mulatta ; *SARS-CoV-2/immunology ; *COVID-19/immunology/virology ; *Immunity, Innate ; *Viral Load ; Antibodies, Viral/immunology/blood ; Lung/immunology/virology ; }, abstract = {INTRODUCTION: An unprecedented breadth of longitudinal viral and multi-scale immunological data has been gathered during SARS-CoV-2 infection. However, due to the high complexity, non-linearity, multi-dimensionality, mixed anatomic sampling, and possible autocorrelation of available immune data, it is challenging to identify the components of the innate and adaptive immune response that drive viral elimination. Novel mathematical models and analytical approaches are required to synthesize contemporaneously gathered cytokine, transcriptomic, flow cytometry, antibody response, and viral load data into a coherent story of viral control, and ultimately to discriminate drivers of mild versus severe infection.
METHODS: We investigated a dataset describing innate, SARS-CoV-2 specific T cell, and antibody responses in the lung during early and late stages of infection in immunologically naïve rhesus macaques. We used multi-model inference and ensemble modeling approaches from ecology and weather forecasting to compare and combine various competing models.
RESULTS AND DISCUSSION: Model outputs suggest that the innate immune response plays a crucial role in controlling early infection, while SARS-CoV-2 specific CD4+ T cells correspond to later viral elimination, and anti-spike IgG antibodies do not impact viral dynamics. Among the numerous genes potentially contributing to the innate response, we identified IFI27 as most closely linked to viral load decline. A 90% knockdown of the innate response from our validated model resulted in a ~10-fold increase in peak viral load during infection. Our approach provides a novel methodological framework for future analyses of similar complex, non-linear multi-component immunologic data sets.}, }
@article {pmid39574748, year = {2024}, author = {Gupta, S and Martinov, T and Thelen, A and Sunahara, M and Mureli, S and Vazquez, A and Gerdts, J and Dandekar, R and Cortese, I and Fouassier, C and Schanzer, E and Urnov, FD and Marson, A and Shy, BR and Greenberg, PD and Wilson, MR}, title = {Antigen-Specific T Cell Receptor Discovery for Treating Progressive Multifocal Leukoencephalopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574748}, issn = {2692-8205}, support = {K08 AI174061/AI/NIAID NIH HHS/United States ; K08 CA273529/CA/NCI NIH HHS/United States ; L30 TR002983/TR/NCATS NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease of the central nervous system caused by JC virus (JCV). Survival is dependent on early diagnosis and ability to re-establish anti-viral T cell immunity. Adoptive transfer of polyomavirus-specific T cells has shown promise; however, there are no readily available HLA-matched anti-viral T cells to facilitate rapid treatment.
OBJECTIVE: Identify epitopes of the JCV major capsid protein VP1 that elicit an immune response in the context of human leukocyte antigen allele A*02:01 (HLA-A2) and isolate cognate T cell receptors (TCRs) from healthy donors. Evaluate individual VP1-specific TCRs for their capacity to be expressed in T cells and clear JCV in vitro.
METHODS: PBMCs from HLA-A2+ healthy donors were stimulated with peptide libraries tiled across the JCV VP1 protein. Multiple rounds of stimulation were performed to identify the antigens that induced the largest expansion and CD8[+] T cell response (measured as INFγ, TNFα, CD137, and CD69 expression). High-affinity, antigen-specific CD8[+] T cells were isolated based on intensity of tetramer binding for downstream single-cell TCR sequencing. Candidate TCRs were selected based on tetramer binding affinity and activation assays. Promising TCRs were introduced into the T cell genome via viral transduction for in vitro validation including peptide-pulsed K562 cells and astrocyte cells, and JCV-infected astrocytes.
RESULTS: Four conserved JCV VP1 epitopes (amino acids 100-108, 251-259, 253-262, and 274-283) presented by HLA-A2 were identified. VP1(100-108) consistently elicited the highest level of IFN-γ production from multiple donors and this peptide is in a highly conserved region of VP1. We next identified fourteen high avidity TCRs specific for VP1(100-108). When virally transduced into primary human T cells, seven of these TCRs demonstrated specific binding to VP1(100-108):HLA-A2 tetramers, and four showed increased IFN-γ response when incubated with peptide. Primary CD8[+] T cells expressing two of these TCRs cleared both HLA-A2 positive K562 cells and HLA-A2 positive SVG astrocyte cell line presenting exogenously added VP1 peptide at a range of E:T ratios. In addition, both TCR-transduced T cell populations effectively lysed JCV-infected astrocytes.
CONCLUSIONS: We identified JCV VP1 epitopes that are immunogenic in the context of HLA-A2 MHC-I, including epitopes that have not been previously described. The VP1(100-108) epitope was used to isolate HLA-A2-restricted TCRs. When cloned into primary human CD8[+] T cells, these TCRs recognized VP1 (100-108)-presenting targets, and the transduced T cells conferred cytotoxic activity and eliminated K562 and astrocyte cells displaying the VP1(100-108) peptide and not sham peptide, as well as JCV-infected astrocytes. Taken together, these data suggest that JCV VP1-specific TCRs could be appealing therapeutics for HLA-A2+ individuals with PML in whom intrinsic T cell immunity cannot be rescued.}, }
@article {pmid39574678, year = {2024}, author = {Zhu, L and Beichman, A and Harris, K}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574678}, issn = {2692-8205}, support = {R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; }, abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with lower mutation rates in species that reproduce quickly and maintain large effective population sizes. A compelling explanation for this trend is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that interfere with the molecular efficacy of DNA repair. However, in multicellular organisms, the relationship of the mutation rate to DNA repair efficacy is complicated by variation in reproductive age. Long generation times leave more time for mutations to accrue each generation, and late reproduction likely amplifies the fitness consequences of any DNA repair defect that creates extra mutations in the sperm or eggs. Here, we present theoretical and empirical evidence that a long generation time amplifies the strength of selection for low mutation rates in the spermatocytes and oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for DNA proofreading and repair in their germ cells. In contrast, species with different generation times accumulate similar mutation loads during embryonic development. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, }
@article {pmid39572695, year = {2024}, author = {Schuermans, A and Pournamdari, AB and Lee, J and Bhukar, R and Ganesh, S and Darosa, N and Small, AM and Yu, Z and Hornsby, W and Koyama, S and Kooperberg, C and Reiner, AP and Januzzi, JL and Honigberg, MC and Natarajan, P}, title = {Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction.}, journal = {Nature cardiovascular research}, volume = {3}, number = {12}, pages = {1516-1530}, pmid = {39572695}, issn = {2731-0590}, support = {K08 HL166687/HL/NHLBI NIH HHS/United States ; R01 HL127564/HL/NHLBI NIH HHS/United States ; R01HL127564//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 979465//American Heart Association (American Heart Association, Inc.)/ ; R00 HG012956/HG/NHGRI NIH HHS/United States ; 940166//American Heart Association (American Heart Association, Inc.)/ ; K08HL166687//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; Paul & Phyllis Fireman Endowed Chair in Vascular Medicine//Massachusetts General Hospital (MGH)/ ; }, mesh = {Humans ; *Proteomics/methods ; Female ; Male ; Middle Aged ; Aged ; *Atrial Fibrillation/blood/epidemiology/metabolism ; United Kingdom/epidemiology ; Mendelian Randomization Analysis ; Biomarkers/blood/metabolism ; Risk Assessment ; Coronary Artery Disease/epidemiology/blood/metabolism ; Heart Diseases/epidemiology/blood/metabolism ; Incidence ; Proteome/metabolism/analysis ; Predictive Value of Tests ; Aortic Valve Stenosis/blood/epidemiology/metabolism ; Heart Failure/epidemiology/metabolism/blood ; Blood Proteins/metabolism ; }, abstract = {Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P < 8.6 × 10[-6]. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases.}, }
@article {pmid39571171, year = {2025}, author = {Chong, EA and Penuel, E and Napier, EB and Lundberg, RK and Budde, LE and Shadman, M and Matasar, MJ and Bartlett, NL and Flinn, IW and Bosch, F and Fay, K and Goy, A and Kumar, A and Nastoupil, LJ and Wei, MC and Wu, M and Yin, S and Fraietta, JA and Chong, ER and Schuster, SJ}, title = {Impact of prior CAR T-cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas.}, journal = {Blood advances}, volume = {9}, number = {4}, pages = {696-703}, pmid = {39571171}, issn = {2473-9537}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Immunotherapy, Adoptive/methods/adverse effects ; *Lymphoma, B-Cell/therapy/pathology ; Aged ; Adult ; *Receptors, Chimeric Antigen/immunology ; Treatment Outcome ; *Antibodies, Bispecific/therapeutic use ; Recurrence ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor (CAR)-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T and subsequently treated on a phase 1/2 study of mosunetuzumab. Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. The median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (P = .006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received 1 intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells per μL; P = .02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells per μL [P = .005] and 243 vs -103 cells per μL [P = .004], respectively). Additionally, responding patients had an increase in activated CD8 cells (median fold change, 1.7; P = .02). Nonresponders had a relative decrease in CAR transgene levels (n = 16; P = .04). This is, to our knowledge, the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAbs after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes and have implications for optimal timing of BsAb after CAR-T. The trial was registered at www.ClinicalTrials.gov as #NCT02500407.}, }
@article {pmid39570997, year = {2024}, author = {Courret, C and Hemmer, LW and Wei, X and Patel, PD and Chabot, BJ and Fuda, NJ and Geng, X and Chang, CH and Mellone, BG and Larracuente, AM}, title = {Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002911}, pmid = {39570997}, issn = {1545-7885}, support = {R35 GM131868/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Centromere/genetics/metabolism ; *DNA, Satellite/genetics ; *Retroelements/genetics ; *Drosophila/genetics ; *Evolution, Molecular ; Female ; In Situ Hybridization, Fluorescence/methods ; Male ; Drosophila melanogaster/genetics ; Meiosis/genetics ; Y Chromosome/genetics ; Drosophila simulans/genetics ; Chromatin/metabolism/genetics ; Biological Evolution ; }, abstract = {Centromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function. To gain insight into the balance between conflict and cooperation at centromeric DNA, we take advantage of the close evolutionary relationships within the Drosophila simulans clade-D. simulans, D. sechellia, and D. mauritiana-and their relative, D. melanogaster. Using chromatin profiling combined with high-resolution fluorescence in situ hybridization on stretched chromatin fibers, we characterize all centromeres across these species. We discovered dramatic centromere reorganization involving recurrent shifts between retroelements and satellite DNAs over short evolutionary timescales. We also reveal the recent origin (<240 Kya) of telocentric chromosomes in D. sechellia, where the X and fourth centromeres now sit on telomere-specific retroelements. Finally, the Y chromosome centromeres, which are the only chromosomes that do not experience female meiosis, do not show dynamic cycling between satDNA and TEs. The patterns of rapid centromere turnover in these species are consistent with genetic conflicts in the female germline and have implications for centromeric DNA function and karyotype evolution. Regardless of the evolutionary forces driving this turnover, the rapid reorganization of centromeric sequences over short evolutionary timescales highlights their potential as hotspots for evolutionary innovation.}, }
@article {pmid39570620, year = {2025}, author = {Jabbour, E and Oehler, VG and Koller, PB and Jamy, O and Lomaia, E and Hunter, AM and Uspenskaya, O and Samarina, S and Mukherjee, S and Cortes, JE and Baer, MR and Zherebtsova, V and Shuvaev, V and Turkina, A and Davydkin, I and Guo, H and Chen, Z and Fu, T and Jiang, L and Wang, C and Wang, H and Yang, D and Zhai, Y and Kantarjian, H}, title = {Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {11}, number = {1}, pages = {28-35}, pmid = {39570620}, issn = {2374-2445}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/pharmacokinetics/administration & dosage ; *Pyridazines/therapeutic use/adverse effects/pharmacokinetics/administration & dosage ; Adult ; Aged ; *Imidazoles/therapeutic use/adverse effects/pharmacokinetics/administration & dosage ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Drug Resistance, Neoplasm/drug effects ; *Pyrazoles/therapeutic use/adverse effects/pharmacokinetics/administration & dosage ; Young Adult ; Aged, 80 and over ; Treatment Outcome ; Tyrosine Kinase Inhibitors ; Niacinamide/analogs & derivatives ; }, abstract = {IMPORTANCE: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.
OBJECTIVE: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.
This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.
INTERVENTIONS: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.
MAIN OUTCOMES AND MEASURES: Pharmacokinetic profile of olverembatinib.
RESULTS: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.
CONCLUSIONS AND RELEVANCE: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04260022.}, }
@article {pmid39570045, year = {2024}, author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN}, title = {Effect of metronidazole on concentrations of vaginal bacteria associated with risk of HIV acquisition.}, journal = {mBio}, volume = {15}, number = {12}, pages = {e0111024}, pmid = {39570045}, issn = {2150-7511}, support = {R01 AI061628/AI/NIAID NIH HHS/United States ; R01 AI-061628//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*Metronidazole/pharmacology ; Humans ; Female ; *HIV Infections ; *Vaginosis, Bacterial/microbiology ; *Vagina/microbiology ; *Bacteria/drug effects/classification/genetics/isolation & purification ; *RNA, Ribosomal, 16S/genetics ; Adult ; *Anti-Bacterial Agents/pharmacology ; Young Adult ; DNA, Bacterial/genetics ; Bacterial Load ; Real-Time Polymerase Chain Reaction ; Middle Aged ; }, abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of human immunodeficiency virus (HIV) acquisition; however, susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for 2 weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all 13 bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.25-4.78 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-7.9 days), with several bacteria (e.g., Sneathia spp., Vaginal TM7, and Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk.IMPORTANCEHuman immunodeficiency virus (HIV) transmission through sex remains a major public health challenge despite efforts at risk reduction and use of anti-retroviral pre-exposure prophylaxis. Many bacterial vaginosis (BV)-associated vaginal bacteria have been associated with increased HIV infection risk among women. If these bacteria help mediate HIV infection risk, then eradication of these bacteria is one potential strategy to reduce this risk. However, the best approach to eradicate HIV-high risk bacteria from the vagina is not known. We analyzed vaginal swabs collected daily from women with BV to determine the impact of metronidazole treatment on 13 vaginal bacterial taxa linked to elevated risk of HIV infection through use of taxon-directed quantitative PCR assays. We conclude that eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk, and we provide evidence that a 5-7-day treatment course may not be sufficient to suppress all bacteria.}, }
@article {pmid39569838, year = {2024}, author = {Triplette, M and Snidarich, M and Heffner, JL and Omernik, B and Ahmed, A and Brooks, E and Telew, B and Crothers, K and Brown, M}, title = {A Community-Engaged Research Study to Inform Tailored Programming for Smoking Cessation and Lung Cancer Screening Among At-Risk LGBTQ+ Elders.}, journal = {Health promotion practice}, volume = {}, number = {}, pages = {15248399241296101}, doi = {10.1177/15248399241296101}, pmid = {39569838}, issn = {1524-8399}, abstract = {Purpose. Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. Many communities within the lesbian, gay, bisexual, transgender and queer/questioning (LGBTQ+) umbrella have high rates of smoking, but focused lung cancer prevention is limited. Our objective was to utilize a community-based participatory research (CBPR) approach to guide the development of a program focused on lung cancer prevention in LGBTQ+ elders. Methods. Through community partnerships, we recruited participants who self-identified as LGBTQ+ and were eligible for lung cancer screening (LCS) to participate in semi-structured qualitative discussions with complementary surveys. Qualitative guides were developed to collect data on determinants of smoking cessation and LCS and to elicit feedback on interventions to support lung cancer prevention through a tailored approach to patient navigation. Qualitative data were analyzed using rapid templated analysis to elucidate themes. Results. The 21 enrolled participants had diverse sexual and gender identities and 57% were of minoritized race/ethnicity. Most (81%) had experience with smoking cessation but few (10%) had undergone LCS. Overall themes suggest interest in personalized (to individuals), tailored (to the LGBTQ+ community) and integrated longitudinal programs to support lung cancer prevention. Themes suggest strong endorsement of focused messaging to LGBTQ+ persons and reducing stigma related to LGBTQ+ identity and smoking. Conclusions. Themes highlight the need for integrated tobacco and LCS programming which can provide longitudinal support, and ideally, center community settings and peer support. This formative work will be utilized to adapt a patient navigation program to assist screen-eligible LGBTQ+ elders.}, }
@article {pmid39567685, year = {2024}, author = {Reyes, RA and Raghavan, SSR and Hurlburt, NK and Introini, V and Bol, S and Kana, IH and Jensen, RW and Martinez-Scholze, E and Gestal-Mato, M and López-Gutiérrez, B and Sanz, S and Bancells, C and Fernández-Quintero, ML and Loeffler, JR and Ferguson, JA and Lee, WH and Martin, GM and Theander, TG and Lusingu, JPA and Minja, DTR and Ssewanyana, I and Feeney, ME and Greenhouse, B and Ward, AB and Bernabeu, M and Pancera, M and Turner, L and Bunnik, EM and Lavstsen, T}, title = {Broadly inhibitory antibodies to severe malaria virulence proteins.}, journal = {Nature}, volume = {636}, number = {8041}, pages = {182-189}, pmid = {39567685}, issn = {1476-4687}, support = {K24 AI113002/AI/NIAID NIH HHS/United States ; R01 AI093615/AI/NIAID NIH HHS/United States ; U19 AI089674/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Humans ; Antibodies, Monoclonal/immunology ; *Antibodies, Protozoan/immunology ; Binding Sites ; Brain/blood supply/parasitology ; Endothelial Protein C Receptor/immunology/metabolism ; Erythrocytes/parasitology/immunology ; *Malaria, Falciparum/immunology/parasitology ; Microvessels/immunology/parasitology ; Models, Molecular ; *Plasmodium falciparum/immunology/pathogenicity ; Protein Binding ; Protein Domains ; *Protozoan Proteins/immunology/chemistry/metabolism ; *Virulence ; *Virulence Factors/chemistry/immunology/metabolism ; *Broadly Neutralizing Antibodies/immunology ; Malaria Vaccines/immunology ; }, abstract = {Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels[1]. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis[2]. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.}, }
@article {pmid39567681, year = {2025}, author = {Leyderman, M and Chandrasekar, T and Grivas, P and Li, R and Bhat, S and Basnet, A and Shapiro, O and Jacob, J and Daneshvar, MA and Kord, E and Bratslavsky, G and Goldberg, H}, title = {Metastasis development in non-muscle-invasive bladder cancer.}, journal = {Nature reviews. Urology}, volume = {22}, number = {6}, pages = {375-386}, pmid = {39567681}, issn = {1759-4820}, mesh = {Humans ; *Urinary Bladder Neoplasms/pathology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Non-Muscle Invasive Bladder Neoplasms ; }, abstract = {Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer presentation and is characterized by a varying probability of recurrence and progression. Sporadically, patients with NMIBC might also develop tumour metastases without any pathological evidence of muscle-invasive disease within the bladder, a condition known as metastatic NMIBC. In the published literature, this phenomenon is limited to several case reports and small reviews, with few data regarding the possible aetiologies. Several possible factors can be potentially associated with metastatic NMIBC, including tumour understaging, the number of transurethral resection procedures received by the patient, the presence of circulating tumour cells, the modality used for diagnostic cystoscopy and possible gender-associated differences. In this Perspective, our aim was to integrate and report currently available data on this relatively rare entity and provide some potential aetiological explanations.}, }
@article {pmid39567499, year = {2024}, author = {Chatterjee, SS and Linares, JF and Cid-Diaz, T and Duran, A and Khan, MIK and Osrodek, M and Brady, NJ and Reina-Campos, M and Marzio, A and Venkadakrishnan, VB and Bakht, MK and Khani, F and Mosquera, JM and Robinson, BD and Moyer, J and Elemento, O and Hsieh, AC and Goodrich, DW and Rickman, DS and Beltran, H and Moscat, J and Diaz-Meco, MT}, title = {Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9755}, pmid = {39567499}, issn = {2041-1723}, support = {R50 CA265332/CA/NCI NIH HHS/United States ; R01 GM135362/GM/NIGMS NIH HHS/United States ; R01 CA274963/CA/NCI NIH HHS/United States ; K22 CA269707/CA/NCI NIH HHS/United States ; R01CA246765//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50 CA283476/CA/NCI NIH HHS/United States ; R01 CA277857/CA/NCI NIH HHS/United States ; R01 CA234162/CA/NCI NIH HHS/United States ; R01CA277857//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P50 CA211024/CA/NCI NIH HHS/United States ; R50CA283476//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50CA265332//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R37 CA230617/CA/NCI NIH HHS/United States ; R01 CA250025/CA/NCI NIH HHS/United States ; R01 CA230913/CA/NCI NIH HHS/United States ; R01 CA275846/CA/NCI NIH HHS/United States ; R01 CA265892/CA/NCI NIH HHS/United States ; R01 CA246765/CA/NCI NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; }, mesh = {*Enhancer of Zeste Homolog 2 Protein/metabolism/genetics ; Male ; *Phenylthiohydantoin/pharmacology ; *Benzamides ; Humans ; *Nitriles/pharmacology ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/metabolism/pathology ; *Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Animals ; Phosphorylation ; Protein Biosynthesis/drug effects ; Mice ; Transforming Growth Factor beta/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Protein Kinase C/metabolism/genetics ; }, abstract = {Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC.}, }
@article {pmid39565920, year = {2025}, author = {Hammarlund, N and Holt, SK and Etzioni, R and Morehead, D and Lee, JR and Wolff, EM and Burrola-Mendez, Y and Sage, L and Gore, JL and Nyame, YA}, title = {The association of where patients with prostate cancer live and receive care on racial treatment inequities.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {4}, pages = {713-718}, pmid = {39565920}, issn = {1460-2105}, support = {//Andy Hill Cancer Research Endowment/ ; P50 CA097186/CA/NCI NIH HHS/United States ; P50 CA097186-17//Specialized Program of Research Excellence/ ; //Cancer Research Endowment/ ; /NH/NIH HHS/United States ; //Department of Defense/ ; }, mesh = {Aged ; Aged, 80 and over ; Humans ; Male ; *Black or African American/statistics & numerical data ; *Healthcare Disparities/ethnology/statistics & numerical data ; Medicare ; Prostatectomy/statistics & numerical data ; *Prostatic Neoplasms/therapy/ethnology ; *Racism ; SEER Program ; United States/epidemiology ; *White/statistics & numerical data ; }, abstract = {BACKGROUND: Black individuals are less likely to be treated for prostate cancer even though they are more than twice as likely to die compared with White individuals. The complex causes of these inequities are influenced by social and structural factors, including racism, which contribute to the differential delivery of care. This study investigates how factors related to the location of where individuals live and receive care affect treatment inequities for prostate cancer between Black and White individuals. We hypothesize that both location and race independently influence treatment inequities.
METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims to estimate the treatment inequity, as defined by differences in radiation or radical prostatectomy. Fixed effects at the physician, hospital, and patient ZIP code levels were incorporated to adjust for all time-invariant factors at these levels.
RESULTS: The results indicate that residential location-related factors explain only half of the treatment inequity, whereas provider- and hospital-level factors do not significantly account for disparities. Even after accounting for all time-invariant factors, significant differences in treatment rates persist.
CONCLUSIONS: The study highlights the importance of understanding race as a social construct and racism as a systemic and structural phenomenon in addressing treatment inequities. These findings provide a necessary step toward understanding equitable care and designing interventions to solve this inequity.}, }
@article {pmid39565908, year = {2025}, author = {Othus, M and Patel, SP and Chae, YK and Dietrich, E and Streicher, H and Sharon, E and Kurzrock, R}, title = {First cycle toxicity and survival in patients with rare cancers treated with checkpoint inhibitors.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {4}, pages = {692-700}, pmid = {39565908}, issn = {1460-2105}, support = {U10CA180888/CA/NCI NIH HHS/United States ; 5U01CA180888-08//Bristol-Myers Squibb Company/ ; UG1 CA233198/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects ; *Immune Checkpoint Inhibitors/adverse effects/administration & dosage ; Ipilimumab/adverse effects/administration & dosage ; *Neoplasms/drug therapy/mortality/pathology/immunology ; Nivolumab/adverse effects/administration & dosage ; Progression-Free Survival ; *Rare Diseases/drug therapy/mortality ; Clinical Trials, Phase II as Topic ; }, abstract = {BACKGROUND: Associations between immune-related adverse events from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers (n = 684) to evaluate associations between immune-related adverse events and overall survival and progression-free survival (PFS).
METHODS: Patients were treated with nivolumab and ipilimumab; the trial was opened at more than 1000 sites. Landmark Cox regression models were used to assess first cycle immune-related adverse event associations with PFS and overall survival.
RESULTS: We found that grade 1-2 treatment-related immune-related adverse events in the first cycle of therapy were associated with longer overall survival (multivariable hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.49 to 0.75; P < .001) compared with no treatment-related immune-related adverse event, while grade 3-4 immune-related adverse events were associated with shorter overall survival (HR = 1.41, 95% CI = 1.04 to 1.90; P = .025). Similar but weaker associations were observed with PFS and grade 1-2 treatment-related immune-related adverse events (HR = 0.83, 95% CI = 0.67 to 1.01; P = .067) and grade 3-4 (HR = 1.35, 95% CI = 1.02 to 1.78; P = .037) compared with no treatment-related immune-related adverse events. Grade 1-2 dermatologic toxicity was associated with improved overall survival compared with other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52 to 0.85; P = .002). There was no statistically significant overall survival difference between patients with grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other grade 1-2 toxicities.
CONCLUSION: In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of immune-related adverse event in the first cycle was predictive for survival.}, }
@article {pmid39565901, year = {2025}, author = {Zhao, Y and Gulati, R and Yang, Z and Newcomb, L and Zheng, Y and Zhu, K and Liu, M and Heijnsdijk, EAM and Haffner, MC and Cooperberg, M and Eggener, SE and De Marzo, AM and Kibel, AS and Rizopoulos, D and Hall, IJ and Etzioni, R}, title = {Projected outcomes of reduced-biopsy management of Grade Group 1 prostate cancer: implications for relabeling.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {4}, pages = {685-691}, pmid = {39565901}, issn = {1460-2105}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; 75D30122C13505/CC/CDC HHS/United States ; U01CA253915/CA/NCI NIH HHS/United States ; //Fred Hutchinson Cancer Center/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/blood/diagnosis/therapy ; *Prostate-Specific Antigen/blood ; Neoplasm Grading ; Biopsy/statistics & numerical data ; Aged ; Middle Aged ; *Watchful Waiting ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Implications of relabeling Grade Group 1 prostate cancer as noncancer will depend on the recommended active surveillance strategy. Whether relabeling should prompt deintensifying, prostate-specific antigen (PSA)-based active monitoring approaches is unclear. We investigated outcomes of biopsy-based active surveillance strategies vs PSA-based active monitoring for Grade Group 1 diagnoses under different patient adherence rates.
METHODS: We analyzed longitudinal PSA levels and time to Grade Group 2 or higher reclassification among 850 patients with a diagnosis of Grade Group 1 disease from the Canary Prostate Active Surveillance Study (2008-2013). We then simulated 20 000 patients over 12 years, comparing Grade Group 2 or higher detection under biennial biopsy against 3 PSA-based strategies: (1) PSA (biopsy for PSA change ≥20% per year), (2) PSA plus magnetic resonance imaging (magnetic resonance imaging for PSA change ≥20% per year and biopsy for Prostate Imaging Reporting & Data System ≥3), and (3) predicted risk (biopsy for predicted upgrading risk ≥10%).
RESULTS: Under biennial biopsies and 20% dropout to active treatment, 17% of patients had a 2-year or longer delay in Grade Group 2 or higher detection. The PSA strategy reduced the number of biopsies by 39% but delayed detection in 32% of patients. The PSA plus magnetic resonance imaging strategy reduced the number of biopsies by 52%, with a 34% delay. The predicted risk strategy reduced the number of biopsies by 31%, with only an 8% delay. These findings are robust to biopsy sensitivity and confirmatory biopsy.
CONCLUSIONS: Prostate-specific antigen-based active monitoring could substantially reduce biopsy frequency; however, a precision strategy based on an individual upgrading risk is most likely to minimize delays in detection of disease progression. This strategy may be preferred if active surveillance is deintensified under relabeling, provided patient adherence remains unaffected.}, }
@article {pmid39565830, year = {2025}, author = {Hannon, PA and Harris, JR and Doody, DR}, title = {Opportunities to Improve Health Equity for Employees in Low-Wage Industries in the United States.}, journal = {Annual review of public health}, volume = {46}, number = {1}, pages = {295-313}, doi = {10.1146/annurev-publhealth-071723-120104}, pmid = {39565830}, issn = {1545-2093}, mesh = {Humans ; United States/epidemiology ; *Health Equity ; COVID-19/epidemiology ; *Occupational Health ; *Health Promotion/organization & administration ; Workplace ; Social Determinants of Health ; SARS-CoV-2 ; }, abstract = {This review describes employees working in low-wage industries in the United States, their health risks, and their access to health promotion and other health-related resources through their employers. We use publicly available datasets to illustrate how low-wage jobs affect employees' social determinants of health, health risk behaviors, and chronic conditions. We also discuss how the COVID-19 pandemic has shifted these employees' and employers' health-related priorities and work settings. We describe employees' access to health supports through federal programs and their employers and the potential ways in which low-wage employers could support employee health and well-being. We close with a brief research and practice agenda to improve health equity for employees in low-wage industries. The goal of this review is to help practitioners and researchers in workplace health promotion, occupational health, and public health reach employees and employers in low-wage industries with interventions that address employees' health risks and employees' and employers' health priorities.}, }
@article {pmid39565459, year = {2025}, author = {Ziu, M and Halasz, LM and Kumthekar, PU and McGranahan, TM and Lo, SS and Olson, JJ}, title = {Congress of Neurological Surgeons systematic review and evidence-based guidelines for the role of chemotherapy in newly diagnosed WHO Grade II diffuse glioma in adults: update.}, journal = {Journal of neuro-oncology}, volume = {171}, number = {2}, pages = {279-298}, pmid = {39565459}, issn = {1573-7373}, mesh = {Humans ; *Glioma/drug therapy/pathology/therapy ; *Brain Neoplasms/drug therapy/pathology/therapy ; Neoplasm Grading ; Evidence-Based Medicine ; World Health Organization ; Adult ; Practice Guidelines as Topic/standards ; Antineoplastic Agents/therapeutic use ; Neurosurgery/standards ; }, abstract = {UNLABELLED: Questions and recommendations from the prior version of these guidelines without changeTarget populationAdult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).QuestionIs there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?RecommendationLevel III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.QuestionWho are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?RecommendationLevel III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patients with residual tumor >1 cm on post-operative MRI, presenting diameter of 4 cm or older than 40 years of age should be considered for adjuvant therapy as well.QuestionAre there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?RecommendationLevel III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.QuestionHow soon should the chemotherapy be started once the diagnosis of LGG is confirmed?RecommendationThere is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.QuestionWhat chemotherapeutic agents should be used for treatment of newly diagnosed LGG?RecommendationThere is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.QuestionWhat is the optimal duration and dosing of chemotherapy as initial treatment for LGG?RecommendationInsufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.QuestionShould chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?RecommendationInsufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.QuestionShould chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?RecommendationLevel II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.Updated Question and Recommendations from the Prior Version of These GuidelinesQuestionIn adult patients with pathologically confirmed WHO Grade II diffuse glioma does chemotherapy alone, combined with radiation therapy or after radiation therapy compared to radiotherapy alone result in better overall survival, progression free survival, local control, fewer complications, neurocognitive preservation, and quality of life?RecommendationLevel I: It is recommended that chemotherapy (PCV) be added to radiation therapy (RT) in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma (Patients younger than 40 unable to get gross total resection and older than 40 regardless of the degree of resection) to improve their overall survival.
LEVEL II: It is recommended that chemotherapy be added to radiation therapy in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve overall survival without a decline in neurocognitive function.
LEVEL III: It is suggested that chemotherapy (temozolomide) be added to RT in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve progression free survival and overall survival.
LEVEL III: It is suggested that chemotherapy alone should be considered in patients with newly diagnosed WHO Grade II diffuse glioma in cases with 1p/19q co-deletion.New questions and recommendationsTarget populationThese recommendations apply to adult patients diagnosed with WHO Grade II diffuse glioma.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of chemotherapy prior to surgical resection improve extent of resection, provide longer progression free survival and overall survival when compared to chemotherapy alone?RecommendationLevel III: Neo-adjuvant temozolomide may be used in patients with WHO Grade II diffuse gliomas deemed unsafe for resection due to infiltration of eloquent areas or with large contralateral extension as an initial step to improve the extent of resection.There is insufficient evidence to support a recommendation regarding the ability of chemotherapy provided prior to surgical resection to improve progression free survival (PFS) and overall survival (OS).QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does the administration of temozolomide increase the rate of malignant transformation when compared to no chemotherapy or other chemotherapy regimens?RecommendationThere is insufficient evidence to support a recommendation against the use of temozolomide for WHO Grade II diffuse gliomas due to concern over increasing the rate of malignant transformation.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of multi-agent chemotherapy improve progression free survival and overall survival when compared to administration of single-agent chemotherapy?RecommendationThere is insufficient evidence to support a recommendation for or against the use of multi-agent chemotherapy to improve progression free survival and overall survival when compared to administration of single-agent chemotherapy in patients with newly diagnosed WHO Grade II diffuse glioma.}, }
@article {pmid39563927, year = {2024}, author = {Kassamali-Escobar, Z and Hartlage, W and Chan, JD and Castillo, A and Martinez-Paz, N and Bajenov, M and Jain, R and Lynch, JB and Bryson-Cahn, C}, title = {Antimicrobial stewardship and quality improvement strategies in critical access hospitals: a process evaluation of an intensive quality improvement cohort.}, journal = {Antimicrobial stewardship & healthcare epidemiology : ASHE}, volume = {4}, number = {1}, pages = {e201}, pmid = {39563927}, issn = {2732-494X}, abstract = {We describe our experience implementing an intensive quality improvement cohort pilot focused on managing asymptomatic bacteriuria in 19 critical access hospitals. Participation in the pilot was high, and almost all sites identified an improvement goal and collected clinical data. Barriers to implementation included staffing shortages, turnover, and lack of bandwidth.}, }
@article {pmid39562313, year = {2025}, author = {Bollinger, BJ and Chrisman, SP and Sahlberg, J and Mendoza, JA and Palermo, TM and Zhou, C and Brooks, MA and Rivara, FP and Pedersen, P and Prentice, E and Hansen, C}, title = {Understanding factors influencing exercise program adherence for youth with persistent post-concussive symptoms (PPCS).}, journal = {Brain injury}, volume = {39}, number = {4}, pages = {286-299}, pmid = {39562313}, issn = {1362-301X}, support = {R01 HD094722/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Adolescent ; *Post-Concussion Syndrome/psychology/rehabilitation ; Motivation ; Child ; Social Support ; *Exercise Therapy/psychology/methods ; *Exercise/psychology ; Qualitative Research ; *Patient Compliance/psychology ; Personal Autonomy ; Goals ; }, abstract = {BACKGROUND: A significant portion of youth sustain a concussion every year, with around 30% experiencing persistent post-concussion symptoms (PPCS). Research has shown exercising just below the exertion level that provokes symptoms can lead to more rapid recovery. However, youth often struggle to adhere to exercise recommendations following concussion.
METHODS: We conducted structured qualitative interviews (n = 32) with concussed youth and their parents to examine factors influencing motivation to engage in exercise post-concussion. Questions were framed through the lens of Self-Determination Theory (SDT) and Thematic Analysis was used to code and analyze transcripts.
RESULTS: Four primary factors appeared to motivate youth to exercise after receiving a concussion: 1) social support, 2) accountability, 3) goal setting, and 4) structure. Utilizing the lens of SDT, one could theorize that including social support and accountability helped fulfill the need of relatedness, setting goals helped fulfill the need of autonomy, and providing program structure helped fulfill the need for competence.
CONCLUSIONS: Our results suggest that Self-Determination Theory may be a useful frame for examining exercise adherence post-concussion. Incorporating social support, accountability, goal setting and structure could increase the effectiveness of exercise prescription post-concussion and should be the focus of further study.}, }
@article {pmid39561920, year = {2025}, author = {Yi, JC and Ballard, S and Walsh, C and Friedman, DN and Ganz, PA and Jacobs, LA and Partridge, AH and Mitchell, SA and Leisenring, WM and Syrjala, KL and Baker, KS}, title = {INteractive survivorship program to improve health care REsources [INSPIRE]: A study protocol testing a digital intervention with stepped care telehealth to improve outcomes for adolescent and young adult survivors.}, journal = {Contemporary clinical trials}, volume = {148}, number = {}, pages = {107745}, pmid = {39561920}, issn = {1559-2030}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA246659/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; *Cancer Survivors/psychology ; Health Literacy ; *Mobile Applications ; Neoplasms/therapy ; Self-Management/methods ; Social Media ; Survivorship ; *Telemedicine/organization & administration ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Adolescents and young adults with cancer (AYAs, ages 15-39 at the time of diagnosis) experience significant adverse health and psychosocial outcomes. AYAs live with emotional distress and health care demands that exceed those of their healthy peers but can have difficulty accessing care. Digitally delivered interventions are an attractive option for AYA survivors, a population that routinely utilizes online resources when seeking health information and support.
AIM: By improving access to survivorship resources and support and strengthening health literacy and self-management skills, the INteractive Survivorship Program to Improve Health care REsources [INSPIRE] is designed to improve adherence to AYA health care guidelines and reduce cancer-related distress. We describe the protocol for a two-arm randomized controlled trial (RCT) testing the AYA-adapted INSPIRE program.
METHODS/DESIGN: The intervention includes an interactive mobile app, study website, and social media platforms, adding telehealth for those with continued distress, lower survivorship health care literacy, or poor engagement with the digital program at 6 weeks. Participants are randomized to INSPIRE or an active control. In the active control arm, survivors receive access to a study website with links to existing AYA survivor resources followed by delayed access to the INSPIRE program. Participants are not blinded; study staff not providing telehealth are blinded. The primary outcomes are cancer-related distress and health care adherence specific to second cancer and cardiometabolic screenings.
DISCUSSION: If effective, the program is positioned for accelerated implementation to improve care for AYA survivors by using a scalable informatics-based administration and largely digital intervention program.}, }
@article {pmid39561770, year = {2024}, author = {Kullo, IJ and Conomos, MP and Nelson, SC and Adebamowo, SN and Choudhury, A and Conti, D and Fullerton, SM and Gogarten, SM and Heavner, B and Hornsby, WE and Kenny, EE and Khan, A and Khera, AV and Li, Y and Martin, I and Mercader, JM and Ng, M and Raffield, LM and Reiner, A and Rowley, R and Schaid, D and Stilp, A and Wiley, K and Wilson, R and Witte, JS and Natarajan, P and , }, title = {The PRIMED Consortium: Reducing disparities in polygenic risk assessment.}, journal = {American journal of human genetics}, volume = {111}, number = {12}, pages = {2594-2606}, pmid = {39561770}, issn = {1537-6605}, support = {U01 HG011717/HG/NHGRI NIH HHS/United States ; U01 CA261339/CA/NCI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; U01 HG011710/HG/NHGRI NIH HHS/United States ; U01 HG011715/HG/NHGRI NIH HHS/United States ; U01 HG011697/HG/NHGRI NIH HHS/United States ; U01 HG011719/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Genotype ; *Multifactorial Inheritance/genetics ; Neoplasms/genetics ; Phenotype ; Risk Assessment ; Risk Factors ; }, abstract = {By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment.}, }
@article {pmid39561372, year = {2025}, author = {Luque Paz, D and Gagelmann, N and Benajiba, L and Riou, J and Salit, R and Orvain, C and Schroeder, T and Bories, C and Gurnari, C and Badbaran, A and Boyer, F and Pagliuca, S and Rautenberg, C and Tavitian, S and Pangiota, V and Ianotto, JC and Thol, F and Cayssials, E and Heuser, M and Rubio, MT and Cassinat, B and Daltro de Oliveira, R and Sauter, C and Maciejewski, JP and Reinhardt, HC and Scott, BL and Ugo, V and Kröger, N and Kiladjian, JJ and Robin, M}, title = {Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.}, journal = {Blood advances}, volume = {9}, number = {4}, pages = {797-807}, pmid = {39561372}, issn = {2473-9537}, mesh = {Humans ; *Primary Myelofibrosis/therapy/mortality/genetics/diagnosis ; Male ; Female ; *Hematopoietic Stem Cell Transplantation ; Middle Aged ; Aged ; Adult ; Prognosis ; Mutation ; Clinical Decision-Making ; }, abstract = {The aim of our study was to analyze the potential survival benefit associated with hematopoietic stem cell transplantation (HSCT) according to clinicobiological scores, which incorporate mutation-enhanced international prognostic score system (MIPSS) to facilitate decision-making in this context. One transplant (n = 241) and 1 nontransplant cohort (n = 239) were used to test the hypothesis that patients with primary myelofibrosis with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. Overall, 105 patients who did not receive transplant could be matched to the 239 patients who did receive transplants. HSCT was associated with a higher 6-year overall survival rate in intermediate-2 (60.1% vs 41.5%) and high-risk DIPSS patients (44.4% vs 6.55%), high-risk MIPSS70 (46.5% vs 23.9%), high-risk (73.2% vs 39.7%) or very high-risk MIPSS70+V2 (51.8% vs 24%). Patients with intermediate MIPSS70 scores have an advantage of survival with HSCT only when their myelofibrosis transplant scoring system (MTSS) were low or intermediate. Patients who received transplant had an increased mortality risk the first year, but a significant benefit with HSCT after the 1-year landmark was observed in higher risk patients. This study confirms that, similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies.}, }
@article {pmid39561007, year = {2024}, author = {Schoenfeld, DA and Djureinovic, D and Su, DG and Zhang, L and Lu, BY and Kamga, L and Mann, JE and Huck, JD and Hurwitz, M and Braun, DA and Jilaveanu, L and Ring, AM and Kluger, HM}, title = {Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma.}, journal = {JCI insight}, volume = {10}, number = {1}, pages = {}, pmid = {39561007}, issn = {2379-3708}, support = {R01 CA269349/CA/NCI NIH HHS/United States ; T32 CA233414/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; K12 CA215110/CA/NCI NIH HHS/United States ; R37 CA279822/CA/NCI NIH HHS/United States ; R01 CA269286/CA/NCI NIH HHS/United States ; P50 CA121974/CA/NCI NIH HHS/United States ; P30 CA016359/CA/NCI NIH HHS/United States ; }, mesh = {*Carcinoma, Renal Cell/drug therapy/genetics/pathology/immunology/metabolism ; *Tumor Microenvironment/immunology ; Humans ; *Kidney Neoplasms/drug therapy/genetics/immunology/pathology ; Animals ; *Interleukin-18/metabolism/genetics ; Mice ; *CTLA-4 Antigen/metabolism/genetics/antagonists & inhibitors ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Female ; Cell Line, Tumor ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; CD8-Positive T-Lymphocytes/immunology/metabolism/drug effects ; }, abstract = {The cytokine IL-18 has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anticancer efficacy. A decoy-resistant form of IL-18 (DR-18) that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pantumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from patients with RCC treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and in circulation within plasma in nonresponding patients, and it decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models, DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intratumoral enrichment and clonal expansion of effector CD8+ T cells, decreased Treg levels, and enrichment of proinflammatory antitumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.}, }
@article {pmid39560823, year = {2025}, author = {Vaidya, R and Till, C and Henry, NL and Fisch, MJ and Hershman, DL and Unger, JM}, title = {Neighborhood socioeconomic deprivation and patient-reported outcomes in symptom management trials for women with breast cancer.}, journal = {Breast cancer research and treatment}, volume = {209}, number = {3}, pages = {603-611}, pmid = {39560823}, issn = {1573-7217}, support = {CA189974//National Cancer Institute at the National Institutes of Health/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/therapy ; *Patient Reported Outcome Measures ; Middle Aged ; Socioeconomic Factors ; Aged ; Adult ; Residence Characteristics ; *Neighborhood Characteristics ; Healthcare Disparities ; Randomized Controlled Trials as Topic ; }, abstract = {PURPOSE: Neighborhood socioeconomic deprivation (NSD) is associated with worse outcomes among patients with cancer, but little is known about NSD-related disparities in patient-reported outcomes (PRO) in clinical trials. We examined the relationship between PROs and NSD in symptom management trials among women with breast cancer.
METHODS: We pooled data from three SWOG randomized trials to examine four outcomes: physical and functional wellbeing (PWB, FWB), average pain, and pain interference. NSD was measured using participants' zip code linked to the area deprivation index (ADI) score, categorized into tertiles. Multivariable linear regression adjusted for sociodemographic and clinical characteristics was used to analyze baseline PROs. Linear mixed models were used to examine if trajectory of PROs from baseline through 24 weeks varied by ADI.
RESULTS: We examined 761 participants, of whom 51% were from least deprived neighborhoods. Participants in the most deprived neighborhoods had worse average pain at baseline (β = .38, 95% CI = .03 to .72, p = .03) while participants in somewhat deprived areas also had worse FWB (β = -1.07, 95% CI = -1.95 to -.20, p = .02) and pain interference (β = 0.42, 95% CI = .09 to .75, p = .01) compared to those from least deprived areas. Hispanic ethnicity and having Medicaid/no insurance were associated with worse outcomes. After adjusting for baseline score, ADI was not associated with any outcome over time.
CONCLUSIONS: Breast cancer patients living in areas with NSD had worse FWB, joint pain, and pain interference at baseline. Clinical trial participants should be screened for community-level needs. Implementing interventions to address those needs could help mitigate disparities.}, }
@article {pmid39560645, year = {2024}, author = {Kohrt, SE and Novak, EJ and Tapadar, S and Wu, B and Strope, J and Asante, Y and Kim, H and Chang, MS and Gurdak, D and Khalil, A and Rood, M and Raftery, E and Stavreva, D and Nguyen, HM and Brown, LG and Ramser, M and Peer, C and Meyers, WM and Aboreden, N and Chakravortee, M and Sallari, R and Nelson, PS and Kelly, KK and Graham, TGW and Darzacq, X and Figg, WD and Oyelere, AK and Corey, E and Adelaiye-Ogala, R and Gryder, BE}, title = {Small-molecule disruption of androgen receptor-dependent chromatin clusters.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {48}, pages = {e2406239121}, pmid = {39560645}, issn = {1091-6490}, support = {W81XWH-19-1-0715//U.S. Department of Defense (DOD)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; CA097186//Prostate Cancer Foundation (PCF)/ ; 5R01CA291963-02//HHS | National Institutes of Health (NIH)/ ; K22 CA255594/CA/NCI NIH HHS/United States ; P50CA97186//HHS | National Institutes of Health (NIH)/ ; 1K22CA255594//HHS | National Institutes of Health (NIH)/ ; RO1 CA266013//HHS | National Institutes of Health (NIH)/ ; R01 CA266013/CA/NCI NIH HHS/United States ; S10 OD024996/OD/NIH HHS/United States ; R01 CA291963/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; }, mesh = {*Receptors, Androgen/metabolism/genetics ; Humans ; *Chromatin/metabolism ; Male ; Cell Line, Tumor ; Animals ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/metabolism/genetics/pathology ; *Androgen Receptor Antagonists/pharmacology/metabolism ; Mice ; Gene Expression Regulation, Neoplastic/drug effects ; Promoter Regions, Genetic ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; }, abstract = {Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.}, }
@article {pmid39560376, year = {2024}, author = {Stafford, E and Dimitrov, D and Trinidad, SB and Matrajt, L}, title = {Closing the gap in race-based inequities for seasonal influenza hospitalizations: a modeling study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae564}, pmid = {39560376}, issn = {1537-6591}, abstract = {BACKGROUND: BIPOC (Black, Indigenous, and other People of Color) communities bear a disproportional burden of seasonal influenza hospitalizations in the United States.
METHODS: We developed a race-stratified (5 racial-ethnic groups) agent-based model of seasonal influenza transmission and quantify the effects of 5 idealized interventions aimed at reducing inequities in symptomatic infections and hospitalizations. The interventions assumed (i) equalized vaccination rates, (ii) equalized comorbidities, (iii) work-risk distribution proportional to the distribution of the population, (iv) reduced work contacts for all, or (v) a combination of equalizing vaccination rates and comorbidities and reducing work contacts.
RESULTS: Our analysis suggests that symptomatic infections could be greatly reduced (by up to 17% in BIPOC adults aged 18-49) by strategies reducing work contacts or equalizing vaccination rates. All tested interventions reduced the inequity in influenza hospitalizations in all racial-ethnic groups, but interventions equalizing comorbidities were the most effective, with over 40% less hospitalizations in BIPOC groups. Inequities in hospitalizations in different racial-ethnic groups responded differently to interventions, pointing to the need of tailored interventions for different populations. Notably, these interventions resulted in better outcomes across all racial-ethnic groups, not only those prioritized by the interventions.
CONCLUSIONS: In this simulation modeling study, equalizing vaccination rates and reducing number of work contacts (e.g., improving air filtration systems, tailored vaccination campaigns) reduced both inequity and the total number of symptomatic infections and hospitalizations in all age and racial-ethnic groups. Reducing inequity in influenza hospitalizations requires different interventions for different groups.}, }
@article {pmid39559248, year = {2024}, author = {Kopmar, NE and Cassaday, RD}, title = {Clinical Insights on Brexucabtagene Autoleucel for the Treatment of Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia.}, journal = {Cancer management and research}, volume = {16}, number = {}, pages = {1587-1596}, pmid = {39559248}, issn = {1179-1322}, abstract = {Autologous chimeric antigen receptor-modified T-cell therapy (CAR-T) has revolutionized treatment paradigms across multiple lymphoid malignancies, including relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The introduction of the CD19-directed CAR-T product brexucabtagene autoleucel (brexu-cel; Tecartus) in October 2021 made this treatment approach available for the first time for adults with R/R B-ALL, a historically challenging clinical entity to treat. In this review, we will discuss the pivotal clinical trial data from the ZUMA-3 study that led to the US Food and Drug Administration (FDA) approval of brexu-cel, including clinical outcomes and key toxicity data (most importantly, the incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). Additionally, we will compare and contrast these data from the ZUMA-3 study with "real-world" data from examinations of patient outcomes with brexu-cel as an FDA-approved therapy in R/R B-ALL, and discuss practical considerations with brexu-cel use in the clinic, including the role of consolidative allografting for patients post-brexu-cel. We finish by discussing future directions for CAR-T use in R/R B-ALL with the anticipated introduction of a new CD19-directed CAR-T product - obecabtagene autoleucel - in the near future.}, }
@article {pmid39556786, year = {2025}, author = {Huang, IJ and Baek, GT and Cohen, J and Khajaviyan, S and Louie, S and Samples, L and Smith, SD and Till, BG and Warren, EH and Gopal, AK and Poh, C and Lynch, RC and Ujjani, CS and Shadman, M}, title = {Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience.}, journal = {JCO oncology practice}, volume = {21}, number = {5}, pages = {671-676}, doi = {10.1200/OP.24.00416}, pmid = {39556786}, issn = {2688-1535}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/pathology ; *Sulfonamides/therapeutic use/adverse effects ; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/adverse effects ; Male ; Female ; Aged ; Retrospective Studies ; *Tumor Lysis Syndrome/etiology ; Middle Aged ; Aged, 80 and over ; *Antineoplastic Agents/therapeutic use/adverse effects ; Clinical Relevance ; }, abstract = {PURPOSE: Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS).
PATIENTS AND METHODS: A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions.
RESULTS: Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required.
CONCLUSION: These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.}, }
@article {pmid39555026, year = {2024}, author = {Huang, Y and Feng, Z}, title = {ASSESSING SCREENING EFFICACY IN THE PRESENCE OF CANCER OVERDIAGNOSIS.}, journal = {The annals of applied statistics}, volume = {18}, number = {2}, pages = {1543-1564}, pmid = {39555026}, issn = {1932-6157}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {Cancer screening facilitates the early detection of cancer, at a stage when treatment is often most effective. However, it also brings the risk of over-diagnosis, where a diagnosis made through screening would not have led to symptoms or death during the patient's lifetime. In this paper, we tackle a significant unresolved issue in the evaluation of screening efficacy: selecting primary endpoints and inferential procedures that efficiently consider potential overdiagnosis in screening trials. This is motivated by the necessity to design and analyze a phase IV Early Detection Initiative (EDI) trial for evaluating a pancreatic cancer screening strategy. We introduce two novel approaches for assessing screening efficacy, grounded on cancer stage-shift. These methods address potential overdiagnosis by: i) borrowing information about clinical diagnosis from the control arm that hasn't undergone screening (the BR approach), and ii) performing sensitivity analysis, contingent upon a conservative bound of the overdiagnosis magnitude (the SEN-T approach). Analytical methods and extensive simulation studies underscore the superiority of our proposed methods, demonstrating enhanced efficiency in estimating and testing screening efficacy compared to existing methods. The latter either overlook overdiagnosis or adhere to a valid, yet conservative, cumulative incidence endpoint. We illustrate the practical application of these approaches using ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The results affirm that our methods bolster an efficient and robust study design for cancer screening trials.}, }
@article {pmid39554199, year = {2024}, author = {Yu, Z and Vromman, A and Nguyen, NQH and Schuermans, A and Rentz, T and Vellarikkal, SK and Uddin, MM and Niroula, A and Griffin, G and Honigberg, MC and Lin, AE and Gibson, CJ and Katz, DH and Tahir, U and Fang, S and Haidermota, S and Ganesh, S and Antoine, T and Weinstock, J and Austin, TR and Ramachandran, VS and Peloso, GM and Hornsby, W and Ganz, P and Manson, JE and Haring, B and Kooperberg, CL and Reiner, AP and Bis, JC and Psaty, BM and Min, YI and Correa, A and Lange, LA and Post, WS and Rotter, JI and Rich, SS and Wilson, JG and Ebert, BL and Yu, B and Ballantyne, CM and Coresh, J and Sankaran, VG and Bick, AG and Jaiswal, S and Gerszten, RE and , and Libby, P and Gupta, RM and Natarajan, P}, title = {Human Plasma Proteomic Profile of Clonal Hematopoiesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39554199}, issn = {2692-8205}, support = {RC2 HL102419/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL134892/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; U01 DK108809/DK/NIDDK NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 MH104964/MH/NIMH NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; R01 HL153499/HL/NHLBI NIH HHS/United States ; R01 HL151283/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL163099/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 DK125782/DK/NIDDK NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; R01 HL127564/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; DP2 HL157540/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; R01 MH123451/MH/NIMH NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL135242/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; R01 HL134320/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; T32 HL007604/HL/NHLBI NIH HHS/United States ; }, abstract = {Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.}, }
@article {pmid39553428, year = {2024}, author = {Nealy, ES and Reed, SJ and Adelmund, SM and Badeau, BA and Shadish, JA and Girard, EJ and Brasel, K and Pakiam, FJ and Mhyre, AJ and Price, JP and Sarkar, S and Kalia, V and DeForest, CA and Olson, JM}, title = {Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics.}, journal = {Bioengineering & translational medicine}, volume = {9}, number = {5}, pages = {e10668}, pmid = {39553428}, issn = {2380-6761}, support = {T32 GM095421/GM/NIGMS NIH HHS/United States ; R01 AI132819/AI/NIAID NIH HHS/United States ; R01 CA114567/CA/NCI NIH HHS/United States ; F32 CA265056/CA/NCI NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable "azidoester" adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8[+] T-cells and the attenuation of tumor growth in a "cold" syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.}, }
@article {pmid39551677, year = {2024}, author = {Simunic, M and McGraw, K and Pavletic, SZ and Rashidi, A}, title = {Intestinal microbiome and myelodysplastic syndromes: Current state of knowledge and perspectives for future.}, journal = {Seminars in hematology}, volume = {61}, number = {6}, pages = {442-448}, pmid = {39551677}, issn = {1532-8686}, support = {ZIA BC011383/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Myelodysplastic Syndromes/immunology/microbiology ; *Gastrointestinal Microbiome/immunology/physiology ; }, abstract = {The intestinal microbiome has been mechanistically linked with health and many disease processes. Cancer is no exception. Both in solid tumors and hematologic malignancies, there is increasing evidence supporting the involvement of the intestinal microbiome in tumor development, disease progression, response to treatment, and treatment toxicity. Consistent with microbiome mediation of the immune system and the potent effect of the immune system on cancer, the most compelling evidence has been obtained in the setting of cancer immunotherapy. Here, we review the current state of knowledge about microbiome effects in myelodysplastic syndromes, identify gaps and challenges in related research, and provide insights for future work.}, }
@article {pmid39550102, year = {2025}, author = {Waghmare, A and Hijano, DR}, title = {SARS-CoV-2 Infection and COVID-19 in Children.}, journal = {Rheumatic diseases clinics of North America}, volume = {51}, number = {1}, pages = {139-156}, doi = {10.1016/j.rdc.2024.09.003}, pmid = {39550102}, issn = {1558-3163}, mesh = {Child ; Humans ; *COVID-19/complications/immunology/physiopathology/therapy ; SARS-CoV-2/immunology/pathogenicity ; *Systemic Inflammatory Response Syndrome/etiology/immunology/physiopathology/therapy ; }, abstract = {Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is common in children, and clinical manifestations can vary depending on age, underlying disease, and vaccination status. Most children will have asymptomatic or mild infection, but certain baseline characteristics can increase the risk of moderate to severe disease. The following article will provide an overview of the clinical manifestations of coronavirus disease 2019 in children, including the post-infectious phenomenon called multisystem inflammatory syndrome in children. Currently available treatment and prophylaxis strategies will be outlined, with the caveat that new therapeutics and clinical efficacy data are constantly on the horizon.}, }
@article {pmid39549763, year = {2025}, author = {Tseng, YD and Stevenson, P and Nguyen, B and Li, DC and Lee, DY and Paydar, I and Nakashima, J and Balogh, A and Ravella, R and Barbour, AB and Post, C and Ababneh, H and Pinnix, CC and Ballas, LK and Binkley, MS and Dedeckova, K and Hoppe, RT and Patel, C and Nabavizadeh, N and Kelsey, CR and Kumar, KA and Landsburg, D and Figura, NB and Lo, AC and Plastaras, JP}, title = {Impact of Myc-Altered Pathology on Radiation Therapy Efficacy Among Patients With Relapsed/Refractory Large-B Cell Lymphoma: A Collaborative Study by ILROG.}, journal = {International journal of radiation oncology, biology, physics}, volume = {121}, number = {5}, pages = {1237-1247}, doi = {10.1016/j.ijrobp.2024.11.072}, pmid = {39549763}, issn = {1879-355X}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Lymphoma, Large B-Cell, Diffuse/radiotherapy/pathology/genetics ; Neoplasm Recurrence, Local/genetics ; Adult ; Aged, 80 and over ; *Proto-Oncogene Proteins c-myc/genetics ; Treatment Outcome ; Proto-Oncogene Proteins c-bcl-2/genetics ; Young Adult ; }, abstract = {PURPOSE: The presence of MYC and BCL2 translocations (ie, double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy.
METHODS AND MATERIALS: Patients with LBCL who received their first course of RT for relapsed/refractory disease between 2008 and 2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per the World Health Organization (fifth edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up.
RESULTS: Three hundred and eighty-three patients (102 DHL, 281 non-DHL, and 44% curative) were treated at 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% of patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post-stem cell transplant. Median biological equivalent dose (alpha/beta: 10) was 28 Gy (range: 3.2-60.0) for palliative and 46.9 Gy (range: 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, the response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI: 1.05-3.67, P = .03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative).
CONCLUSIONS: Relapsed/refractory LBCL remains radioresponsive with a 60%-80% response rate to RT. Although DHL pathology does not appear to influence RT response, its presence is associated with higher rates of LR, suggesting that it may be more radioresistant.}, }
@article {pmid39546840, year = {2024}, author = {Bellows, AL and Palmer, AC and Curriero, F and Thorne-Lyman, AL and Shamim, AA and Shaikh, S and Haque, R and Ali, H and Sugimoto, JD and Christian, P and West, KP and Labrique, AB}, title = {Changes in urbanicity and household availability of and proximity to food vendors from 2004 to 2020 in a rural district of northwestern Bangladesh.}, journal = {Health & place}, volume = {90}, number = {}, pages = {103374}, pmid = {39546840}, issn = {1873-2054}, mesh = {Bangladesh ; Humans ; *Rural Population/statistics & numerical data ; *Commerce/statistics & numerical data ; *Food Supply/statistics & numerical data ; *Family Characteristics ; Female ; Male ; Adult ; Residence Characteristics/statistics & numerical data ; Socioeconomic Factors ; Urban Population/statistics & numerical data ; }, abstract = {BACKGROUND: The nutrition transition underway in South Asia is likely mediated by changes to the food environment. Yet, few studies have been conducted in rural areas of South Asia to describe how the food environment has changed.
OBJECTIVE: This analysis assessed changes in household availability of and proximity to markets, grocery shops, and tea shops over a 16-year time period in Gaibandha, Bangladesh.
METHODS: We analyzed household demographic and geospatial data collected at 3 time points from 2004 to 2020 in a contiguous rural area (435 km[2]). We defined availability as number of food vendors within 400- and 1600-m radius of households and proximity as distance to nearest vendor. We used linear and Poisson models to estimate associations between household socioeconomic status (SES) and food vendor availability and proximity. We used multi-level models to conduct similar analyses for community-level urbanicity.
RESULTS: From 2004 to 2020, the numbers of markets, grocery shops and tea shops increased by 21%, 66% and 270%, respectively. Food vendor proximity did not change by household SES, but less urban households witnessed larger increases in proximity to markets (p for interaction<0.001) and tea shops (p for interaction<0.001) over time. Grocery shop and tea shop availability was initially higher and increased more over time for households in higher urbanicity areas (p for interaction<0.001).
CONCLUSION: Over a 16-year period, this rural area of Bangladesh became more urbanized, increasing the availability of and proximity to markets, grocery shops, and tea shops. Further research is needed to see how these changes impact rural residents' intake and nutritional status.}, }
@article {pmid39543541, year = {2024}, author = {Pan, C and Ng, K and Voutsinas, J and Barber, B and Rizvi, ZH and Marchiano, E and Ferrandino, RM and Futran, N and Laramore, GE and Liao, JJ and Parvathaneni, U and Panjwani, N and Martins, RG and Rodriguez, CP and Wu, QV}, title = {Development of a prognostic signature for overall survival using peripheral blood biomarkers in head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1406}, pmid = {39543541}, issn = {1471-2407}, support = {T32 DC000018/DC/NIDCD NIH HHS/United States ; T32 DC000018/NH/NIH HHS/United States ; }, mesh = {Humans ; Male ; *Immune Checkpoint Inhibitors/therapeutic use ; *Squamous Cell Carcinoma of Head and Neck/blood/drug therapy/mortality ; Female ; Middle Aged ; Prognosis ; Aged ; *Biomarkers, Tumor/blood ; *Head and Neck Neoplasms/blood/drug therapy/mortality ; *Neutrophils ; Adult ; Aged, 80 and over ; L-Lactate Dehydrogenase/blood ; }, abstract = {BACKGROUND: We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs).
METHODS: Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset.
RESULTS: Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) - 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17-3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets.
CONCLUSIONS: We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS.}, }
@article {pmid39542703, year = {2025}, author = {Demirci, RA and Ghodsi, A and Gulati, R and Behnia, S and Nelson, PS and Cheng, HH and Yezefski, TA and Haffner, MC and Hawley, JE and Montgomery, RB and Yu, EY and Schweizer, MT and Chen, DL and Iravani, A}, title = {PET-Based TheraP Eligibility and Outcomes of VISION-Eligible Patients with Metastatic Castration-Resistant Prostate Cancer Who Received [177]Lu-PSMA-617: Importance of [18]F-FDG-Avid Discordant Findings.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {47-53}, pmid = {39542703}, issn = {1535-5667}, support = {R37 CA286450/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/radiotherapy/diagnostic imaging ; Aged ; *Lutetium ; *Dipeptides/therapeutic use ; *Fluorodeoxyglucose F18 ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; Treatment Outcome ; Neoplasm Metastasis ; Positron-Emission Tomography ; Middle Aged ; Prostate-Specific Antigen/blood ; Patient Selection ; Aged, 80 and over ; }, abstract = {The VISION and TheraP trials introduced different PET-based criteria for patient selection for treatment with [177]Lu-PSMA-617 (LuPSMA). TheraP used a higher prostate-specific membrane antigen (PSMA) uptake threshold than VISION and required [18]F-FDG PET to exclude patients with discordant findings. Although the screen-failed patients had shorter overall survival (OS) than those treated with LuPSMA, it remains unclear whether their outcomes might have been modified if they had been exposed to LuPSMA. In this study, we evaluated associations between the TheraP eligibility criteria and subgroups and the treatment outcomes of patients who were deemed suitable and treated on the basis of VISION criteria. Methods: Consecutive patients who were treated with LuPSMA and who underwent pretreatment PSMA and [18]F-FDG PET were classified as TheraP-eligible (TheraP-E) and TheraP-ineligible (TheraP-I), the latter of which were subclassified as low PSMA or discordant. Odds ratios for an at least 50% decline in prostate-specific antigen (PSA50) were computed using logistic regression, and hazard ratios (HRs) for PSA progression-free survival (PSA-PFS) and OS were computed using Cox regressions. Multivariable analyses were adjusted for baseline imaging and clinical parameters. Results: Of 75 patients, 31 (41%) were deemed TheraP-I; of those, 24 were subclassified as having discordant disease. TheraP-I patients had a lower PSA50 rate than that of TheraP-E patients (28% vs. 67%; odds ratio, 0.19; 95% CI, 0.06-0.52; P = 0.002) and a higher risk of PSA progression (HR, 2.0; 95% CI, 1.2-3.3; P = 0.007). OS in the TheraP-I group was numerically shorter than in the TheraP-E group, but the comparison was only marginally significant (10.4 mo vs. not reached; HR, 1.9; 95% CI, 1.0-3.7; P = 0.054). TheraP-I patients with low PSMA had no significantly different risk of death (P = 0.9) from that of TheraP-E patients, but those with discordant findings had higher risk of death (HR, 2.3; 95% CI, 1.1-4.6; P = 0.02). Discordant disease remained prognostic for OS after adjusting for baseline imaging and clinical parameters (HR, 3.0; 95% CI, 1.3-6.8; P = 0.01). Conclusion: In VISION-eligible patients who were treated with LuPSMA, TheraP-I patients with discordant findings had lower PSA50, PSA-PFS, and OS. Our study suggests that the shorter OS of TheraP-I patients is mainly driven by the presence of discordant disease.}, }
@article {pmid39542654, year = {2024}, author = {Shatila, M and Zhang, HC and Shirwaikar Thomas, A and Machado, AP and Naz, S and Mittal, N and Catinis, C and Varatharajalu, K and Colli Cruz, C and Lu, E and Wu, D and Brahmer, JR and Carbonnel, F and Hanauer, SB and Lashner, B and Schneider, B and Thompson, JA and Obeid, M and Farris, DP and Wang, Y}, title = {Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, pmid = {39542654}, issn = {2051-1426}, mesh = {Humans ; *Immune Checkpoint Inhibitors/adverse effects ; *Gastrointestinal Diseases/chemically induced ; Immunotherapy/adverse effects/methods ; Pancreatic Diseases/chemically induced ; Neoplasms/drug therapy ; }, abstract = {Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.}, }
@article {pmid39542408, year = {2025}, author = {Wechkin, HA and Menzel, PT and Loggers, ET and Macauley, RC and Pope, TM and Reagan, PL and Quill, TE}, title = {"Mr. Smith Has No Mealtimes": Minimal Comfort Feeding for Patients with Advanced Dementia.}, journal = {Journal of pain and symptom management}, volume = {69}, number = {2}, pages = {216-222}, doi = {10.1016/j.jpainsymman.2024.11.001}, pmid = {39542408}, issn = {1873-6513}, mesh = {Humans ; *Dementia/therapy ; Palliative Care/methods ; Patient Comfort ; Caregivers ; Advance Directives ; Hunger ; }, abstract = {While Comfort Feeding Only is appropriate for patients with advanced dementia, its emphasis on assiduous hand-feeding that may prolong life for years fails to accommodate the preferences of those who do not want to continue living with this illness. Some have proposed advance directives to completely halt the provision of oral nutrition and hydration once a person has reached an advanced stage of dementia. However, these directives may fail to address patients' discomfort, caregivers' obligations, or current care and regulatory standards when patients reside in facilities. In response to these dilemmas, we introduce Minimal Comfort Feeding (MCF). Rather than offering food and liquids proactively as with Comfort Feeding Only, caregivers provide nutrition and hydration only in response to signs of hunger and thirst. While further study is required to define and negotiate challenges in operationalizing this approach, MCF provides a framework that resolves competing ethical and clinical considerations in caring for those with advanced dementia.}, }
@article {pmid39542140, year = {2024}, author = {Welch, SR and Bilello, JP and Carter, K and Delang, L and Dirr, L and Durantel, D and Feng, JY and Gowen, BB and Herrero, LJ and Janeba, Z and Kleymann, G and Lee, AA and Meier, C and Moffat, J and Schang, LM and Schiffer, JT and Seley-Radtke, KL and Sheahan, TP and Spengler, JR}, title = {Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20-24, 2024, organized by the International Society for Antiviral Research.}, journal = {Antiviral research}, volume = {232}, number = {}, pages = {106037}, pmid = {39542140}, issn = {1872-9096}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, mesh = {Animals ; Humans ; *Antiviral Agents/therapeutic use/pharmacology ; Australia ; COVID-19 ; COVID-19 Drug Treatment ; Drug Development ; Drug Discovery ; Vaccine Development ; }, abstract = {The 37th International Conference on Antiviral Research (ICAR) was held in Gold Coast, Australia, May 20-24, 2024. ICAR 2024 featured over 75 presentations along with two poster sessions and special events, including those specifically tailored for trainees and early-career scientists. The meeting served as a platform for the exchange of cutting-edge research, with presentations and discussions covering novel antiviral compounds, vaccine development, clinical trials, and therapeutic advancements. A comprehensive array of topics in antiviral science was covered, from the latest breakthroughs in antiviral drug development to innovative strategies for combating emerging viral threats. The keynote presentations provided fascinating insight into two diverse areas fundamental to medical countermeasure development and use, including virus emergence at the human-animal interface and practical considerations for bringing antivirals to the clinic. Additional sessions addressed a variety of timely post-pandemic topics, such as the hunt for broad spectrum antivirals, combination therapy, pandemic preparedness, application of in silico tools and AI in drug discovery, the virosphere, and more. Here, we summarize all the presentations and special sessions of ICAR 2024 and introduce the 38th ICAR, which will be held in Las Vegas, USA, March 17-21, 2025.}, }
@article {pmid39541580, year = {2024}, author = {Nagarajan, R and Kondo, M and Salas, F and Sezgin, E and Yao, Y and Klotzman, V and Godambe, SA and Khan, N and Limon, A and Stephenson, G and Taraman, S and Walton, N and Ehwerhemuepha, L and Pandit, J and Pandita, D and Weiss, M and Golden, C and Gold, A and Henderson, J and Shippy, A and Celi, LA and Hogan, WR and Oermann, EK and Sanger, T and Martel, S}, title = {Economics and Equity of Large Language Models: Health Care Perspective.}, journal = {Journal of medical Internet research}, volume = {26}, number = {}, pages = {e64226}, pmid = {39541580}, issn = {1438-8871}, mesh = {Humans ; *Delivery of Health Care ; Language ; }, abstract = {Large language models (LLMs) continue to exhibit noteworthy capabilities across a spectrum of areas, including emerging proficiencies across the health care continuum. Successful LLM implementation and adoption depend on digital readiness, modern infrastructure, a trained workforce, privacy, and an ethical regulatory landscape. These factors can vary significantly across health care ecosystems, dictating the choice of a particular LLM implementation pathway. This perspective discusses 3 LLM implementation pathways-training from scratch pathway (TSP), fine-tuned pathway (FTP), and out-of-the-box pathway (OBP)-as potential onboarding points for health systems while facilitating equitable adoption. The choice of a particular pathway is governed by needs as well as affordability. Therefore, the risks, benefits, and economics of these pathways across 4 major cloud service providers (Amazon, Microsoft, Google, and Oracle) are presented. While cost comparisons, such as on-demand and spot pricing across the cloud service providers for the 3 pathways, are presented for completeness, the usefulness of managed services and cloud enterprise tools is elucidated. Managed services can complement the traditional workforce and expertise, while enterprise tools, such as federated learning, can overcome sample size challenges when implementing LLMs using health care data. Of the 3 pathways, TSP is expected to be the most resource-intensive regarding infrastructure and workforce while providing maximum customization, enhanced transparency, and performance. Because TSP trains the LLM using enterprise health care data, it is expected to harness the digital signatures of the population served by the health care system with the potential to impact outcomes. The use of pretrained models in FTP is a limitation. It may impact its performance because the training data used in the pretrained model may have hidden bias and may not necessarily be health care-related. However, FTP provides a balance between customization, cost, and performance. While OBP can be rapidly deployed, it provides minimal customization and transparency without guaranteeing long-term availability. OBP may also present challenges in interfacing seamlessly with downstream applications in health care settings with variations in pricing and use over time. Lack of customization in OBP can significantly limit its ability to impact outcomes. Finally, potential applications of LLMs in health care, including conversational artificial intelligence, chatbots, summarization, and machine translation, are highlighted. While the 3 implementation pathways discussed in this perspective have the potential to facilitate equitable adoption and democratization of LLMs, transitions between them may be necessary as the needs of health systems evolve. Understanding the economics and trade-offs of these onboarding pathways can guide their strategic adoption and demonstrate value while impacting health care outcomes favorably.}, }
@article {pmid39541411, year = {2024}, author = {Lin, L and Spreng, RL and Seaton, KE and Dennison, SM and Dahora, LC and Schuster, DJ and Sawant, S and Gilbert, PB and Fong, Y and Kisalu, N and Pollard, AJ and Tomaras, GD and Li, J}, title = {GeM-LR: Discovering predictive biomarkers for small datasets in vaccine studies.}, journal = {PLoS computational biology}, volume = {20}, number = {11}, pages = {e1012581}, pmid = {39541411}, issn = {1553-7358}, support = {P01 AI162242/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers ; *Vaccines/immunology ; Logistic Models ; *Computational Biology/methods ; Algorithms ; Vaccination/statistics & numerical data ; }, abstract = {Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal. Moreover, in early phase vaccine clinical trials, small datasets are prevalent, raising the need and challenge of building a robust and explainable prediction model that can reveal heterogeneity in small datasets. We propose a new model named Generative Mixture of Logistic Regression (GeM-LR), which combines characteristics of both a generative and a discriminative model. In addition, we propose a set of model selection strategies to enhance the robustness and interpretability of the model. GeM-LR extends a linear classifier to a non-linear classifier without losing interpretability and empowers the notion of predictive clustering for characterizing data heterogeneity in connection with the outcome variable. We demonstrate the strengths and utility of GeM-LR by applying it to data from several studies. GeM-LR achieves better prediction results than other popular methods while providing interpretations at different levels.}, }
@article {pmid39540294, year = {2025}, author = {Karra, P and Hardikar, S and Winn, M and Anderson, GL and Haaland, B and Shadyab, AH and Neuhouser, ML and Seguin-Fowler, RA and Thomson, CA and Coday, M and Wactawski-Wende, J and Stefanick, ML and Zhang, X and Cheng, TD and Karanth, S and Sun, Y and Saquib, N and Pichardo, MS and Jung, SY and Tabung, FK and Summers, SA and Holland, WL and Jalili, T and Gunter, MJ and Playdon, MC}, title = {Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women's Health Initiative.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {18}, number = {2}, pages = {63-72}, pmid = {39540294}, issn = {1940-6215}, support = {5R00CA218694-03//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; R00 CA218694/CA/NCI NIH HHS/United States ; F99 CA264400/CA/NCI NIH HHS/United States ; K00 CA264400/CA/NCI NIH HHS/United States ; P30CA040214//Huntsman Cancer Institute, University of Utah (HCI)/ ; K00 CA253745/CA/NCI NIH HHS/United States ; R01 HL170575/HL/NHLBI NIH HHS/United States ; K00CA253745//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; 001/WHO_/World Health Organization/International ; F99CA264400//Division of Cancer Prevention, National Cancer Institute (DCP, NCI)/ ; U01 CA272529/CA/NCI NIH HHS/United States ; R01 DK130296/DK/NIDDK NIH HHS/United States ; K07 CA222060/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Obesity/complications/metabolism/epidemiology ; Middle Aged ; Body Mass Index ; Phenotype ; Aged ; Risk Factors ; *Neoplasms/epidemiology/etiology/metabolism ; Women's Health ; Insulin Resistance ; Follow-Up Studies ; Biomarkers ; Postmenopause ; }, abstract = {Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared with normal BMI without metabolic dysfunction. Postmenopausal women (n = 20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers [blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and high-sensitive C-reactive protein (hs-CRP)] were included. Metabolic phenotype (metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese) was classified using four definitions of metabolic dysfunction: (i) Wildman criteria, (ii) National Cholesterol Education Program Adult Treatment Panel III, (iii) HOMA-IR, and (iv) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR, 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among metabolically unhealthy normal weight (HR = 1.12, 95% CI, 0.90-1.39), metabolically healthy overweight/obese (HR = 1.15, 95% CI, 1.00-1.32), and metabolically unhealthy overweight/obese (HR = 1.35, 95% CI, 1.18-1.54) individuals compared with metabolically healthy normal weight individuals using Wildman criteria. The results were similar using Adult Treatment Panel III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the CIs of each category overlapped. Prevention Relevance: Recognizing metabolic dysfunction as a significant risk factor for ORCs underscores the importance of preventive measures targeting metabolic health improvement across all BMI categories.}, }
@article {pmid39540227, year = {2025}, author = {Zelikson, V and Gurumurthi, A and Sawalha, Y and Annunzio, K and Saha, A and Dong, N and Qualls, D and Amoozgar, B and Kahl, B and Baird, J and Challa, P and Huntington, SF and Santos, J and Bair, S and Narkhede, M and Li, S and Frosch, Z and Ho, C and Smith, SD and Winter, A and Landsburg, D and Furqan, F and Hamadani, M and Baird, K and Romancik, J and Alharthy, H and Law, J and Bojanini, L and Advani, R and Hu, B and Johnson, PC and Grover, NS and Merril, M and Crombie, JL and Shafagati, N and Sterling, C and Nastoupil, LJ and Epperla, N and Ayers, EC}, title = {Loncastuximab in high-risk and heavily pretreated relapsed/refractory diffuse large B-cell lymphoma: a realworld analysis from 21 US centers.}, journal = {Haematologica}, volume = {110}, number = {3}, pages = {706-714}, pmid = {39540227}, issn = {1592-8721}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/mortality/pathology ; Male ; Female ; Aged ; Middle Aged ; United States/epidemiology ; Retrospective Studies ; Adult ; Aged, 80 and over ; *Immunoconjugates/therapeutic use/adverse effects/administration & dosage ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Drug Resistance, Neoplasm ; Treatment Outcome ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Benzodiazepines ; }, abstract = {Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the LOTIS-2 population, including a higher proportion of patients with bulky disease (17% vs. 0%), high-grade B-cell histology (22% vs. 8%), and increased number of prior lines of therapy (median 4 vs. 3). The complete response rate was 14% and overall response rate was 32%. The median event-free survival and overall survival were 2.1 and 4.6 months, respectively. Those with bulky disease and high-grade B-cell histology had significantly worse outcomes, and those with non-germinal center cell of origin and a complete response to the most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the real-world setting, the response rates, event-free survival and overall survival were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients in the real world compared to the patients enrolled on a clinical study.}, }
@article {pmid39538264, year = {2024}, author = {Carnegie, L and McCrone, JT and du Plessis, L and Hasan, M and Ali, MZ and Begum, R and Hassan, MZ and Islam, S and Rahman, MH and Uddin, ASM and Sarker, MS and Das, T and Hossain, M and Khan, M and Razu, MH and Akram, A and Arina, S and Hoque, E and Molla, MMA and Nafisaa, T and Angra, P and Rambaut, A and Pullan, ST and Osman, KL and Hoque, MA and Biswas, P and Flora, MS and Raghwani, J and Fournié, G and Samad, MA and Hill, SC}, title = {Genomic epidemiology of early SARS-CoV-2 transmission dynamics in Bangladesh.}, journal = {Virology journal}, volume = {21}, number = {1}, pages = {291}, pmid = {39538264}, issn = {1743-422X}, support = {BB/T008709/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; BB/S011269/1//UK Research and Innovation/ ; BB/S011269/1//UK Research and Innovation/ ; 223038200//Zoonosis and Transboundary Animal Diseases Prevention and Control project/ ; 220414/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Bangladesh/epidemiology ; *COVID-19/transmission/epidemiology/virology ; Humans ; *SARS-CoV-2/genetics/classification ; *Genome, Viral ; *Phylogeography ; Phylogeny ; Whole Genome Sequencing ; Genomics ; Molecular Epidemiology ; Male ; Adult ; Female ; Middle Aged ; Young Adult ; Adolescent ; Child ; }, abstract = {BACKGROUND: Genomic epidemiology has helped reconstruct the global and regional movement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still a lack of understanding of SARS-CoV-2 spread in some of the world's least developed countries (LDCs).
METHODS: To begin to address this disparity, we studied the transmission dynamics of the virus in Bangladesh during the country's first COVID-19 wave by analysing case reports and whole-genome sequences from all eight divisions of the country.
RESULTS: We detected > 50 virus introductions to the country during the period, including during a period of national lockdown. Additionally, through discrete phylogeographic analyses, we identified that geographical distance and population -density and/or -size influenced virus spatial dispersal in Bangladesh.
CONCLUSIONS: Overall, this study expands our knowledge of SARS-CoV-2 genomic epidemiology in Bangladesh, shedding light on crucial transmission characteristics within the country, while also acknowledging resemblances and differences to patterns observed in other nations.}, }
@article {pmid39538107, year = {2024}, author = {Timperanza, C and Gustafsson-Lutz, A and Bäck, T and Green, DJ and Lindegren, S and Aneheim, E}, title = {Modified poly-L-lysine for use as a clearing agent in pretargeted radioimmunotherapy.}, journal = {EJNMMI radiopharmacy and chemistry}, volume = {9}, number = {1}, pages = {76}, pmid = {39538107}, issn = {2365-421X}, support = {2021:354//Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer/ ; 21 1842 Pj 01 H//Cancerfonden/ ; }, abstract = {BACKGROUND: Pretargeted radioimmunotherapy of cancer has the potential to increase tumor specific uptake of activity when compared with conventional radioimmunotherapy. This is especially true in radioimmunotherapy with nuclides that exhibit a relatively short half-life. When administering antibody-based pretargeting molecules systemically, the antibodies often show a relatively slow clearance from the blood. Therefore, the use of a clearing agent is advantageous to remove unbound pretargeting molecules from the circulation, facilitating a reduction in the nonspecific radiation exposure to normal tissue while maximizing the dose delivered to the tumors.
RESULTS: In the current study, two types of poly-L-lysine based clearing agents were produced for two different pretargeting systems: (strept)avidin/biotin and Tetrazine/Transcyclooctene. Poly-L-lysine was used as scaffold for production of clearing agents. The polymer is available in multiple sizes and can readily be modified with several functional groups, allowing different pretargeting strategies to be used. In vivo evaluation of the biotin-functionalized poly-L-lysine clearing agent, 110 repeating units, resulted in a decrease in blood concentration of the Iodine-125 labeled pretargeting agent of 50%, circa 23 h after injection, compared to controls. Two sizes, 68 and 143 repeating units, of the tetrazine-functionalized poly-L-lysine clearing agent were also evaluated, which at 23 h after injection decreased the blood concentration of the Iodine-125 labeled pretargeting agent to 58 and 38% respectively.
CONCLUSION: The straightforward synthesis of poly-L-lysine based clearing agents makes kit preparation possible and these agents show good potential for further evaluation, especially within the Tetrazine/Transcyclooctene pretargeting system where no liver or kidney accumulation was observed.}, }
@article {pmid39537980, year = {2025}, author = {Sheridan, L and Pocobelli, G and Anderson, M and Li, CI and Kruse, GR and Tiro, JA and Kamineni, A}, title = {Cervical cancer screening rates in females living with HIV at three healthcare settings in the United States, 2010-2019.}, journal = {Cancer causes & control : CCC}, volume = {36}, number = {3}, pages = {275-284}, pmid = {39537980}, issn = {1573-7225}, support = {UM1CA221940//National Cancer Institute of the National Institutes of Health/ ; }, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/diagnosis/epidemiology/virology ; Middle Aged ; Adult ; *Early Detection of Cancer/statistics & numerical data ; *HIV Infections/epidemiology/complications/virology ; United States/epidemiology ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; Cohort Studies ; Mass Screening/statistics & numerical data ; }, abstract = {PURPOSE: Females living with human immunodeficiency virus (FLWHIV) are at increased risk of cervical cancer and U.S. guidelines, first published in 2009 and updated since then, recommend more frequent screening in this population. We examined screening rates among FLWHIV in the U.S. during 2010-2019.
METHODS: This cohort study included 18-89-year-old FLWHIV during 2010-2019 at three U.S. healthcare settings. Sociodemographics, comorbidities, and cervical cancer screening tests were ascertained from administrative and clinical databases. We reported cervical cancer screening rates overall and by modality. Generalized estimating equations with Poisson distribution were used to estimate screening rate ratios (SRRs) and 95% confidence intervals (CIs) for the associations between screening rates and calendar year, age, race and ethnicity, and comorbidity.
RESULTS: Among 3,556 FLWHIV, a total of 7,704 cervical cancer screening tests were received over 18,605 person-years during 2010-2019 (screening rate = 41.4 per 100 person-years). Relatively lower screening rates were associated with later calendar years (SRR = 0.71 [95% CI 0.68-0.75] for 2017-2019 versus 2010-2013), older age (SRR = 0.82 [95% CI 0.74-0.89] for 50-65-year-olds versus 18-29-year-olds), non-Hispanic white race versus non-Hispanic Black race (SRR = 0.89 [95% CI 0.81-0.98]) and greater comorbidity burden (SRR = 0.89 [95% CI 0.82-0.98] for ≥ 9 versus 0-6 comorbidity score).
CONCLUSION: The decrease in cervical cancer screening rates during 2010-2019 in this large cohort of FLWHIV may be explained at least partly by guideline changes during the study period recommending longer screening intervals. Our findings of relatively lower screening rates in FLWHIV who were non-Hispanic white, older, and with greater comorbidity burden should be confirmed in other U.S.}, }
@article {pmid39536820, year = {2025}, author = {Nilius, H and Naas, S and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Nakas, C and Nagler, M}, title = {The dynamic range of immunoassays for heparin-induced thrombocytopenia.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {23}, number = {2}, pages = {684-691}, doi = {10.1016/j.jtha.2024.10.026}, pmid = {39536820}, issn = {1538-7836}, mesh = {Humans ; *Heparin/adverse effects/immunology ; *Thrombocytopenia/chemically induced/diagnosis/blood/immunology/epidemiology ; Platelet Factor 4/immunology/blood ; Prospective Studies ; Female ; Enzyme-Linked Immunosorbent Assay ; Predictive Value of Tests ; Male ; Middle Aged ; Aged ; Immunoassay/methods ; *Anticoagulants/adverse effects/immunology ; Platelet Activation/drug effects ; Immunoglobulin G/blood ; Luminescent Measurements ; Reproducibility of Results ; Prevalence ; Aged, 80 and over ; Adult ; }, abstract = {BACKGROUND: Following the current guidelines, immunoassays for the diagnosis of heparin-induced thrombocytopenia (HIT) are interpreted dichotomously, with test results categorized as either positive or negative. However, the extent to which test results hold diagnostic significance across the entire dynamic range remains unclear.
OBJECTIVES: We utilized data from the prospective towards precise and rapid diagnosis of heparin-induced thrombocytopenia study, comprising 1393 consecutive patients with suspected HIT, to assess the diagnostic significance of 2 heparin/platelet factor 4 immunoassay test results across their respective dynamic ranges: HemoSil Acustar HIT IgG (chemiluminescence immunoassay [CLIA]) and Lifecodes PF4 immunoglobulin G (enzyme-linked immunosorbent assay [ELISA]).
METHODS: HIT diagnosis was determined by a washed platelet heparin-induced platelet activation assay. For each measurement point in the dataset, we computed likelihood ratios (LRs), sensitivities, and specificities. To provide posttest probabilities for individual test results, we calculated interval-specific LRs and integrated them into a web-based calculator.
RESULTS: The prevalence of HIT was 8.5% (n = 119). An LR of ≥10 was first achieved at 0.3% of the dynamic range (0.4 U/mL; CLIA) and then at 16% (0.64 optical density; ELISA). An LR of ≥100 was present at 9.4% (12 U/mL; CLIA) and 75.0% (3.0 optical density; ELISA). The slope of the linear regression line (LR ∼ dynamic range) was 9.5 (CLIA) and 0.9 (ELISA).
CONCLUSION: Despite both immunoassays showing an association between results and diagnostic significance, the strength of the association varies by assay. CLIA has a larger increase per measurement unit. Posttest probabilities for individual patients can be estimated using a web-based calculator: https://pcd-research.shinyapps.io/BayesianCalculator/.}, }
@article {pmid39536447, year = {2024}, author = {Oehler, VG and Huang, IJ and Siu, C and Kim, M and Signorelli, J and Bell, CS and Hobbs, GS}, title = {Dose Modifications in the Management of Chronic Phase Chronic Myeloid Leukemia: Who, What, and When.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7044}, pmid = {39536447}, issn = {1540-1413}, mesh = {Humans ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration & dosage ; Leukemia, Myeloid, Chronic-Phase/drug therapy ; Antineoplastic Agents/therapeutic use/administration & dosage/adverse effects ; Fusion Proteins, bcr-abl/antagonists & inhibitors/genetics ; Treatment Outcome ; Quality of Life ; Disease Management ; }, abstract = {With the availability of BCR::ABL1 targeted tyrosine kinase inhibitors (TKIs), outcomes for most individuals with chronic phase chronic myeloid leukemia (CP-CML) are outstanding, with life expectancy similar to age-matched peers. Treatment-emergent adverse events (TEAEs) impair quality of life and many patients struggle with low-level chronic AEs, which for some individuals impact emotional well-being as well as social and work functioning. An emerging body of data supports that many TEAEs are related to therapy dose and can improve with dose reduction. However, it is critical that dose reductions do not alter current outcomes, especially in the rare patients who are at greater risk of losing response or transforming to acute leukemia. Organizations including the National Comprehensive Cancer Network have begun to address when dose reductions may be considered in patients with CP-CML. In this manuscript, we review retrospective and prospective data reporting outcomes in patients after dose reduction and review data supporting lower dose preemptive dosing in first-line and later-line therapy. Switching therapy for intolerance can result in improvements in symptoms and limit toxicity, but other TEAEs may occur. Additionally, emerging therapeutics such as the new class of BCR::ABL1 allosteric inhibitors are under evaluation with a goal of improving tolerability. However, with many TKIs on the cusp of becoming generic, dose reduction becomes an appealing and important cost-effective strategy to minimize TEAEs and improve quality of life while preserving outstanding outcomes in CP-CML.}, }
@article {pmid39536442, year = {2024}, author = {Xu, YG and Lim, Y and Bordeaux, JS and Aasi, SZ and Alam, M and Chen, PL and Contreras, CM and DiMaio, D and Donigan, JM and Farma, JM and Grekin, RC and Mark, L and Nehal, KS and Nghiem, P and Olino, K and Patel, T and Scott, J and Shaha, AR and Srivastava, D and Schmults, CD}, title = {Achieving Adherence With NCCN Guidelines for Nonmelanoma Skin Cancer Regarding Peripheral and Deep En Face Margin Assessment (PDEMA).}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7037}, pmid = {39536442}, issn = {1540-1413}, mesh = {Humans ; *Skin Neoplasms/pathology/surgery/therapy/diagnosis ; *Margins of Excision ; *Mohs Surgery/methods/standards ; Guideline Adherence/statistics & numerical data ; Practice Guidelines as Topic ; Carcinoma, Squamous Cell/pathology/surgery/therapy/diagnosis ; }, abstract = {Peripheral and deep en face margin assessment (PDEMA), formerly termed by NCCN as complete circumferential peripheral and deep margin assessment (CCPDMA), has the advantages of histologic visualization of the entire marginal surface, highly accurate resection of involved tissue, and sparing of uninvolved tissue. Owing to its highest reported cure rates, PDEMA is the NCCN-preferred treatment for dermatofibrosarcoma protuberans, high-risk basal cell carcinoma, and very-high-risk cutaneous squamous cell carcinoma. In the United States, Mohs micrographic surgery (Mohs) is the most common method of PDEMA. In Germany and some other countries, non-Mohs methods of PDEMA referred to as the Tubingen torte and muffin techniques are more widely used. The Tubingen methods of PDEMA require close communication between surgeon and pathologist. This article describes the background of both Mohs and Tubingen PDEMA, reviews what constitutes PDEMA, and provides a protocol for Tubingen PDEMA detailing critical components in a stepwise fashion using illustrative photos and diagrams. We hope to broaden understanding of the NCCN Guidelines and their rationale, align practice, and optimize patient outcomes.}, }
@article {pmid39534377, year = {2024}, author = {Brusselmans, M and Carvalho, LM and L Hong, S and Gao, J and Matsen Iv, FA and Rambaut, A and Lemey, P and Suchard, MA and Dudas, G and Baele, G}, title = {On the importance of assessing topological convergence in Bayesian phylogenetic inference.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae081}, pmid = {39534377}, issn = {2057-1577}, abstract = {Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies-one on Ebola virus and one on HIV-illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.}, }
@article {pmid39529638, year = {2024}, author = {Treekitkarnmongkol, W and Dai, J and Liu, S and Sankaran, D and Nguyen, T and Balasenthil, S and Hurd, MW and Chen, M and Katayama, H and Roy-Chowdhuri, S and Calin, GA and Brand, RE and Lampe, PD and Hu, TY and Maitra, A and Koay, EJ and Killary, AM and Sen, S}, title = {Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples.}, journal = {Gastro hep advances}, volume = {3}, number = {8}, pages = {1098-1115}, pmid = {39529638}, issn = {2772-5723}, abstract = {BACKGROUND AND AIMS: Clinically validated biomarker of pancreatic ductal adenocarcinoma (PDAC), carbohydrate antigen 19-9 (CA19-9), has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers.
METHODS: 2083 miRNAs in 15 μl of plasma from multicenter age-matched cohorts (N = 203: healthy controls, n = 46; pancreatitis controls, n = 36; diagnosed cases: n = 121) and a prediagnostic Prostate, Lung, Colorectal, and Ovarian age- and gender-matched cohort (N = 96; controls, n = 48; prediagnosed cases, n = 48) were interrogated. A three-miRNA biomarker signature was developed for early-stage PDAC.
RESULTS: The three-miRNA signature (let-7i-5p, miR-130a-3p and miR-221-3p) detected PDAC from healthy controls independently (area under the curve [AUC] of stage I, II, I-IV = 0.970, 0.975, 0.974) and in combination with CA19-9 (AUC of stage I, II, I-IV = 1.000, 0.992, 0.995). It also discriminated chronic pancreatitis (AUC of stage I, II, I-IV = 0.932, 0.931, 0.929), improving performance of CA19-9 alone (AUC of stage I, II, I-IV = 0.763, 0.701, 0.735) in combination (AUC of stage I, II, I-IV = 0.971, 0.943, 0.951). Blinded validation in prediagnostic Prostate, Lung, Colorectal, and Ovarian cohort revealed lead-time trajectory increase in AUC from 0.702 to 0.729 to 0.757 at twelve-, six-, and three-months before PDAC diagnosis, respectively. The signature also helped stratification of patients with different circulating tumor DNA and imaging subtypes.
CONCLUSION: Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers.}, }
@article {pmid39533017, year = {2025}, author = {Liang, EC and Rejeski, K and Fei, T and Albittar, A and Huang, JJ and Portuguese, AJ and Wu, Q and Raj, S and Subklewe, M and Shouval, R and Gauthier, J}, title = {Correction: Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.}, journal = {Bone marrow transplantation}, volume = {60}, number = {2}, pages = {254}, doi = {10.1038/s41409-024-02453-6}, pmid = {39533017}, issn = {1476-5365}, }
@article {pmid39532861, year = {2024}, author = {Carpp, LN and Hyrien, O and Fong, Y and Benkeser, D and Roels, S and Stieh, DJ and Van Dromme, I and Van Roey, GA and Kenny, A and Huang, Y and Carone, M and McDermott, AB and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Amoa-Awua, O and Basappa, M and Flach, B and Lin, BC and Moore, C and Naisan, M and Naqvi, M and Narpala, S and O'Connell, S and Mueller, A and Serebryannyy, L and Castro, M and Wang, J and Petropoulos, CJ and Luedtke, A and Lu, Y and Yu, C and Juraska, M and Hejazi, NS and Wolfe, DN and Sadoff, J and Gray, GE and Grinsztejn, B and Goepfert, PA and Bekker, LG and Gaur, AH and Veloso, VG and Randhawa, AK and Andrasik, MP and Hendriks, J and Truyers, C and Vandebosch, A and Struyf, F and Schuitemaker, H and Douoguih, M and Kublin, JG and Corey, L and Neuzil, KM and Follmann, D and Koup, RA and Donis, RO and Gilbert, PB and , and , and , }, title = {Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9785}, pmid = {39532861}, issn = {2041-1723}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Ad26COVS1/immunology ; *Antibodies, Neutralizing/immunology/blood ; *Antibodies, Viral/immunology/blood ; *COVID-19/immunology/prevention & control/virology ; *COVID-19 Vaccines/immunology/administration & dosage ; *SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Vaccination ; Vaccine Efficacy ; }, abstract = {Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [<4.8975 International Units (IU)50/ml], 85.2% (47.2%, 95.3%) at just-quantifiable (5.2 IU50/ml), and 95.1% (81.1%, 96.9%) at 90[th] percentile (30.2 IU50/ml). At the same titers, VE against moderate COVID-19 is 32.5% (11.8%, 48.4%), 33.9% (19.1%, 59.3%), and 60.7% (40.4%, 76.4%). Protection against moderate vs. severe disease may require higher antibody levels, and very low antibody levels and/or other immune responses may associate with protection against severe disease.}, }
@article {pmid39532048, year = {2024}, author = {Grivas, P and Barata, P and Moon, H and Gupta, S and Hutson, T and Sternberg, CN and Brown, JR and Dave, V and Downey, C and Shillington, AC and Katzenstein, HM and Kirker, M and Hanson, S and Liu, FX and Morris, V and Bhanegaonkar, A and Sonpavde, GP}, title = {Avelumab First-Line Maintenance for Locally Advanced or Metastatic Urothelial Carcinoma: Results From the Real-World US PATRIOT-II Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102238}, doi = {10.1016/j.clgc.2024.102238}, pmid = {39532048}, issn = {1938-0682}, mesh = {Humans ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Aged ; Retrospective Studies ; Middle Aged ; Carcinoma, Transitional Cell/drug therapy/mortality/pathology/secondary ; United States ; Maintenance Chemotherapy ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Urinary Bladder Neoplasms/drug therapy/pathology ; Progression-Free Survival ; Aged, 80 and over ; Urologic Neoplasms/drug therapy/pathology/mortality ; Treatment Outcome ; }, abstract = {INTRODUCTION: In JAVELIN Bladder 100, avelumab first-line maintenance (1LM) improved overall survival (OS) and progression-free survival (PFS) in patients with locally advanced/metastatic urothelial carcinoma (la/mUC) without progression following 1L platinum-based chemotherapy (PBC) versus best supportive care. PATRIOT-II describes real-world outcomes with avelumab 1LM.
PATIENTS AND METHODS: This observational, retrospective study of avelumab 1LM in US community/academic centers used medical record data collected from avelumab initiation for ≥12 months to assess survival, safety, and healthcare resource utilization; analyses are descriptive.
RESULTS: The study included 160 patients from 37 centers (median age, 70 years; 77% male). Avelumab 1LM was initiated at a median of 4 weeks (IQR 3-6) after PBC completion. Median follow-up from avelumab 1LM was 16 months (IQR 11-21). At study end, 19.4% of patients continued avelumab; 73.7% had discontinued due to progression, adverse events (AEs), or performance status deterioration. Median PFS and OS from avelumab initiation were 5.4 months (95% CI, 3.8-6.9) and 24.4 months (95% CI, 20.4-28.4), respectively. Grade ≥3 treatment-related AEs (TRAEs) occurred in 15 patients (9.4%); 35 (21.9%) had any-grade immune-related AEs, and 23 (14.3%) received high-dose systemic corticosteroids for AEs. Forty-four patients (27.5%) were hospitalized during the avelumab treatment period, of whom 13 (8.1%) were hospitalized due to TRAEs. Limitations of this study include a small sample size, potential selection bias, and missing/unknown data.
CONCLUSION: These results align with the JAVELIN Bladder 100 clinical trial and other real-world studies, supporting avelumab 1LM use in patients with la/mUC without progression following 1L PBC.}, }
@article {pmid39531474, year = {2024}, author = {Dadonaite, B and Ahn, JJ and Ort, JT and Yu, J and Furey, C and Dosey, A and Hannon, WW and Vincent Baker, AL and Webby, RJ and King, NP and Liu, Y and Hensley, SE and Peacock, TP and Moncla, LH and Bloom, JD}, title = {Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002916}, pmid = {39531474}, issn = {1545-7885}, support = {S10 OD028685/OD/NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; *Ferrets ; Mice ; *Mutation ; Humans ; Influenza, Human/virology/epidemiology/immunology ; Orthomyxoviridae Infections/virology ; Influenza A virus/genetics/immunology ; Female ; Antibodies, Viral/immunology/blood ; }, abstract = {H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.}, }
@article {pmid39530736, year = {2024}, author = {Shearer, T and Comstock, M and Williams, RL and Johnson, MC and Cendrowicz, E and Leonowens, C and Smith, M and Baughman, TM and Breitbach, CJ and Cheng, S and Green, DJ}, title = {Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.}, journal = {Cancer research communications}, volume = {4}, number = {12}, pages = {3114-3123}, pmid = {39530736}, issn = {2767-9764}, mesh = {*Multiple Myeloma/drug therapy/immunology/pathology/therapy ; *B-Cell Maturation Antigen/immunology ; Humans ; *Plasma Cells/drug effects/immunology ; Animals ; Mice ; Cell Line, Tumor ; Kinetics ; Xenograft Model Antitumor Assays ; }, abstract = {ABSTRACT: B-cell maturation antigen (BCMA) is the target of several investigational and approved drugs for multiple myeloma. BCMA expressed on plasma cells (PC) and multiple myeloma cells is cleaved by the enzyme γ-secretase, reducing membrane-bound BCMA (mbBCMA) receptor density. γ-Secretase inhibitors (GSI) have been shown to increase mbBCMA density and may enhance efficacy of BCMA-targeted therapies. The pharmacodynamic profile of the GSI nirogacestat was evaluated in multiple myeloma cell lines and a phase I study in healthy volunteers. In multiple myeloma cell lines, mbBCMA density and soluble BCMA concentrations were measured before and after short-duration nirogacestat exposure and at serial time points following washout. In the phase I study, 23 participants were administered a single oral dose of nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every 12 hours for up to 48 hours; mbBCMA density on PCs (from whole blood and bone marrow) and nirogacestat plasma concentrations were measured at baseline and postdose. After single-dose administration, serum nirogacestat concentrations rapidly increased (Tmax ∼1 hour), and a two-compartment model with linear absorption and clearance best described nirogacestat pharmacokinetics. In multiple myeloma cells and healthy volunteers’ PCs, nirogacestat resulted in rapid and robust increases in mbBCMA density, with increases up to 20-fold within 4 to 8 hours of exposure. Concomitant decreases in soluble BCMA were observed. Nirogacestat is currently being evaluated in combination with several BCMA-directed therapeutic agents in patients with multiple myeloma. Elucidating the kinetics of BCMA in response to nirogacestat is key to guiding dosing and therapeutic strategies in multiple myeloma.
SIGNIFICANCE: GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.}, }
@article {pmid39528599, year = {2025}, author = {Paik, J and Kim, A and Fogassy, K and Snyder, JM and Brabb, T and Dill-McFarland, KA and He, Q and Amory, JK}, title = {Weight loss and metabolic effects of an ALDH1A1-specific inhibitor, FSI-TN42, in a diet induced mouse model of obesity.}, journal = {International journal of obesity (2005)}, volume = {49}, number = {3}, pages = {507-515}, pmid = {39528599}, issn = {1476-5497}, support = {P30 DK035816/DK/NIDDK NIH HHS/United States ; R01 DK124197/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Obesity/drug therapy/metabolism ; Mice ; Male ; Mice, Inbred C57BL ; *Weight Loss/drug effects ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Aldehyde Dehydrogenase 1 Family/antagonists & inhibitors ; Retinal Dehydrogenase/antagonists & inhibitors ; Energy Metabolism/drug effects ; }, abstract = {BACKGROUND: Retinoic acid (RA) participates in weight regulation and energy metabolism. Mice lacking ALDH1A1, one of the major enzymes responsible for RA biosynthesis, are resistant to diet-induced obesity. Previously, we identified FSI-TN42 (N42) as an ALDH1A1-specific inhibitor and reported its pharmacokinetics and pharmacodynamics as well as its efficacy in weight suppression.
METHODS: In the first study, C57BL/6 J male mice were fed a high fat diet for 8 weeks to induce obesity. Mice were then divided into three groups and fed (1) moderate fat diet (MFD), (2) MFD + WIN 18,446 (1 g/kg diet), or (3) MFD + N42 (1 g/kg diet) for 8 weeks. A control group of mice were fed a low-fat diet for the entire period. Mice were weighed weekly and fasting glucose was determined every 4 weeks. Tissues were examined for potential toxicity using histopathology and complete blood counts. In the second study, we examined influences of N42 on energy balance and/or appetite by determining food intake, activity and energy expenditure in mice with obesity treated with MFD or MFD + N42. Lastly, we tested fertility with a mating study.
RESULTS: N42 significantly accelerated weight loss compared to MFD alone in mice with obesity by reducing fat mass without decreasing lean mass. N42 did not alter food intake or activity levels. While mice treated with N42 lost significantly more weight, they maintained a similar level of energy expenditure compared to mice fed MFD only. Mice fed N42 preferentially used fat postprandially, especially under thermoneutral or mild cold challenge. N42 did not affect male fertility.
CONCLUSIONS: N42 promotes weight loss when used with MFD in mice with diet-induced obesity without causing significant organ toxicity or male infertility. Future studies will determine if N42 can be used to promote further weight loss if combined with current weight loss drugs.}, }
@article {pmid39528488, year = {2024}, author = {Giaccherini, M and Clay-Gilmour, AI and Liotti, R and Macauda, A and Gentiluomo, M and Brown, EE and Machiela, MJ and Chanock, SJ and Hildebrandt, MAT and Norman, AD and Manasanch, E and Rajkumar, SV and Hofmann, JN and Berndt, SI and Bhatti, P and Giles, GG and Ziv, E and Kumar, SK and Camp, NJ and Cozen, W and Slager, SL and Canzian, F and Gemignani, F and Vachon, CM and Campa, D}, title = {Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {200}, pmid = {39528488}, issn = {2044-5385}, }
@article {pmid39527587, year = {2024}, author = {Dankwa, S and Kosman, C and Dennis, M and Giorgi, EE and Vuong, K and Pahountis, I and Garza, A and Binuya, C and McCarthy, J and Mayer, BT and Ngo, JT and Enemuo, CA and Carnathan, DG and Stanfield-Oakley, S and Berendam, SJ and Weinbaum, C and Engelman, K and Magnani, DM and Chan, C and Ferrari, G and Silvestri, G and Amara, RR and Chahroudi, A and Permar, SR and Fouda, GG and Goswami, R}, title = {A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0312411}, pmid = {39527587}, issn = {1932-6203}, support = {P01 AI131276/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; U42 OD011023/OD/NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta ; *Immunization, Passive/methods ; *HIV Antibodies/immunology/blood ; *HIV Infections/immunology/drug therapy/prevention & control ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology/blood ; Humans ; HIV-1/immunology ; Broadly Neutralizing Antibodies/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control/immunology ; }, abstract = {To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.}, }
@article {pmid39522103, year = {2025}, author = {Abbaspour, E and Mansoori, B and Karimzadhagh, S and Chalian, M and Pouramini, A and Sheida, F and Daskareh, M and Haseli, S}, title = {Machine learning and deep learning models for preoperative detection of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis.}, journal = {Abdominal radiology (New York)}, volume = {50}, number = {5}, pages = {1927-1941}, pmid = {39522103}, issn = {2366-0058}, mesh = {Humans ; *Colorectal Neoplasms/pathology/diagnostic imaging ; *Deep Learning ; *Lymphatic Metastasis/diagnostic imaging/pathology ; *Machine Learning ; Preoperative Care/methods ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: To evaluate the diagnostic performance of Machine Learning (ML) and Deep Learning (DL) models for predicting preoperative Lymph Node Metastasis (LNM) in Colorectal Cancer (CRC) patients.
METHODS: A systematic review and meta-analysis were conducted following PRISMA-DTA and AMSTAR-2 guidelines. We searched PubMed, Web of Science, Embase, and Cochrane Library databases until February 16, 2024. Study quality and risk of bias were assessed using the QUADAS-2 tool. Data were analyzed using STATA v18, applying random-effects models to all analyses.
RESULTS: Twelve studies involving 8321 patients were included, with most published in 2021-2024 (9/12). The pooled AUC of ML models for predicting LNM in CRC patients was 0.87 (95% CI: 0.82-0.91, I[2]:86.17) with a sensitivity of 78% (95% CI: 69-87%) and a specificity of 77% (95% CI: 64%-90%). In addition, when assessing the AUC reported by radiologists, both junior and senior radiologists had similar performance, significantly lower than the ML models. (P < 0.001). Subgroup analysis revealed higher AUCs in prospective studies (0.95, 95% CI: 0.87-1) compared to retrospective studies (0.85, 95% CI: 0.81-0.89) (P = 0.03). Studies without external validation exhibited significantly higher AUCs than those with external validation (P < 0.01). While there was no significant difference in AUC and sensitivity between the T1-T2 and T2-T4 stages, specificity was significantly higher in the T2-T4 stages than the low stages of T1 and T2 (95%, 95% CI: 92-98% vs. 61%, 95% CI: 44-78%; P < 0.01).
CONCLUSION: ML models demonstrate strong potential for preoperative LNM staging and treatment planning in CRC, potentially reducing the need for additional surgeries and related health and financial burdens. Further prospective multicenter studies, with standardized reporting of algorithms, modality parameters, and LNM staging, are needed to validate these findings.}, }
@article {pmid39522029, year = {2024}, author = {Gregg, JR and Newcomb, L and Wu, R and Dennison, J and Davis, JW and Pettaway, C and Pisters, L and Ward, JF and Chapin, BF and Chéry, L and Urkmez, A and Fang, AM and Higgason, N and Troncoso, P and Daniel, CR and Logothetis, C and Thompson, TC and Hahn, AW and Liu, M and Zheng, Y and Lin, DW and Hanash, S and Irajizad, E and Fahrmann, J}, title = {Validation of a prognostic blood-based sphingolipid panel for men with localized prostate cancer followed on active surveillance.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {134}, pmid = {39522029}, issn = {2050-7771}, support = {P50 CA140388/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We previously reported that increases in circulating sphingolipids are associated with elevated risk of biopsy Gleason grade group (GG) upgrading in men on Active Surveillance (AS) for prostate cancer. Here, we aimed to validate these findings and establish a blood-based sphingolipid biomarker panel for identifying men on AS who are at high-risk of biopsy GG upgrading.
METHODS: Men diagnosed with low- or intermediate-risk prostate cancer in one of two AS cohorts (CANARY PASS and MDACC) were followed for GG upgrading after diagnostic and confirmatory biopsy. The PASS cohort consisted of 544 patients whereas the MDACC Cohort consisted of 697 patients. The number of patients with GG upgrading during course of study follow-up in the PASS and MDACC cohorts were 98 (17.7%) and 133 (19.1%), respectively. Plasmas collected prior to confirmatory biopsy were used for mass spectrometry-based quantitation of 87 unique sphingolipid species. A neural network layer based on 21 sphingolipids was developed in the CANARY PASS cohort for predicting biopsy GG upgrading. Tertile-based thresholds for low-, intermediate-, and high-risk strata were subsequently developed for the sphingolipid panel as well as a model that combined the sphingolipid panel with PSA density and rate of core positivity on diagnostic biopsy. The resultant models and risk thresholds for GG upgrading were validated in the MDACC cohort. Performance was assessed using Cox proportional hazard models, C-index, AUC, and cumulative incidence curves.
RESULTS: The sphingolipid panel had a HR (per unit standard deviation increase) of 1.36 (95% CI: 1.07-1.70) and 1.35 (95% CI: 1.11-1.64) for predicting GG biopsy upgrading in the PASS and MDACC cohort, respectively. The model that combined the sphingolipid panel with PSA density and rate of core positivity achieved a HR of 1.63 (95% CI: 1.33-2.00) and 1.44 (1.25-1.66), respectively. Tertile-based thresholds, established in the PASS cohort, were applied to the independent MDACC cohort. Compared to the low-risk group, MDACC patients in the high-risk strata had a GG biopsy upgrade HR of 3.65 (95% CI: 2.21-6.02), capturing 50% of the patients that had biopsy upgrading during study follow-up.
CONCLUSIONS: The sphingolipid panel is independently associated with GG biopsy upgrading among men in two independent AS cohorts who have previously undergone diagnostic and confirmatory biopsy. The sphingolipid panel, together with clinical factors, provides a potential means for risk stratification to better guide clinical management of men on AS.}, }
@article {pmid39521703, year = {2025}, author = {Niraula, S and Gouli, S and Baran, AM and O'Regan, R and Tyburski, H and Zhang, H and Hardy, S and Mohile, N and Anders, CK and Dhakal, A}, title = {Effect of Breast Cancer Receptor Subtypes and CSF Cytology Status on Survival of Patients With Leptomeningeal Disease.}, journal = {Clinical breast cancer}, volume = {25}, number = {1}, pages = {65-74.e5}, doi = {10.1016/j.clbc.2024.09.019}, pmid = {39521703}, issn = {1938-0666}, mesh = {Humans ; Female ; Retrospective Studies ; Middle Aged ; *Receptor, ErbB-2/metabolism ; *Receptors, Estrogen/metabolism ; Aged ; *Receptors, Progesterone/metabolism ; *Breast Neoplasms/pathology/mortality/cerebrospinal fluid ; Adult ; Meningeal Neoplasms/cerebrospinal fluid/mortality/pathology ; Biomarkers, Tumor/cerebrospinal fluid/metabolism ; Triple Negative Breast Neoplasms/mortality/pathology/cerebrospinal fluid ; Prognosis ; Meningeal Carcinomatosis/cerebrospinal fluid/mortality/pathology ; Kaplan-Meier Estimate ; Aged, 80 and over ; }, abstract = {BACKGROUND: It is unclear whether breast cancer (BC) subtypes or CSF cytology results are associated with overall survival (OS) among patients with BC leptomeningeal disease (LMD). This single-institution retrospective study compares OS among BC patients with LMD across various breast cancer subtypes and CSF cytology results.
METHODOLOGY: The study enrolled BC patients diagnosed with LMD between 2010 and 2023. Breast cancer subtypes were classified as A. ER+/HER2-, HER2+, or triple-negative BC (TNBC); B. HER2+, HER2-Low, HER2-Zero. CSF cytology subtypes included CSF+, CSF-, or CSF not tested (NT). OS was summarized via Kaplan-Meier analysis and compared using log-rank test. Cox models were used for multivariate analyses.
RESULTS: Out of 69 patients registered, median OS (95% CI) for ER+/HER2- (n = 33), HER2+ (n = 12) and TNBC (n = 24) subtypes were 8.0 (3.02, 24.8), 5.71 (1.61, not estimated) and 3.2 (1.11, 4.95) months (P = .17). In multivariate analysis, TNBC was associated with worse OS versus ER+/HER2- [Hazard Ratio (HR), 95% CI: 2.64, 1.23-5.80, P = .04]. HER2 subtypes (HER2-Zero, n = 21; HER2-Low, n = 32; HER2+, n = 12) showed no significant differences in OS. Median OS (95% CI) for CSF+ (n = 16), CSF- (n = 18), and CSF NT (n = 35) groups were 3.54 (1.61, 12.72), 13.41 (4.95, 61.93) and 3.28 (1.44, 6.92) months (P = .04). Multivariate analysis showed both CSF+ and CSF NT were associated with shorter OS compared to CSF- group [HR (95% CI) 4.50 (1.75, 12.11) for CSF+ vs. CSF-; 2.91 (1.45, 6.26) for CSF NT vs. CSF-; P = .002].
CONCLUSION: TNBC LMD group was associated with worse OS than ER+/HER2- BC LMD when adjusting for other prognostic factors. CSF- LMD patients had better OS than CSF+ or CSF NT LMD.}, }
@article {pmid39521614, year = {2024}, author = {Liao, JB and Dai, JY and Reichow, JL and Lim, JB and Hitchcock-Bernhardt, KM and Stanton, SE and Salazar, LG and Gooley, TA and Disis, ML}, title = {Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, pmid = {39521614}, issn = {2051-1426}, mesh = {Humans ; Female ; *Cancer Vaccines/immunology/therapeutic use ; *T-Lymphocytes/immunology ; Middle Aged ; Receptor, ErbB-2/immunology ; Male ; Aged ; Vaccination ; Adult ; Neoplasms/immunology ; }, abstract = {BACKGROUND: For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.
METHODS: To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.
RESULTS: Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.}, }
@article {pmid39521255, year = {2025}, author = {Fujiwara, N and Lopez, C and Marsh, TL and Raman, I and Marquez, CA and Paul, S and Mishra, SK and Kubota, N and Katz, C and Kanzaki, H and Gonzalez, M and Quirk, L and Deodhar, S and Selvakumar, P and Raj, P and Parikh, ND and Roberts, LR and Schwartz, ME and Nguyen, MH and Befeler, AS and Page-Lester, S and Srivastava, S and Feng, Z and Reddy, KR and Khaderi, S and Asrani, SK and Kanwal, F and El-Serag, HB and Marrero, JA and Singal, AG and Hoshida, Y}, title = {Phase 3 Validation of PAaM for Hepatocellular Carcinoma Risk Stratification in Cirrhosis.}, journal = {Gastroenterology}, volume = {168}, number = {3}, pages = {556-567.e7}, pmid = {39521255}, issn = {1528-0012}, support = {U01 CA230997/CA/NCI NIH HHS/United States ; R01 CA186566/CA/NCI NIH HHS/United States ; U01 CA283935/CA/NCI NIH HHS/United States ; R01 CA222900/CA/NCI NIH HHS/United States ; P01 CA263025/CA/NCI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; R01 CA255621/CA/NCI NIH HHS/United States ; R01 CA233794/CA/NCI NIH HHS/United States ; U01 CA230694/CA/NCI NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; R01 CA237659/CA/NCI NIH HHS/United States ; 101021417/ERC_/European Research Council/International ; R01 CA282178/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Hepatocellular/epidemiology/diagnosis/mortality/etiology/blood ; *Liver Neoplasms/epidemiology/diagnosis/mortality/blood/etiology ; Male ; Female ; *Liver Cirrhosis/complications/diagnosis/mortality/blood ; Middle Aged ; Risk Assessment/methods ; Aged ; *Biomarkers, Tumor/blood ; *Early Detection of Cancer/methods ; alpha-Fetoproteins/analysis/metabolism ; Risk Factors ; Incidence ; Texas/epidemiology ; Prospective Studies ; Retrospective Studies ; Bilirubin/blood ; Prognosis ; Predictive Value of Tests ; Platelet Count ; Reproducibility of Results ; Serum Albumin/analysis ; }, abstract = {BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.
METHODS: Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.
RESULTS: Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.
CONCLUSIONS: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.}, }
@article {pmid39520444, year = {2025}, author = {Shetty, NS and Gaonkar, M and Pampana, A and Patel, N and Morrison, AC and Reiner, AP and Carson, AP and Yu, B and Psaty, BM and Kooperberg, C and Fatkin, D and Boerwinkle, E and Rotter, JI and Taylor, KD and Hou, L and Irvin, MR and Hall, ME and Maurer, M and Fornage, M and Armstrong, ND and Bart, N and Goyal, P and Rich, SS and Vasan, RS and Li, P and Arora, G and Arora, P}, title = {Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers.}, journal = {JACC. Heart failure}, volume = {13}, number = {1}, pages = {91-101}, doi = {10.1016/j.jchf.2024.08.019}, pmid = {39520444}, issn = {2213-1787}, support = {R01 HL160982/HL/NHLBI NIH HHS/United States ; R01 HL163081/HL/NHLBI NIH HHS/United States ; R01 HL163852/HL/NHLBI NIH HHS/United States ; T32 HL007457/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Black or African American/genetics ; Cardiovascular Diseases/genetics/epidemiology ; Cross-Sectional Studies ; Diabetes Mellitus/genetics/epidemiology ; Genotype ; *Heart Disease Risk Factors ; *Heart Failure/genetics/epidemiology ; Heterozygote ; Hypercholesterolemia/genetics/epidemiology ; Hypertension/genetics/epidemiology ; Obesity/genetics/epidemiology/complications ; *Prealbumin/genetics ; Risk Factors ; United States/epidemiology ; }, abstract = {BACKGROUND: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown.
OBJECTIVES: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers.
METHODS: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference.
RESULTS: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14).
CONCLUSIONS: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.}, }
@article {pmid39516665, year = {2024}, author = {Xu, Y and Miller, CP and Xue, J and Zheng, Y and Warren, EH and Tykodi, SS and Akilesh, S}, title = {Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {23}, pmid = {39516665}, issn = {2731-9377}, support = {KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).
METHODS: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.
RESULTS: TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling. This phenotype was shared with hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes which promoted resistance to apoptosis after vascular endothelial growth factor removal and increased adhesiveness to subsets of immune cells including regulatory T-cells.
CONCLUSIONS: Our studies demonstrate that TECs have a distinct phenotype that is shared by TECs from different tumor types and stable in ex vivo culture. The distinct adhesive interaction of TECs with immune cells raises the possibility of their modulation to improve immune cell-based therapies for RCC.}, }
@article {pmid39516359, year = {2024}, author = {Stockem, CF and Einerhand, SMH and Rodríguez, IM and Salhi, Y and Pérez, E and Bakaloudi, DR and Talukder, R and Caramelo, B and Morales-Barrera, R and De Meulenaere, A and Rametta, A and Bottelli, A and Lefort, F and Giannatempo, P and Vulsteke, C and Carles, J and Duran, I and Grivas, P and de Liaño, AG and Robbrecht, DGJ and Valderrama, BP and van der Noort, V and van der Heijden, MS}, title = {Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {84}, pmid = {39516359}, issn = {2731-9377}, abstract = {BACKGROUND: Anti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.
METHODS: We collected data from patients with advanced UC treated with anti-PD-(L)1 between 2013 and 2023. Overall- and progression-free survival (OS, PFS) were determined using the Kaplan-Meier method. Independent variables were analysed by uni- and multivariate Cox regression for their association with OS and PFS.
RESULTS: Survival analyses included 552 patients. Patient characteristics in our cohort were consistent with those of a typical advanced UC population. After median follow-up of 49 months, five-year OS and PFS rates were 16.0% and 6.9% respectively. The absence of visceral and/or bone metastases and elevated C-reactive protein level, gamma-glutamyltransferase level and neutrophil-to-lymphocyte ratio were identified as favourable prognostic factors for OS.
CONCLUSIONS: A selected subset of patients with advanced UC may experience long-term clinical benefit from anti-PD-(L)1 treatment. We identified prognostic factors that might be used for risk assessment and clinical trial stratification.}, }
@article {pmid39513720, year = {2024}, author = {Hansman, GS and Reese, T and Pancera, M and Rudd, PA and Masic, V and Haselhorst, T and von Itzstein, M}, title = {Structural analysis of a non-pathogenic hare calicivirus capsid bound to a histo-blood group antigen co-factor.}, journal = {Journal of virology}, volume = {98}, number = {12}, pages = {e0167524}, pmid = {39513720}, issn = {1098-5514}, }
@article {pmid39513224, year = {2024}, author = {Bazhenova, L and Kim, DW and Cho, BC and Goel, S and Heist, R and Werner, TL and Eaton, KD and Wang, JS and Pant, S and Adkins, DR and Blakely, CM and Yan, X and Neuteboom, S and Christensen, JG and Chao, R and Bauer, T}, title = {Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study.}, journal = {Future oncology (London, England)}, volume = {20}, number = {39}, pages = {3213-3227}, pmid = {39513224}, issn = {1744-8301}, support = {N/A//Mirati Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neoplasms/genetics/drug therapy/mortality/pathology ; Aged ; Adult ; Aged, 80 and over ; Mutation ; Young Adult ; Treatment Outcome ; }, abstract = {Aim: We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study.Materials & methods: Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of MET, AXL, RET, NTRK, DDR2, KDR, PDGFRA, KIT or CBL received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR).Results: In total, 113 patients were enrolled following a median of 3 (range 1-18) prior systemic regimens. Altered RET (n = 31), CBL (n = 31) and MET (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with RET-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; p = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the RET-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts.Conclusion: Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.}, }
@article {pmid39512128, year = {2024}, author = {Baxter-Lowe, LA and Wang, T and Kuxhausen, M and Spellman, SR and Maiers, M and Lee, S and Saultz, J and Arrieta-Bolaños, E and Gadalla, SM and Bolon, YT and Betts, BC}, title = {Novel Scoring System for Ranking Hematopoietic Stem Cell Transplantation.}, journal = {Clinical transplantation}, volume = {38}, number = {11}, pages = {e15478}, pmid = {39512128}, issn = {1399-0012}, support = {//Pediatric Transplantation and Cellular Therapy Consortium/ ; //Seagen Inc./ ; U24 CA076518/CA/NCI NIH HHS/United States ; //BioLineRX/ ; //Omeros Corporation/ ; //PPD Development, LP/ ; //Kyowa Kirin/ ; //OriGen BioMedical/ ; //Stemcell Technologies/ ; //MorphoSys/ ; //Med Learning Group/ ; //Blueprint Medicines/ ; //Karius/ ; //Vor Biopharma Inc./ ; /HL/NHLBI NIH HHS/United States ; //Blue Spark Technologies/ ; //Sanofi/ ; //Neovii Pharmaceuticals AG/ ; //Mesoblast/ ; //OptumHealth/ ; //Miller Pharmacal Group, Inc./ ; //ADC Therapeutics/ ; //BeiGene/ ; //the National Heart, Lung and Blood Institute/ ; //National Institute of Allergy and Infectious Diseases/ ; N00014-23-1-2057//Office of Naval Research/ ; //HistoGenetics/ ; //Miltenyi Biomedicine/ ; //Mallinckrodt Pharmaceuticals/ ; //Miltenyi Biotec, Inc./ ; //Janssen Research & Development, LLC/ ; //U.S. Public Health Service/ ; //Pharmacyclics, LLC, An AbbVie Company/ ; //Kite, a Gilead Company/ ; //Janssen/Johnson & Johnson/ ; //REGiMMUNE/ ; //AstraZeneca/ ; //Bristol Myers Squibb Co./ ; //Adienne SA/ ; //Kiadis Pharma/ ; //Actinium Pharmaceuticals, Inc./ ; //Novartis Pharmaceuticals Corporation/ ; //Medical College of Wisconsin/ ; //DKMS/ ; //Kashi Clinical Laboratories/ ; //STEMSOFT/ ; //Rigel Pharmaceuticals/ ; //Incyte Corporation/ ; //Alexion/ ; //Pfizer, Inc./ ; //Amgen, Inc./ ; N00014-24-1-2057//Office of Naval Research/ ; //Adaptive Biotechnologies Corporation/ ; //AlloVir, Inc./ ; //Stemline Technologies/ ; //Astellas Pharma US/ ; //Takeda Pharmaceuticals/ ; //AbbVie/ ; //Editas Medicine/ ; //Sarah Cannon/ ; //Gift of Life Marrow Registry/ ; //Sobi, Inc./ ; //CytoSen Therapeutics, Inc./ ; 27307C0011/ES/NIEHS NIH HHS/United States ; //bluebird bio, inc./ ; //Ossium Health, Inc./ ; //Registry Partners/ ; //MSA-EDITLife/ ; //Atara Biotherapeutics/ ; //Orca Biosystems, Inc./ ; //Millennium, the Takeda Oncology Co./ ; //Labcorp/ ; 27398C0011/ES/NIEHS NIH HHS/United States ; //CSL Behring/ ; //Medac GmbH/ ; //Gateway for Cancer Research/ ; //GlaxoSmithKline/ ; //Merck & Co./ ; //Gamida-Cell, Ltd./ ; //CareDx Inc./ ; //Legend Biotech/ ; //Vertex Pharmaceuticals/ ; //Jazz Pharmaceuticals, Inc./ ; //Jasper Therapeutics/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; //Xenikos BV/ ; //Iovance/ ; 27305C0011/ES/NIEHS NIH HHS/United States ; //Talaris Therapeutics/ ; //Eurofins Viracor, DBA Eurofins Transplant Diagnostics/ ; //NMDP/ ; //Gift of Life Biologics/ ; //Elevance Health/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Female ; Male ; Middle Aged ; *Graft vs Host Disease ; Adult ; Prognosis ; *HLA Antigens/immunology ; Follow-Up Studies ; *Histocompatibility Testing ; *Myelodysplastic Syndromes/therapy ; Young Adult ; Adolescent ; Survival Rate ; Aged ; Leukemia/therapy/mortality ; Child ; Unrelated Donors ; Retrospective Studies ; Child, Preschool ; }, abstract = {BACKGROUND: When human leukocyte antigen (HLA)-matched donors are not available for hematopoietic stem cell transplants (HSCT), there are no well-accepted guidelines for ranking 7/8 HLA-matched unrelated donors to achieve optimal transplant outcomes. A novel scoring system for ranking HLA mismatches for these donors was investigated.
METHODS: High-resolution HLA types were used to determine amino acid mismatches located in the HLA antigen-recognition domain. The location and physicochemical properties of mismatched amino acids were used to assign scores for peptide binding, T-cell receptor docking, and HLA structure/function. The scores were tested using a cohort of 2319 patients with leukemia or myelodysplastic syndrome who received their first unrelated donor transplant using conventional graft-versus-host disease (GVHD) prophylaxis between 2000 and 2014. Donors were 7/8 HLA-matched with a single HLA Class I mismatch. Primary outcomes were overall survival and acute GVHD.
RESULTS: The scores did not significantly (p < 0.01) associate with transplant outcomes, although a Peptide Score = 0 (i.e., no differences in peptide binding; N = 146, 6.3%) appears to have lower transplant-related mortality (TRM) compared to higher scores (p = 0.019). HLA mismatches with Peptide Score = 0 were predominately HLA-C*03:03/03:04 (62%), previously reported to be a permissive mismatch, and a group of 28 other HLA mismatches (38%) that showed similar associations with TRM.
CONCLUSIONS: This study suggests that HLA mismatches that do not alter peptide binding or orientation (Peptide Score = 0) could expand the number of permissive HLA mismatches. Further investigation is needed to confirm this observation and to explore alternative scoring systems for ranking HLA mismatched donors.}, }
@article {pmid39510589, year = {2024}, author = {Demirci, RA and Gulati, R and Hawley, JE and Yezefski, T and Haffner, MC and Cheng, HH and Montgomery, RB and Schweizer, MT and Yu, EY and Nelson, PS and Chen, DL and Iravani, A}, title = {SPECT/CT in Early Response Assessment of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving [177]Lu-PSMA-617.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {12}, pages = {1945-1951}, pmid = {39510589}, issn = {1535-5667}, support = {R37 CA286450/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/radiotherapy/diagnostic imaging/pathology ; Aged ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Lutetium ; *Single Photon Emission Computed Tomography Computed Tomography ; Retrospective Studies ; *Dipeptides/therapeutic use ; Treatment Outcome ; *Neoplasm Metastasis ; Aged, 80 and over ; Prostate-Specific Antigen/blood ; Middle Aged ; }, abstract = {[177]Lu-PSMA-617 (LuPSMA) is a newly established treatment for patients with metastatic castration-resistant prostate cancer (mCRPC), but survival outcomes vary widely, and predictors of treatment responses are needed. This study investigated the role of total tumor volumes (TTVs) and new lesions (NLs) determined by LuPSMA SPECT/CT in early cycles to predict subsequent outcomes in a real-world practice setting. Methods: Between June and December 2022, consecutive patients with mCRPC who received at least 2 administrations of LuPSMA with SPECT/CT 24 h after treatment were retrospectively reviewed. We evaluated associations between TTVs and the appearance of NLs at cycles 2 and 3 with subsequent prostate-specific antigen (PSA) progression-free survival and overall survival (OS) using multivariate Cox regression. All analyses were adjusted for changes in PSA level relative to baseline. Results: Sixty-six mCRPC patients (median age, 74 y) received a median of 4 (interquartile range, 3-5) cycles of LuPSMA. Median follow-up starting at cycle 2 was 42 wk (interquartile range, 33-48 wk), with 24 of 66 patients deceased at the time of the analysis. Changes in TTV measured at the start of cycles 2 and 3 relative to baseline correlated significantly with corresponding changes in PSA level (r = 0.55 and 0.56), but absolute TTVs did not correlate significantly (r = 0.00 and 0.18). Patients with a higher absolute TTV at the start of cycle 2 had worse PSA progression-free survival and OS (hazard ratio [HR], 1.4 [95% CI, 1.1-1.8] and 2.1 [95% CI, 1.5-2.9]), with consistent results at the start of cycle 3 (HR, 2 [95% CI, 1.4-2.9] and 2 [95% CI, 1.2-3.2]). NLs were identified in 13 of 66 and 11 of 51 patients at the start of cycles 2 and 3. NLs at the start of cycle 2 were associated with worse OS (HR, 5.8 [95% CI, 1.9-17.5]), with consistent results at the start of cycle 3 (HR, 4.9 [95% CI, 1.3-18.6]). In multivariate analysis, a higher TTV and the appearance of NLs at the start of cycles 2 and 3 were independently associated with poorer OS. Conclusion: Higher TTVs and NLs on LuPSMA SPECT/CT at the start of cycles 2 and 3 were independently associated with higher risk of death. These measures provided prognostic information independent of changes in PSA. Development of prognostic and predictive models including TTV, NLs, and PSA changes is warranted.}, }
@article {pmid39509091, year = {2024}, author = {Unger, JM and Till, C and Tangen, CM and Hershman, DL and Goodman, PJ and LeBlanc, M and Barlow, WE and Vaidya, R and Minasian, LM and Parnes, HL and Thompson, IM}, title = {Long-Term Adverse Effects and Complications After Prostate Cancer Treatment.}, journal = {JAMA oncology}, volume = {10}, number = {12}, pages = {1654-1662}, pmid = {39509091}, issn = {2374-2445}, abstract = {IMPORTANCE: Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities.
OBJECTIVE: To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males.
This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024.
EXPOSURE: Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records.
MAIN OUTCOMES AND MEASURES: Ten potential PCA treatment-related complications identified from Medicare claims data.
RESULTS: The study sample comprised 29 196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P < .001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P < .001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P < .001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P < .001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P < .001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants.
CONCLUSIONS AND RELEVANCE: This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.}, }
@article {pmid39508344, year = {2025}, author = {Chappidi, MR and Lin, DW and de la Calle, CM}, title = {Editorial Comment.}, journal = {The Journal of urology}, volume = {213}, number = {2}, pages = {190-191}, doi = {10.1097/JU.0000000000004307}, pmid = {39508344}, issn = {1527-3792}, }
@article {pmid39507884, year = {2024}, author = {Childs-Kean, LM and Beieler, AM and Cortés-Penfield, N and Keller, SC and Rivera, CG and Ryan, KL and Yoke, LH and Mahoney, MV}, title = {A Bundle of the "Top 10" Outpatient Parenteral Antimicrobial Therapy Publications in 2023.}, journal = {Open forum infectious diseases}, volume = {11}, number = {11}, pages = {ofae635}, pmid = {39507884}, issn = {2328-8957}, abstract = {Outpatient parenteral antimicrobial therapy (OPAT) has become more common in infectious diseases practice settings. Similarly, OPAT-related publications have also increased. The objective of this article was to summarize clinically important OPAT-related publications from 2023. Eighty-one articles were found on initial search, with 52 meeting inclusion criteria. A survey containing the 19 articles that had at least 1 citation was sent to an email listserv of multidisciplinary clinicians with OPAT experience. This article summarizes the "top 10" 2023 OPAT articles from the survey results.}, }
@article {pmid39505858, year = {2024}, author = {Srinivasan, S and Kryza, T and Bock, N and Tse, BWC and Sokolowski, KA and Janaththani, P and Fernando, A and Moya, L and Stephens, C and Dong, Y and Röhl, J and Alinezhad, S and Vela, I and Perry-Keene, JL and Buzacott, K and Nica, R and , and Gago-Dominguez, M and , and Schleutker, J and Maier, C and Muir, K and Tangen, CM and Gronberg, H and Pashayan, N and Albanes, D and Wolk, A and Stanford, JL and Berndt, SI and Mucci, LA and Koutros, S and Cussenot, O and Sorensen, KD and Grindedal, EM and Travis, RC and Haiman, CA and MacInnis, RJ and Vega, A and Wiklund, F and Neal, DE and Kogevinas, M and Penney, KL and Nordestgaard, BG and Brenner, H and John, EM and Gamulin, M and Claessens, F and Melander, O and Dahlin, A and Stattin, P and Hallmans, G and Häggström, C and Johansson, R and Thysell, E and Rönn, AC and Li, W and Brown, N and Dimeski, G and Shepherd, B and Dadaev, T and Brook, MN and Spurdle, AB and Stenman, UH and Koistinen, H and Kote-Jarai, Z and Klein, RJ and Lilja, H and Ecker, RC and Eeles, R and , and , and Clements, J and Batra, J}, title = {A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9587}, pmid = {39505858}, issn = {2041-1723}, support = {AQIRF175-2019RD2//State of Queensland | Advance Queensland/ ; R01 CA244948/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA199338/CA/NCI NIH HHS/United States ; R01 CA175491/CA/NCI NIH HHS/United States ; W81XWH-19-1-0343//U.S. Department of Defense (United States Department of Defense)/ ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism/mortality ; *Polymorphism, Single Nucleotide ; *Prostate-Specific Antigen/blood/metabolism ; *Kallikreins/genetics/metabolism ; Genetic Predisposition to Disease ; Aged ; Animals ; Chromosomes, Human, Pair 19/genetics ; Middle Aged ; Mice ; Alleles ; Cell Line, Tumor ; }, abstract = {Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.}, }
@article {pmid39505278, year = {2025}, author = {Sutherland, NM and Zhou, B and Zhang, L and Ong, MS and Hong, JS and Pak, A and Liu, KJ and Frigault, MJ and Maus, MV and Hill, JA and Reynolds, K and Walter, JE and Camargo, CA and Barmettler, S}, title = {Association of CD19[+]-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality.}, journal = {The Journal of allergy and clinical immunology}, volume = {155}, number = {2}, pages = {605-615}, pmid = {39505278}, issn = {1097-6825}, support = {K23 AI163350/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; *Agammaglobulinemia/mortality/immunology/etiology ; Female ; Middle Aged ; *Antigens, CD19/immunology ; *Immunotherapy, Adoptive/adverse effects ; Retrospective Studies ; Aged ; *Infections/mortality/etiology/immunology ; Adult ; *Receptors, Chimeric Antigen/immunology ; *Hematologic Neoplasms/therapy/mortality/immunology ; Risk Factors ; Aged, 80 and over ; }, abstract = {BACKGROUND: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19[+] receptors on B cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.
OBJECTIVES: We sought to evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.
METHODS: We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (IgG ≤600 mg/dL), infections prior to and after CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.
RESULTS: Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy levels (587 to 362 mg/dL; P < .0001). Thirty-seven percent of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia prior to CAR-T therapy was associated with worsening hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia post CAR-T therapy was associated with an increased risk of serious infection following CAR-T therapy (incidence rate ratio: 2.7; 95% CI: 1.5-5.2; P = .002). Risk factors for mortality included mild hypogammaglobulinemia (400 mg/dL < IgG ≤ 600 mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality.
CONCLUSIONS: We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia before CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia after CAR-T therapy, which was associated with an increased risk of serious infection and mortality post CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.}, }
@article {pmid39505259, year = {2025}, author = {Karim, NA and Miao, J and Reckamp, KL and Gay, CM and Byers, LA and Zhao, YQ and Redman, MW and Carrizosa, DR and Wang, WL and Petty, WJ and Mehta, K and Faller, BA and Agamah, ES and Kasbari, SS and Malisetti, RK and Kumar, A and Schallenkamp, J and Alluri, KC and Gray, JE and Kelly, K}, title = {Phase II Randomized Study of Maintenance Atezolizumab Versus Atezolizumab Plus Talazoparib in Patients With SLFN11 Positive Extensive-Stage SCLC: S1929.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {3}, pages = {383-394}, doi = {10.1016/j.jtho.2024.10.021}, pmid = {39505259}, issn = {1556-1380}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; *Lung Neoplasms/drug therapy/pathology/metabolism ; Neoplasm Staging ; *Nuclear Proteins/metabolism ; *Small Cell Lung Carcinoma/drug therapy/pathology/metabolism ; Survival Rate ; Phthalazines ; }, abstract = {OBJECTIVE: To evaluate whether the addition of a poly (adenosine diphosphate-ribose) polymerase inhibitor talazoparib to maintenance immune checkpoint inhibitor atezolizumab after frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive-stage SCLC (ES-SCLC).
METHODS: Patients with newly diagnosed SLFN11 expressing (H-score ≥ 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) after frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a one-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate, overall survival, and toxicity. The target sample size was 84 eligible patients.
RESULTS: From June 15, 2020, to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). Progression-free survival was improved with AT versus A (hazard ratio = 0.66, 80% confidence interval: 0.50-0.86, one-sided p = 0.019) with a median PFS of 2.9 and 2.4 months; overall survival was not different between groups (hazard ratio = 0.98, 80% confidence interval: 0.71-1.36, one-sided p = 0.47). Grade 3 and higher non-hematologic treatment-related adverse events occurred in 17% of patients with AT and 14% of patients with A. Grade 3 and higher hematological treatment-related adverse events were more common in AT (50%) than in A (4%) (p < 0.001).
CONCLUSION: Maintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress after initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.}, }
@article {pmid39503494, year = {2024}, author = {Greninger, AL and Larcena, A and Patel, A and Webster, B and Ulen, C and Green, DF and King, D and Patel, DR and McElvania, E and Harnett, G and Jandali, I and Gibson, J and Killion, J and Atwi, J and Bergmann, K and Slade, L and Allen Staat, M and Faron, M and Washington, M and Patel, R and Annamalai, R and Ackerman, R and Stewart, WP and Amador, YM and Rao, D and Liu, X and Raman, A}, title = {Prospective, multi-site evaluation of the Cepheid Xpert Xpress CoV-2 plus test on nasal and nasopharyngeal swabs.}, journal = {Journal of clinical microbiology}, volume = {62}, number = {12}, pages = {e0121924}, pmid = {39503494}, issn = {1098-660X}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; Young Adult ; *COVID-19/diagnosis/virology ; COVID-19 Nucleic Acid Testing/methods ; COVID-19 Testing/methods ; *Nasopharynx/virology ; Nose/virology ; *Point-of-Care Testing ; Prospective Studies ; *SARS-CoV-2/isolation & purification/genetics ; Sensitivity and Specificity ; Specimen Handling/methods ; United States ; }, abstract = {UNLABELLED: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues its largely aseasonal spread with millions of cases per year. Highly sensitive, point-of-care testing is critical for rapid detection of coronavirus disease 2019 (COVID-19) cases and initiation of antiviral therapy to avert adverse health outcomes and reduce onward transmission of the virus. While hundreds of COVID-19 diagnostics received emergency use authorization from the FDA during the pandemic, significantly fewer have navigated the course to FDA clearance or approval. Here, we determined the clinical performance of the Cepheid Xpert Xpress CoV-2 plus for detection of SARS-CoV-2 in 3,750 anterior nasal swab (NS) specimens and nasopharyngeal swab (NPS) from 32 sites in comparison to the FDA-authorized BioFire Respiratory Panel 2.1. Three-quarters of specimens collected were tested on the Xpert Xpress CoV-2 plus in the point-of-care setting. Overall positive percent agreement (PPA) was 98.1% (95% CI: 96.7%-98.9%) and negative percent agreement (NPA) was 98.3% (97.7%-98.7%). Performance of the Xpert Xpress CoV-2 plus was slightly improved in NS compared to NPS specimens, with PPA of 99.3% versus 97.0% (Fisher's exact test, P = 0.06) and NPA of 98.3% versus 98.2% (P = 0.89), respectively. Assay PPA was similar between untrained and trained users (98.7% vs 97.3%, P = 0.75), while NPA was slightly improved for untrained users (99.0% vs 97.6%, P = 0.0003). This study showed that Cepheid Xpert Xpress COV-2 plus is highly sensitive and specific/has high PPA and NPA for detection of SARS-CoV-2 from both NS and NPS specimens.
IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause millions of infections and tens of thousands of deaths per year in the United States. While the FDA authorized hundreds of SARS-CoV-2 tests during the public health emergency, significantly fewer have made the transition to being cleared or approved. There continues to be a need for FDA-authorized point-of-care SARS-CoV-2 testing that can be performed by untrained users. We conducted a large prospective study of the Cepheid Xpert Xpress CoV-2 plus test for detection of SARS-CoV-2 in both nasal and nasopharyngeal swabs by trained and untrained users. The assay demonstrated excellent clinical performance characteristics and, as a result of this study, was cleared by the FDA.}, }
@article {pmid39499893, year = {2024}, author = {Iyer, G and Tangen, CM and Sarfaty, M and Regazzi, AM and Lee, IL and Fong, M and Choi, W and Dinney, CPN and Flaig, TW and Thompson, IM and Lerner, SP and McConkey, DJ and Rosenberg, JE}, title = {DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400287}, pmid = {39499893}, issn = {2473-4284}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy/genetics/pathology ; Male ; Female ; *Neoadjuvant Therapy ; Middle Aged ; Aged ; *DNA Damage ; Xeroderma Pigmentosum Group D Protein/genetics ; Cisplatin/therapeutic use ; Neoplasm Invasiveness ; Adult ; }, abstract = {PURPOSE: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.
METHODS: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to
RESULTS: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for
CONCLUSION: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.}, }
@article {pmid39498208, year = {2024}, author = {Hyde, ET and Nguyen, S and LaMonte, MJ and Di, C and Bellettiere, J and Tinker, LF and Foraker, RE and Tindle, HA and Stefanick, ML and LaCroix, AZ}, title = {Influence of physical activity measurement on the association between Life's Essential 8 and incident cardiovascular disease in older women.}, journal = {Preventive medicine reports}, volume = {47}, number = {}, pages = {102904}, pmid = {39498208}, issn = {2211-3355}, support = {T32 HL079891/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: The American Heart Association's Life's Essential 8 (LE8) metric includes self-reported physical activity as one of the metrics for assessing cardiovascular health. Self-reported physical activity is prone to misclassification, whereas accelerometer measures are less biased. We examined associations of LE8 and incident cardiovascular disease (CVD) using self-reported and accelerometer-measured physical activity.
METHODS: Participants in the Women's Health Initiative (WHI) Objective Physical Activity and Cardiovascular Health Study (n = 4,243; mean age = 79 ± 7 years) with no CVD history completed the WHI physical activity questionnaire and the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire prior to wearing a hip-worn accelerometer for up to seven days in 2012-2014. LE8 components (physical activity, diet, sleep, body mass index, smoking, blood pressure, non-HDL cholesterol, and glucose) were scored according to guidelines. Scores were created using five physical activity measures: WHI questionnaire (LE8WHI), CHAMPS (LE8CHAMPS), accelerometer-measured physical activity (LE8A), and sample quantiles of accelerometer-measured physical activity (LE8AQ) and daily steps (LE8STEPS). Hazard ratios (HR) for physician-adjudicated CVD were estimated using Cox regression.
RESULTS: 707 incident CVD events occurred over an average 7.5 years. Multivariable HRs (95 % CI) comparing women in the highest vs. lowest quartiles of LE8 scores were: LE8WHI = 0.53 (0.43-0.67), LE8CHAMPS = 0.47 (0.38-0.60), LE8A = 0.44 (0.36-0.56), LE8AQ = 0.44 (0.35-0.55), and LE8STEPS = 0.45 (0.35-0.57).
CONCLUSIONS: The LE8-incident CVD association varies by physical activity measurement, however all methods showed reduced risk. Device-measures of physical activity may be more accurate in the LE8, but when impractical to implement, also support use of self-reported measures.}, }
@article {pmid39495136, year = {2024}, author = {Singal, AG and Parikh, ND and Kanwal, F and Marrero, JA and Deodhar, S and Page-Lester, S and Lopez, C and Feng, Z and Tayob, N}, title = {National Liver Cancer Screening Trial (TRACER) study protocol.}, journal = {Hepatology communications}, volume = {8}, number = {11}, pages = {}, pmid = {39495136}, issn = {2471-254X}, support = {U01 CA271887/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; alpha-Fetoproteins/analysis ; Biomarkers, Tumor/blood ; Carcinoma, Hepatocellular/diagnosis/blood/diagnostic imaging ; *Early Detection of Cancer/methods ; Hepatitis B, Chronic/diagnosis/blood ; Liver Cirrhosis/blood/diagnosis/diagnostic imaging ; *Liver Neoplasms/diagnosis/blood/diagnostic imaging ; Pragmatic Clinical Trials as Topic ; Protein Precursors/blood ; Prothrombin/analysis ; Ultrasonography ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase IV as Topic ; }, abstract = {BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice.
METHODS: The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5.
DISCUSSION: The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel.
TRIAL REGISTRATION: NCT06084234.
TRIAL STATUS: The TRACER Study is actively enrolling.}, }
@article {pmid39493537, year = {2024}, author = {Colquhoun, R and O'Toole, Á and Hill, V and McCrone, JT and Yu, X and Nicholls, SM and Poplawski, R and Whalley, T and Groves, N and Ellaby, N and Loman, N and Connor, T and Rambaut, A}, title = {A phylogenetics and variant calling pipeline to support SARS-CoV-2 genomic epidemiology in the UK.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae083}, pmid = {39493537}, issn = {2057-1577}, support = {MR/L015080/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {In response to the escalating SARS-CoV-2 pandemic, in March 2020 the COVID-19 Genomics UK (COG-UK) consortium was established to enable national-scale genomic surveillance in the UK. By the end of 2020, 49% of all SARS-CoV-2 genome sequences globally had been generated as part of the COG-UK programme, and to date, this system has generated >3 million SARS-CoV-2 genomes. Rapidly and reliably analysing this unprecedented number of genomes was an enormous challenge. To fulfil this need and to inform public health decision-making, we developed a centralized pipeline that performs quality control, alignment, and variant calling and provides the global phylogenetic context of sequences. We present this pipeline and describe how we tailored it as the pandemic progressed to scale with the increasing amounts of data and to provide the most relevant analyses on a daily basis.}, }
@article {pmid39492698, year = {2024}, author = {Heldman, MR and Boeckh, MJ and Limaye, AP}, title = {Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae535}, pmid = {39492698}, issn = {1537-6591}, abstract = {Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.}, }
@article {pmid39490766, year = {2024}, author = {Bricker, JB and Sullivan, BM and Mull, KE and Lavista-Ferres, J and Santiago-Torres, M}, title = {Efficacy of a conversational chatbot for cigarette smoking cessation: Protocol of the QuitBot full-scale randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107727}, pmid = {39490766}, issn = {1559-2030}, support = {R01 CA247156/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Cigarette Smoking/therapy/psychology ; Communication ; Counseling/methods ; *Motivation ; *Smoking Cessation/methods/psychology ; *Text Messaging ; Randomized Controlled Trials as Topic ; }, abstract = {Globally, cigarette smoking results in over 8 million premature annual deaths. Addressing this issue requires high-impact, cost-effective population-level interventions for smoking cessation. Conversational chatbots offer a potential solution given the recent advancements in machine learning and large language models. Chatbots can deliver supportive, empathetic behaviors, personalized responses, and timely advice tailored to users' needs that is engaging through therapeutic conversations aimed at creating lasting social-emotional connections. Despite their promise, little is known about the efficacy and underlying mechanisms of chatbots for cigarette smoking cessation. We developed QuitBot, a quit smoking program of two to three-minute conversations covering topics ranging from motivations to quit, setting a quit date, choosing cessation medications, coping with triggers, maintaining abstinence, and recovering from a relapse. QuitBot employs conversational interactions, powered by an expert-curated large language model, allowing users to ask questions and receive personalized guidance on quitting smoking. Here, we report the design and execution of a randomized clinical trial comparing QuitBot (n = 760) against Smokefree TXT (SFT) text messaging program (n = 760), with a 12-month follow-up period. Both interventions include 42-days of content on motivations to quit, skills to cope with triggers, and relapse prevention. The key distinction between QuitBot and SFT is that QuitBot has communication and engagement features. This study aims to determine: whether QuitBot yields higher quit rates than SFT; and whether therapeutic alliance processes and engagement are mechanisms underlying cessation outcomes. Additionally, we will explore whether baseline factors including trust, social support, and demographics, moderate the efficacy of QuitBot. Trial Registration numberClinicalTrials.govNCT04308759.}, }
@article {pmid39490125, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {A Winding Road to Health Care Equity in Sickle Cell Disease.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {693-704}, doi = {10.1016/j.cll.2024.07.005}, pmid = {39490125}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; Health Equity ; Health Services Accessibility ; Healthcare Disparities ; }, abstract = {Sickle cell disease (SCD) is a genetic disorder where red blood cells sickle, causing anemia and pain. Historically linked to marginalized groups, SCD saw little progress in treatment strategies for decades. Addressing these requires holistic strategies including dedicated centers, education, patient inclusion, and tackling implicit bias. Efforts must ensure treatments are accessible and stigma-free. Progress depends on collaboration and advocacy, aiming for an equitable, patient-focused health care system responsive to the unique needs of those with SCD. This review illustrates the actionable steps that the medical community can take to improve care for patients with SCD.}, }
@article {pmid39490124, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {History, Advances, and Challenges of Sickle Cell Disease Treatment.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {679-691}, doi = {10.1016/j.cll.2024.07.004}, pmid = {39490124}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; *Genetic Therapy ; Antisickling Agents/therapeutic use ; History, 20th Century ; History, 21st Century ; }, abstract = {Sickle cell disease (SCD) is marked by red blood cells that deform into a sickle shape, causing severe health complications. Historic neglect and slow therapeutic progress have left many, especially African descendants, vulnerable. Recent treatment strides include novel drugs and gene therapy, promising improved management. Nonetheless, challenges persist with treatment adoption because of cost, adverse effects, and accessibility. Advancements hold hope for enhanced life quality and longevity for SCD patients.}, }
@article {pmid39489920, year = {2024}, author = {Li, C and Georgakopoulou, A and Paschoudi, K and Anderson, AK and Huang, L and Gil, S and Giannaki, M and Vlachaki, E and Newby, GA and Liu, DR and Yannaki, E and Kiem, HP and Lieber, A}, title = {Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {12}, pages = {4353-4371}, pmid = {39489920}, issn = {1525-0024}, support = {R01 AI174304/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Anemia, Sickle Cell/therapy/genetics ; *Gene Editing/methods ; Mice ; *Genetic Vectors/genetics/administration & dosage ; *Disease Models, Animal ; *Hematopoietic Stem Cells/metabolism ; Humans ; *Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation/methods ; Mutation ; Adenoviridae/genetics ; Hemoglobin, Sickle/genetics ; Transduction, Genetic ; CRISPR-Cas Systems ; }, abstract = {Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.}, }
@article {pmid39487536, year = {2024}, author = {Patty, BJ and Jordan, C and Lardo, SM and Troy, K and Hainer, SJ}, title = {H3.3K122A results in a neomorphic phenotype in mouse embryonic stem cells.}, journal = {Epigenetics & chromatin}, volume = {17}, number = {1}, pages = {32}, pmid = {39487536}, issn = {1756-8935}, support = {R35 GM133732/GM/NIGMS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; R35GM133732/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Histones/metabolism ; Mice ; *Mouse Embryonic Stem Cells/metabolism/cytology ; *Phenotype ; Cell Differentiation ; Protein Processing, Post-Translational ; Acetylation ; }, abstract = {Canonical histone H3 and histone variant H3.3 are posttranslationally modified with the genomic distribution of these marks denoting different features and these modifications may influence transcription. While the majority of posttranslational modifications occur on histone tails, there are defined modifications within the globular domain, such as acetylation of H3K122/H3.3K122. To understand the function of the amino acid H3.3K122 in transcriptional regulation, we attempted to generate H3.3K122A mouse embryonic stem (mES) cells but were unsuccessful. Through multi-omic profiling of mutant cell lines harboring two or three of four H3.3 targeted alleles, we have uncovered that H3.3K122A is neomorphic and results in lethality. This is surprising as prior studies demonstrate H3.3-null mES cells are viable and pluripotent but exhibit a reduced differentiation capacity. Together, these studies have uncovered a novel dependence of a globular domain residue within H3.3 for viability and broadened our understanding of how histone variants contribute to transcription regulation and pluripotency in mES cells.}, }
@article {pmid39484623, year = {2024}, author = {Jagota, M and Hsu, C and Mazumder, T and Sung, K and DeWitt, WS and Listgarten, J and Matsen, FA and Ye, CJ and Song, YS}, title = {Learning antibody sequence constraints from allelic inclusion.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484623}, issn = {2692-8205}, support = {R35 GM134922/GM/NIGMS NIH HHS/United States ; }, abstract = {Antibodies and B-cell receptors (BCRs) are produced by B cells, and are built of a heavy chain and a light chain. Although each B cell could express two different heavy chains and four different light chains, usually only a unique pair of heavy chain and light chain is expressed-a phenomenon known as allelic exclusion. However, a small fraction of naive-B cells violate allelic exclusion by expressing two productive light chains, one of which has impaired function; this has been called allelic inclusion. We demonstrate that these B cells can be used to learn constraints on antibody sequence. Using large-scale single-cell sequencing data from humans, we find examples of light chain allelic inclusion in thousands of naive-B cells, which is an order of magnitude larger than existing datasets. We train machine learning models to identify the abnormal sequences in these cells. The resulting models correlate with antibody properties that they were not trained on, including polyreactivity, surface expression, and mutation usage in affinity maturation. These correlations are larger than what is achieved by existing antibody modeling approaches, indicating that allelic inclusion data contains useful new information. We also investigate the impact of similar selection forces on the heavy chain in mouse, and observe that pairing with the surrogate light chain significantly restricts heavy chain diversity.}, }
@article {pmid39484446, year = {2024}, author = {, and Dekker, J and Oksuz, BA and Zhang, Y and Wang, Y and Minsk, MK and Kuang, S and Yang, L and Gibcus, JH and Krietenstein, N and Rando, OJ and Xu, J and Janssens, DH and Henikoff, S and Kukalev, A and Willemin, A and Winick-Ng, W and Kempfer, R and Pombo, A and Yu, M and Kumar, P and Zhang, L and Belmont, AS and Sasaki, T and van Schaik, T and Brueckner, L and Peric-Hupkes, D and van Steensel, B and Wang, P and Chai, H and Kim, M and Ruan, Y and Zhang, R and Quinodoz, SA and Bhat, P and Guttman, M and Zhao, W and Chien, S and Liu, Y and Venev, SV and Plewczynski, D and Azcarate, II and Szabó, D and Thieme, CJ and Szczepińska, T and Chiliński, M and Sengupta, K and Conte, M and Esposito, A and Abraham, A and Zhang, R and Wang, Y and Wen, X and Wu, Q and Yang, Y and Liu, J and Boninsegna, L and Yildirim, A and Zhan, Y and Chiariello, AM and Bianco, S and Lee, L and Hu, M and Li, Y and Barnett, RJ and Cook, AL and Emerson, DJ and Marchal, C and Zhao, P and Park, P and Alver, BH and Schroeder, A and Navelkar, R and Bakker, C and Ronchetti, W and Ehmsen, S and Veit, A and Gehlenborg, N and Wang, T and Li, D and Wang, X and Nicodemi, M and Ren, B and Zhong, S and Phillips-Cremins, JE and Gilbert, DM and Pollard, KS and Alber, F and Ma, J and Noble, WS and Yue, F}, title = {An integrated view of the structure and function of the human 4D nucleome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484446}, issn = {2692-8205}, support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; U01 CA200147/CA/NCI NIH HHS/United States ; UM1 HG011593/HG/NHGRI NIH HHS/United States ; U01 HL130007/HL/NHLBI NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA052769/DA/NIDA NIH HHS/United States ; U01 DA040612/DA/NIDA NIH HHS/United States ; U01 DK127420/DK/NIDDK NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; U01 CA200059/CA/NCI NIH HHS/United States ; U01 HL157989/HL/NHLBI NIH HHS/United States ; }, abstract = {The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.}, }
@article {pmid39484284, year = {2024}, author = {Violari, A and Otwombe, K and Hahn, W and Chen, S and Josipovic, D and Baba, V and Angelidou, A and Smolen, KK and Levy, O and Mkhize, NN and Woodward, AS and Martin, TM and Haynes, B and Williams, WB and Sagawa, ZK and Kublin, J and Polakowski, L and Isaacs, MB and Yen, C and Tomaras, G and Corey, L and Janes, H and Gray, G}, title = {Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484284}, support = {K08 AI168487/AI/NIAID NIH HHS/United States ; U19 AI168643/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; HHSN272201800047C/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.
METHODS: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.
RESULTS: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.
CONCLUSIONS: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04607408.
FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).}, }
@article {pmid39486411, year = {2024}, author = {Davar, D and Morrison, RM and Dzutsev, AK and Karunamurthy, A and Chauvin, JM and Amatore, F and Deutsch, JS and Das Neves, RX and Rodrigues, RR and McCulloch, JA and Wang, H and Hartman, DJ and Badger, JH and Fernandes, MR and Bai, Y and Sun, J and Cole, AM and Aggarwal, P and Fang, JR and Deitrick, C and Bao, R and Duvvuri, U and Sridharan, SS and Kim, SW and A Choudry, H and Holtzman, MP and Pingpank, JF and O'Toole, JP and DeBlasio, R and Jin, Y and Ding, Q and Gao, W and Groetsch, C and Pagliano, O and Rose, A and Urban, C and Singh, J and Divarkar, P and Mauro, D and Bobilev, D and Wooldridge, J and Krieg, AM and Fury, MG and Whiteaker, JR and Zhao, L and Paulovich, AG and Najjar, YG and Luke, JJ and Kirkwood, JM and Taube, JM and Park, HJ and Trinchieri, G and Zarour, HM}, title = {Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial.}, journal = {Cancer cell}, volume = {42}, number = {11}, pages = {1898-1918.e12}, pmid = {39486411}, issn = {1878-3686}, support = {P50 CA254865/CA/NCI NIH HHS/United States ; R01 CA257265/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA222203/CA/NCI NIH HHS/United States ; U01 CA268806/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/immunology/genetics ; *Nivolumab/administration & dosage/therapeutic use ; Male ; Female ; Middle Aged ; *Neoadjuvant Therapy/methods ; Prospective Studies ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; Adult ; Lymphocytes, Tumor-Infiltrating/immunology/drug effects ; Tumor Microenvironment/immunology/drug effects ; Gastrointestinal Microbiome/drug effects ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/administration & dosage ; }, abstract = {Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8[+] tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67[+]CD8[+] T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.}, }
@article {pmid39486408, year = {2024}, author = {Borda, V and Loesch, DP and Guo, B and Laboulaye, R and Veliz-Otani, D and French, JN and Leal, TP and Gogarten, SM and Ikpe, S and Gouveia, MH and Mendes, M and Abecasis, GR and Alvim, I and Arboleda-Bustos, CE and Arboleda, G and Arboleda, H and Barreto, ML and Barwick, L and Bezzera, MA and Blangero, J and Borges, V and Caceres, O and Cai, J and Chana-Cuevas, P and Chen, Z and Custer, B and Dean, M and Dinardo, C and Domingos, I and Duggirala, R and Dieguez, E and Fernandez, W and Ferraz, HB and Gilliland, F and Guio, H and Horta, B and Curran, JE and Johnsen, JM and Kaplan, RC and Kelly, S and Kenny, EE and Konkle, BA and Kooperberg, C and Lescano, A and Lima-Costa, MF and Loos, RJF and Manichaikul, A and Meyers, DA and Naslavsky, MS and Nickerson, DA and North, KE and Padilla, C and Preuss, M and Raggio, V and Reiner, AP and Rich, SS and Rieder, CR and Rienstra, M and Rotter, JI and Rundek, T and Sacco, RL and Sanchez, C and Sankaran, VG and Santos-Lobato, BL and Schumacher-Schuh, AF and Scliar, MO and Silverman, EK and Sofer, T and Lasky-Su, J and Tumas, V and Weiss, ST and , and , and , and Mata, IF and Hernandez, RD and Tarazona-Santos, E and O'Connor, TD}, title = {Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100692}, pmid = {39486408}, issn = {2666-979X}, support = {R01 HL105756/HL/NHLBI NIH HHS/United States ; R56 NS029993/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Latin America ; *Genetics, Population ; Genome-Wide Association Study ; Haplotypes ; Algorithms ; Genetic Variation/genetics ; Software ; }, abstract = {Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.}, }
@article {pmid39486012, year = {2025}, author = {Dubois, MM and Jao, J and Sun, S and Legbedze, J and Schenkel, S and Mmasa, N and Kgole, SW and Masasa, G and Happel, AU and Iwase, SC and Haghighat, R and Moyo, S and Sharma, TS and Edlefsen, PT and Shao, D and Jaspan, H and Powis, KM}, title = {Infectious Morbidity and All-cause Mortality of Infants HIV-exposed Uninfected Compared to Infants HIV-unexposed Uninfected in Botswana.}, journal = {The Pediatric infectious disease journal}, volume = {44}, number = {3}, pages = {214-216}, pmid = {39486012}, issn = {1532-0987}, support = {R01 AI142670/AI/NIAID NIH HHS/United States ; R01 DK109881/DK/NIDDK NIH HHS/United States ; T32 AI007433/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Botswana/epidemiology ; *HIV Infections/epidemiology/mortality/transmission ; Infant ; Retrospective Studies ; Female ; Male ; Infant, Newborn ; Hospitalization/statistics & numerical data ; Pregnancy ; *Infectious Disease Transmission, Vertical ; Prevalence ; Morbidity ; }, abstract = {Some studies have reported increased infectious morbidity and all-cause mortality risk among infants HIV-exposed uninfected compared with infants HIV-unexposed uninfected. In a retrospective analysis of infants enrolled in the Botswana-based Tshilo Dikotla study, we found no difference in the prevalence of infectious hospitalizations or deaths from any cause in the first year of life by perinatal HIV exposure.}, }
@article {pmid39485483, year = {2025}, author = {Roberti, S and van Leeuwen, FE and Diallo, I and de Vathaire, F and Schaapveld, M and Leisenring, WM and Howell, RM and Armstrong, GT and Moskowitz, CS and Smith, SA and Aleman, BMP and Krul, IM and Russell, NS and Pfeiffer, RM and Hauptmann, M}, title = {Prediction of breast cancer risk for adolescents and young adults with Hodgkin lymphoma.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {4}, pages = {619-628}, pmid = {39485483}, issn = {1460-2105}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; KWF10004//Dutch Cancer Society/ ; /CA/NCI NIH HHS/United States ; //NIH/ ; //The Childhood Cancer Survivor Study/ ; CA55727/CA/NCI NIH HHS/United States ; //Childhood Cancer Survivor Study/ ; //St Jude Children's Research Hospital/ ; CA21765//Cancer Center Support/ ; //American Lebanese-Syrian Associated Charities/ ; }, mesh = {Humans ; Female ; *Hodgkin Disease/radiotherapy/epidemiology/complications ; *Breast Neoplasms/epidemiology/etiology ; Adolescent ; Adult ; Young Adult ; Child ; Risk Assessment ; Netherlands/epidemiology ; Risk Factors ; Incidence ; *Neoplasms, Radiation-Induced/epidemiology/etiology ; *Breast/radiation effects ; Age Factors ; Cancer Survivors ; }, abstract = {BACKGROUND: Although female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses.
METHODS: Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch 5-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to 10 breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, and ages at menopause and first live birth. Models were independently validated using US Childhood Cancer Survivor Study cohort participants.
RESULTS: Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24 with less than 10 Gy mean breast radiation dose and who were menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, with at least 25 Gy mean breast dose and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific dose model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively.
CONCLUSION: Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making.}, }
@article {pmid39485274, year = {2025}, author = {Larson, JD and Heitkamp, NA and Murray, LE and Popchock, AR and Biggins, S and Asbury, CL}, title = {Kinetochores grip microtubules with directionally asymmetric strength.}, journal = {The Journal of cell biology}, volume = {224}, number = {1}, pages = {}, pmid = {39485274}, issn = {1540-8140}, support = {F32 GM136010/GM/NIGMS NIH HHS/United States ; T32HL007312/NH/NIH HHS/United States ; T32 HL007312/HL/NHLBI NIH HHS/United States ; R01 GM079373/GM/NIGMS NIH HHS/United States ; //University of Washington/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM064386/GM/NIGMS NIH HHS/United States ; //Washington Research Foundation/ ; R35 GM134842/GM/NIGMS NIH HHS/United States ; }, mesh = {*Kinetochores/metabolism ; *Microtubules/metabolism ; Humans ; *Mitosis ; Saccharomyces cerevisiae/metabolism/genetics ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Chromosome Segregation ; HeLa Cells ; }, abstract = {For accurate mitosis, all chromosomes must achieve "biorientation," with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends through a trial-and-error process; accurate biorientation depends on the selective release of erroneous attachments. Proposed mechanisms for error-correction have focused mainly on plus-end attachments. Whether erroneous side attachments are distinguished from correct side attachments is unknown. Here, we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping sixfold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip is conserved in human and yeast subcomplexes, and it correlates with changes in the axial arrangement of subcomplexes within the kinetochore, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore's directional grip promotes accuracy during early mitosis by stabilizing correct attachments even before both sisters have found plus ends.}, }
@article {pmid39485107, year = {2025}, author = {Loroña, NC and Othus, M and Malone, KE and Linden, HM and Tang, MC and Li, CI}, title = {Metabolic Syndrome and Risks of Breast Cancer Outcomes for Luminal, Triple-Negative, and HER2-Overexpressing Subtypes.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {1}, pages = {117-124}, pmid = {39485107}, issn = {1538-7755}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; 261201000029C//National Cancer Institute (NCI)/ ; HHSN261201000029C/CA/NCI NIH HHS/United States ; T32CA009168//National Cancer Institute (NCI)/ ; BC112721//U.S. Department of Defense (DOD)/ ; }, mesh = {Humans ; Female ; Middle Aged ; *Metabolic Syndrome/complications/epidemiology/metabolism ; Adult ; Aged ; Prospective Studies ; *Receptor, ErbB-2/metabolism ; *Breast Neoplasms/mortality/pathology/metabolism ; Risk Factors ; Triple Negative Breast Neoplasms/mortality/pathology/metabolism ; Receptors, Progesterone/metabolism ; Young Adult ; Receptors, Estrogen/metabolism ; Neoplasm Recurrence, Local/epidemiology ; }, abstract = {BACKGROUND: We evaluated the association between metabolic syndrome (MetS; obesity plus two metabolic risk factors) and breast cancer outcomes according to molecular subtype.
METHODS: This population-based prospective cohort consisted of 3,267 women ages 20 to 69 years diagnosed with a first primary invasive breast cancer from 2004 to 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor, and HER2 expression: luminal (ER+), triple-negative (ER-/progesterone receptor negative/HER2-), and HER2-overexpressing (H2E; ER-/HER2+) subtypes. We used time-varying Cox models to assess the association of prevalent and incident MetS with risks of recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality (ACM).
RESULTS: MetS was associated with a greater risk of recurrence [HR, 3.24; 95% confidence interval (CI), 1.13-9.33] and BCSM (HR, 5.34; 95% CI, 2.32-12.31) only for the H2E subtype and greater risks of ACM for luminal (HR, 1.92; 95% CI, 1.37-2.68), H2E (HR, 5.09; 95% CI, 2.51-10.32), and all cases combined (HR, 1.90; 95% CI, 1.42-2.53). We also observed heterogeneity in recurrence and mortality outcomes across specific components of MetS and molecular subtypes.
CONCLUSIONS: MetS is associated with ACM among women with breast cancer and with BCSM among women with the H2E subtype.
IMPACT: These results highlight the importance of managing comorbidities to decrease the risk for adverse outcomes among breast cancer survivors.}, }
@article {pmid39479331, year = {2024}, author = {Armenian, SH and Hudson, MM and Lindenfeld, L and Chen, S and Chow, EJ and Colan, S and Echevarria, M and Wong, FL and Chen, MH and Bhatia, S}, title = {Carvedilol to Improve Cardiac Remodeling in Anthracycline-Exposed Childhood Cancer Survivors: Subgroup Analysis of COG ALTE1621.}, journal = {JACC. CardioOncology}, volume = {6}, number = {5}, pages = {791-793}, pmid = {39479331}, issn = {2666-0873}, support = {R01 CA196854/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; K12 CA001727/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, }
@article {pmid39478506, year = {2024}, author = {Lynch, MM and Al-Marayaty, R and Obeidin, F and Alexiev, BA and Chen, EY and Viveiros, P and Schroeder, BA and Hudkins, K and Fan, TM and Redman, MW and Baker, KK and Jour, G and Cranmer, LD and Pollack, SM}, title = {B7-H3 is widely expressed in soft tissue sarcomas.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1336}, pmid = {39478506}, issn = {1471-2407}, support = {R01CA244872/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *B7 Antigens/metabolism ; *Sarcoma/metabolism/pathology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Immunohistochemistry ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.
PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.
RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.
CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.}, }
@article {pmid39478321, year = {2024}, author = {Dombrowski, JC and Donnell, D and Grabow, C and Cohen, SE and Cannon, CA and Brown, CE and Buchbinder, SP and Celum, C and Luetkemeyer, AF}, title = {Evidence-Informed Provision of Doxycycline Post-Exposure Prophylaxis for Prevention of Bacterial Sexually Transmitted Infections.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae527}, pmid = {39478321}, issn = {1537-6591}, support = {R01 AI143439/AI/NIAID NIH HHS/United States ; }, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces the risk of bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. In the United States, doxy-PEP is in an early stage of integration into clinical practice, and national guidelines for its use were recently released. The goal of this manuscript is to provide practical guidance for clinicians who are considering or currently prescribing doxy-PEP. We address five clinical questions using post hoc analyses of data from the DoxyPEP randomized controlled trial and discuss the potential implications and limitations of each question with the goal of informing clinical practice and implementation of doxy-PEP programs. The questions address patient eligibility criteria for doxy-PEP, the expected benefit and associated doxy-PEP doses for the average patient, the initial number of doses prescribed, and laboratory monitoring of persons taking doxy-PEP.}, }
@article {pmid39477498, year = {2024}, author = {Huang, RR and Zuo, C and Mona, CE and Holzgreve, A and Morrissey, C and Nelson, PS and Brady, L and True, L and Sisk, A and Czernin, J and Calais, J and Ye, H}, title = {FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {65}, number = {12}, pages = {1952-1958}, pmid = {39477498}, issn = {1535-5667}, mesh = {Aged ; Aged, 80 and over ; Humans ; Male ; Middle Aged ; *Antigens, Surface/metabolism ; *Endopeptidases ; Gelatinases/metabolism ; Gene Expression Regulation, Neoplastic ; *Glutamate Carboxypeptidase II/metabolism ; *Immunohistochemistry ; Membrane Proteins/metabolism ; Pilot Projects ; Positron-Emission Tomography ; *Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/metabolism/pathology ; *Serine Endopeptidases/metabolism ; Translational Research, Biomedical ; Clinical Trials, Phase I as Topic ; }, abstract = {Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [[68]Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.}, }
@article {pmid39475359, year = {2024}, author = {Fléchon, A and Morales-Barrera, R and Powles, T and Alva, A and Özgüroğlu, M and Csöszi, T and Loriot, Y and Rodriguez-Vida, A and Géczi, L and Cheng, SY and Fradet, Y and Oudard, S and Vulsteke, C and Gunduz, S and Mamtani, R and Yu, EY and Montesa Pino, A and Anido, U and Sendur, MAN and Gravis, G and Révész, J and Kostorov, V and Huillard, O and Ma, J and Rajasagi, M and Vajdi, A and Lunceford, J and Cristescu, R and Imai, K and Homet Moreno, B and Matsubara, N}, title = {Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {23}, pages = {5353-5364}, pmid = {39475359}, issn = {1557-3265}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/administration & dosage/therapeutic use ; *B7-H1 Antigen/genetics ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Mutation ; Female ; Male ; Aged ; Middle Aged ; Exome Sequencing ; Biomarkers, Tumor/genetics ; Carcinoma, Transitional Cell/drug therapy/genetics/pathology/mortality ; Urologic Neoplasms/drug therapy/genetics/pathology/mortality ; Urinary Bladder Neoplasms/drug therapy/genetics/pathology/mortality ; Antineoplastic Agents, Immunological/therapeutic use ; Aged, 80 and over ; }, abstract = {PURPOSE: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.
PATIENTS AND METHODS: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1).
RESULTS: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone.
CONCLUSIONS: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.}, }
@article {pmid39475323, year = {2024}, author = {Kessler, RC and Bossarte, RM and Hwang, I and Luedtke, A and Naifeh, JA and Nock, MK and Petukhova, M and Sadikova, E and Sampson, NA and Sverdrup, E and Zubizarreta, JR and Wager, S and Wagner, J and Stein, MB and Ursano, RJ}, title = {A prediction model for differential resilience to the effects of combat-related stressors in US army soldiers.}, journal = {International journal of methods in psychiatric research}, volume = {33}, number = {4}, pages = {e70006}, pmid = {39475323}, issn = {1557-0657}, support = {U01MH087981/MH/NIMH NIH HHS/United States ; HU0001-15-2-0004//U.S. Department of Defense/ ; U01MH087981//U.S. Army/ ; }, mesh = {Humans ; *Military Personnel/psychology ; *Resilience, Psychological ; Adult ; Male ; Female ; *Stress Disorders, Post-Traumatic/diagnosis ; United States ; Young Adult ; *Combat Disorders/diagnosis ; Follow-Up Studies ; Afghan Campaign 2001- ; Retrospective Studies ; Adolescent ; Stress, Psychological ; }, abstract = {OBJECTIVES: To develop a composite score for differential resilience to effects of combat-related stressors (CRS) on persistent DSM-IV post-traumatic stress disorder (PTSD) among US Army combat arms soldiers using survey data collected before deployment.
METHODS: A sample of n = 2542 US Army combat arms soldiers completed a survey shortly before deployment to Afghanistan and then again two to three and 8-9 months after redeployment. Retrospective self-reports were obtained about CRS. Precision treatment methods were used to determine whether differential resilience to persistent PTSD in the follow-up surveys could be developed from pre-deployment survey data in a 60% training sample and validated in a 40% test sample.
RESULTS: 40.8% of respondents experienced high CRS and 5.4% developed persistent PTSD. Significant test sample heterogeneity was found in resilience (t = 2.1, p = 0.032), with average treatment effect (ATE) of high CRS in the 20% least resilient soldiers of 17.1% (SE = 5.5%) compared to ATE = 3.8% (SE = 1.2%) in the remaining 80%. The most important predictors involved recent and lifetime pre-deployment distress disorders.
CONCLUSIONS: A reliable pre-deployment resilience score can be constructed to predict variation in the effects of high CRS on persistent PTSD among combat arms soldiers. Such a score could be used to target preventive interventions to reduce PTSD or other resilience-related outcomes.}, }
@article {pmid39474526, year = {2024}, author = {McCamy, W and Yousefiasl, M and Tretiakova, M and Jagtiani, M and Hall, E}, title = {Metastatic SMARCB1-Deficient Renal Medullary Carcinoma without Hemoglobinopathy with Durable and Dramatic Response to Pembrolizumab plus Lenvatinib: Case Report.}, journal = {Case reports in oncology}, volume = {17}, number = {1}, pages = {1025-1033}, pmid = {39474526}, issn = {1662-6575}, abstract = {INTRODUCTION: Renal medullary carcinoma (RMC) is a rare form of renal cell carcinoma (RCC) that is typically associated with a loss of function in SMARCB1 and diagnosis of sickle cell or other hemoglobinopathy. In rare cases, this disease can be seen in patients without hemoglobinopathy and is classified as "SMARCB1-deficient RMC without hemoglobinopathy" or referred to as "RCC unclassified with medullary phenotype" in some of the literature. Platinum-based cytotoxic chemotherapy is currently the recommended first-line treatment for this rare disease.
CASE PRESENTATION: Here we report a 53-year-old male who was diagnosed with metastatic SMARCB1-deficient RMC without hemoglobinopathy after presenting with left flank and abdominal pain. After initiating first-line pembrolizumab and lenvatinib systemic therapy, imaging showed regression at 6 weeks. To date, this patient continues to show a near complete response to this treatment regimen.
CONCLUSION: To our knowledge, this is the first documented case of SMARCB1-deficient RMC without hemoglobinopathy to receive this treatment regimen and show such a response.}, }
@article {pmid39473183, year = {2025}, author = {Rao, H and Weiss, MC and Moon, JY and Perreira, KM and Daviglus, ML and Kaplan, R and North, KE and Argos, M and Fernández-Rhodes, L and Sofer, T}, title = {Advancements in genetic research by the Hispanic Community Health Study/Study of Latinos: A 10-year retrospective review.}, journal = {HGG advances}, volume = {6}, number = {1}, pages = {100376}, pmid = {39473183}, issn = {2666-2477}, support = {R01 HL163262/HL/NHLBI NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; R01 HG013163/HG/NHGRI NIH HHS/United States ; F30 ES033510/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Hispanic or Latino/genetics ; Retrospective Studies ; *Genetic Research/ethics ; Longitudinal Studies ; United States ; Adult ; Female ; Male ; }, abstract = {The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, longitudinal cohort study designed to evaluate environmental, lifestyle, and genetic risk factors as they relate to cardiometabolic and other chronic diseases among Hispanic/Latino populations in the United States. Since the study's inception in 2008, as a result of the study's robust genetic measures, HCHS/SOL has facilitated major contributions to the field of genetic research. This 10-year retrospective review highlights the major findings for genotype-phenotype relationships and advancements in statistical methods owing to the HCHS/SOL. Furthermore, we discuss the ethical and societal challenges of genetic research, especially among Hispanic/Latino adults in the United States. Continued genetic research, ancillary study expansion, and consortia collaboration through HCHS/SOL will further drive knowledge and advancements in human genetics research.}, }
@article {pmid39472576, year = {2024}, author = {Janssens, DH and Duran, M and Otto, DJ and Wu, W and Xu, Y and Kirkey, D and Mullighan, CG and Yi, JS and Meshinchi, S and Sarthy, JF and Ahmad, K and Henikoff, S}, title = {MLL oncoprotein levels influence leukemia lineage identities.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9341}, pmid = {39472576}, issn = {2041-1723}, support = {Henikoff//Howard Hughes Medical Institute (HHMI)/ ; R01 HG010492/HG/NHGRI NIH HHS/United States ; Derek Janssens//Hartwell Foundation (The Hartwell Foundation)/ ; NCI R35 CA297695//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Mullighan//American Lebanese Syrian Associated Charities (ALSAC)/ ; }, mesh = {*Myeloid-Lymphoid Leukemia Protein/metabolism/genetics ; Humans ; *Leukemia, Myeloid, Acute/genetics/metabolism ; *Oncogene Proteins, Fusion/metabolism/genetics ; *Cell Lineage/genetics ; *Histone-Lysine N-Methyltransferase/metabolism/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism/pathology ; Gene Expression Regulation, Leukemic ; Proto-Oncogene Proteins/metabolism/genetics ; Mutation ; Translocation, Genetic ; Hematopoietic Stem Cells/metabolism ; Chromatin/metabolism ; }, abstract = {Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.}, }
@article {pmid39472320, year = {2024}, author = {Zhang, R and Bozic, I}, title = {Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer.}, journal = {Bulletin of mathematical biology}, volume = {86}, number = {12}, pages = {142}, pmid = {39472320}, issn = {1522-9602}, support = {DMS-2045166//National Science Foundation/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; *Disease Progression ; *Mutation ; *Mathematical Concepts ; *Oncogenes/genetics ; *Models, Genetic ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/pathology ; Neoplasms/genetics/pathology ; Carcinogenesis/genetics ; Mutation Accumulation ; Precancerous Conditions/genetics/pathology ; Computer Simulation ; }, abstract = {Cancers are typically fueled by sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in homeostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings.}, }
@article {pmid39472202, year = {2025}, author = {Oh, WK and Agarwal, N and Bryce, A and Barata, P and Bugler, C and Carlsson, SV and Cornell, B and Dahut, W and George, D and Loeb, S and Montgomery, B and Morris, D and Mucci, LA and Omlin, A and Palapattu, G and Riaz, IB and Ryan, C and Schoen, MW and Washington, SL and Gillessen, S}, title = {What's in a Name? Why Words Matter in Advanced Prostate Cancer.}, journal = {European urology}, volume = {87}, number = {2}, pages = {101-103}, doi = {10.1016/j.eururo.2024.10.017}, pmid = {39472202}, issn = {1873-7560}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/classification ; *Terminology as Topic ; }, abstract = {Much of the disease nomenclature used for patients with advanced prostate cancer has negative connotations and can be confusing or intimidating. Experts in the field convened to recommend a clearer and more accurate approach to defining the nomenclature.}, }
@article {pmid39470729, year = {2024}, author = {Nelson, BH and Hamilton, P and Phung, MT and Milne, K and Harris, B and Thornton, S and Stevens, D and Kalaria, S and Singh, K and Laumont, CM and Moss, E and Alimujiang, A and Meagher, NS and Bolithon, A and Fereday, S and Kennedy, CJ and Hendley, J and Ariyaratne, D and Alsop, K and Traficante, N and Goode, EL and Karnezis, A and Shen, H and Richardson, J and McKinnonDeurloo, C and Chase, A and Grout, B and Doherty, JA and Harris, HR and Cushing-Haugen, KL and Anglesio, M and Heinze, K and Huntsman, D and Talhouk, A and Hanley, GE and Alsop, J and Jimenez-Linan, M and Pharoah, PD and Boros, J and Brand, AH and Harnett, PR and Sharma, R and Hecht, JL and Sasamoto, N and Terry, KL and Karlan, B and Lester, J and Carney, ME and Goodman, MT and Hernandez, BY and Wilkens, LR and Behrens, S and Turzanski Fortner, R and Fasching, PA and Bisinotto, C and Candido Dos Reis, FJ and Ghatage, P and Köbel, M and Elishaev, E and Modugno, F and Cook, L and Le, N and Gentry-Maharaj, A and Menon, U and García, MJ and Rodriguez-Antona, C and Farrington, K and Kelemen, LE and Kommoss, S and Staebler, A and Garsed, DW and Brenton, JD and Piskorz, AM and Bowtell, DD and DeFazio, A and Ramus, SJ and Pike, MC and Pearce, CL}, title = {Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {24}, pages = {}, pmid = {39470729}, issn = {1558-8238}, support = {R21 CA267050/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; MC_UU_00004/01/MRC_/Medical Research Council/United Kingdom ; 10119/CRUK_/Cancer Research UK/United Kingdom ; UL1 TR001881/TR/NCATS NIH HHS/United States ; 10124/CRUK_/Cancer Research UK/United Kingdom ; P30 CA046592/CA/NCI NIH HHS/United States ; M01 RR000056/RR/NCRR NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Cancer Survivors ; CD8-Positive T-Lymphocytes/immunology/pathology ; Neoplasm Proteins/genetics/immunology/metabolism ; *Ovarian Neoplasms/immunology/pathology/genetics ; *Tumor Microenvironment/immunology ; }, abstract = {BACKGROUNDDespite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.METHODSWe evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.RESULTSPositive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8+ T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.CONCLUSIONThe tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy.FUNDINGOvarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.}, }
@article {pmid39470275, year = {2024}, author = {Piliper, EA and Reed, JC and Greninger, AL}, title = {Clinical validation of an RSV neutralization assay and analysis of cross-sectional sera associated with 2021-2023 RSV outbreaks to investigate the immunity debt hypothesis.}, journal = {Microbiology spectrum}, volume = {12}, number = {12}, pages = {e0211524}, pmid = {39470275}, issn = {2165-0497}, abstract = {UNLABELLED: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections and hospitalization in infants and the elderly. Newly approved vaccines and the prophylactic antibody nirsevimab have heightened interest in RSV immunologic surveillance, necessitating the development of high-throughput assays assessing anti-RSV neutralizing activity. Quantitative viral neutralization remains the best correlate of protection for RSV infection and the gold standard for RSV immunological testing. Here, we developed a high-throughput RSV strain A2 focus-reduction neutralization test validated to Clinical Laboratory Improvement Amendments (CLIA)/ Good Clinical Laboratory Practices (GCLP) standards using both clinical specimens and commercially available reference sera. The assay is highly accurate, generating reference serum neutralizing titers within twofold of established assays, with an analytical measurement range between 8 and 1,798 international units per mL (IU/mL). Neutralizing activity measured by the assay strongly correlated with antibody titer determined via indirect enzyme-linked immunosorbent assay (ELISA) (ρ = 1.0, P = 0.0014). Individuals recently having tested positive via quantitative reverse transcription polymerase chain reaction (RT-qPCR) for RSV had a 9.1-fold higher geometric mean neutralizing titer relative to RSV PCR negatives (P-value = 0.09). The validated assay was then used to investigate the immunity debt hypothesis for resurgent RSV outbreaks in the 2022-2023 season, using adult clinical remnant sera sent for herpes simplex virus (HSV)-1/2 antibody testing. There was no difference in geometric mean anti-RSV neutralizing titers between sera sampled before and after the 2022-2023 RSV outbreak (P = 0.68). These data are consistent with limited changes in RSV-neutralizing antibody levels in adults across the 2022-23 RSV outbreak.
IMPORTANCE: Population surveillance studies of serum-neutralizing activity against RSV are crucial for evaluating RSV vaccine efficacy and vulnerabilities to new strains. Here, we designed and validated a high-throughput assay for assessing anti-RSV neutralizing activity, standardized its measurements for comparison with other methodologies, and demonstrated its applicability to real-world samples. Our assay is precise, linear, and yields measurements consistent with other standardized assays, offering a methodology useful for large-scale studies of RSV immunity. We also find no significant difference in neutralizing titers among adults between those taken before and after large RSV outbreaks associated with the latter stages of the coronavirus disease of 2019 (COVID-19) public health emergency, underlining the need for a greater understanding of the dynamics of serological responses to RSV infection.}, }
@article {pmid39468273, year = {2024}, author = {Kim, D and Cooper, JA and Helfman, DM}, title = {Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25786}, pmid = {39468273}, issn = {2045-2322}, support = {NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; }, mesh = {Female ; Humans ; Breast/metabolism/pathology ; Breast Neoplasms/pathology/metabolism/genetics ; *Cell Movement ; Cellular Senescence ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Epithelial Cells/metabolism ; Intercellular Adhesion Molecule-1/metabolism/genetics ; *Myosin-Light-Chain Kinase/metabolism/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Senescence-Associated Secretory Phenotype ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Tumor Suppressor Protein p53/metabolism/genetics ; }, abstract = {Overexpression or activation of oncogenes or loss of tumor-suppressor genes can induce cellular senescence as a defense mechanism against tumor development, thereby maintaining cellular homeostasis. However, cancer cells can circumvent this senescent state and continue to spread. Myosin light chain kinase (MLCK) is downregulated in many breast cancers. Here we report that downregulation of MLCK in normal breast epithelial cells induces a senescence-associated secretory phenotype and stimulates migration. The reduction of MLCK results in increased p21[Cip1] expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21[Cip1] promotes the secretion of soluble ICAM-1, IL-1α, IL-6 and IL-8, thereby enhancing collective cell migration in a non-cell-autonomous manner. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression.}, }
@article {pmid39468212, year = {2024}, author = {Tsue, AF and Kania, EE and Lei, DQ and Fields, R and McGann, CD and Marciniak, DM and Hershberg, EA and Deng, X and Kihiu, M and Ong, SE and Disteche, CM and Kugel, S and Beliveau, BJ and Schweppe, DK and Shechner, DM}, title = {Multiomic characterization of RNA microenvironments by oligonucleotide-mediated proximity-interactome mapping.}, journal = {Nature methods}, volume = {21}, number = {11}, pages = {2058-2071}, pmid = {39468212}, issn = {1548-7105}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; R01 GM129090/GM/NIGMS NIH HHS/United States ; GM131745//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM137916/GM/NIGMS NIH HHS/United States ; S10OD021502//U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)/ ; T32HG000035//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; T32GM007750//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL160825/HL/NHLBI NIH HHS/United States ; 1R35GM137916//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R35GM150919-01//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01HL160825-01//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 902616//American Heart Association (American Heart Association, Inc.)/ ; UM1 HG011586/HG/NHGRI NIH HHS/United States ; R37CA241472//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; S10 OD016240/OD/NIH HHS/United States ; R01 GM138799/GM/NIGMS NIH HHS/United States ; DEB2016186//National Science Foundation (NSF)/ ; T32 HG000035/HG/NHGRI NIH HHS/United States ; 1R01GM138799-01//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM129090//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM150919/GM/NIGMS NIH HHS/United States ; UM1HG011586//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; T32 GM007750/GM/NIGMS NIH HHS/United States ; S10 OD021502/OD/NIH HHS/United States ; R35 GM131745/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *In Situ Hybridization, Fluorescence/methods ; Biotinylation ; Oligonucleotides/genetics/chemistry ; Humans ; RNA, Long Noncoding/genetics ; RNA/genetics/metabolism ; }, abstract = {RNA molecules form complex networks of molecular interactions that are central to their function and to cellular architecture. But these interaction networks are difficult to probe in situ. Here, we introduce Oligonucleotide-mediated proximity-interactome MAPping (O-MAP), a method for elucidating the biomolecules near an RNA of interest, within its native context. O-MAP uses RNA-fluorescence in situ hybridization-like oligonucleotide probes to deliver proximity-biotinylating enzymes to a target RNA in situ, enabling nearby molecules to be enriched by streptavidin pulldown. This induces exceptionally precise biotinylation that can be easily optimized and ported to new targets or sample types. Using the noncoding RNAs 47S, 7SK and Xist as models, we develop O-MAP workflows for discovering RNA-proximal proteins, transcripts and genomic loci, yielding a multiomic characterization of these RNAs' subcellular compartments and new regulatory interactions. O-MAP requires no genetic manipulation, uses exclusively off-the-shelf parts and requires orders of magnitude fewer cells than established methods, making it accessible to most laboratories.}, }
@article {pmid39466880, year = {2024}, author = {Ruiz, F and Foreman, WB and Lilly, M and Baharani, VA and Depierreux, DM and Chohan, V and Taylor, AL and Guenthoer, J and Ralph, D and Matsen Iv, FA and Chu, HY and Bieniasz, PD and Côté, M and Starr, TN and Overbaugh, J}, title = {Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses.}, journal = {PLoS pathogens}, volume = {20}, number = {10}, pages = {e1012650}, pmid = {39466880}, issn = {1553-7374}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; P01 AI165075/AI/NIAID NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; S10 OD021644/OD/NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, mesh = {*SARS-CoV-2/immunology ; *Cross Reactions/immunology ; *Antibodies, Viral/immunology ; Humans ; Animals ; *Spike Glycoprotein, Coronavirus/immunology ; *Antibodies, Neutralizing/immunology ; *COVID-19/immunology/virology ; Epitopes/immunology ; Mice ; Severe acute respiratory syndrome-related coronavirus/immunology ; Betacoronavirus/immunology ; }, abstract = {The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.}, }
@article {pmid39466048, year = {2025}, author = {Fogel, JM and Persaud, D and Piwowar-Manning, E and Richardson, P and Szewczyk, J and Marzinke, MA and Wang, Z and Guo, X and McCauley, M and Farrior, J and Tran, HV and Ungsedhapand, C and Mathew, CA and Mpendo, J and Rinehart, AR and Rooney, JF and Cohen, MS and Hanscom, B and Grinsztejn, B and Hosseinipour, MC and Delany-Moretlwe, S and Landovitz, RJ and Eshleman, SH and , }, title = {HIV DNA Levels in Persons Who Acquired HIV in the Setting of Long-Acting Cabotegravir for HIV Prevention: Analysis of Cases from HPTN 083 and 084.}, journal = {AIDS research and human retroviruses}, volume = {41}, number = {1}, pages = {30-36}, pmid = {39466048}, issn = {1931-8405}, mesh = {Humans ; *HIV Infections/drug therapy/prevention & control/virology ; Male ; Adult ; *Anti-HIV Agents/therapeutic use ; Female ; *Pyridones/therapeutic use ; *DNA, Viral/blood ; *Pre-Exposure Prophylaxis ; Leukocytes, Mononuclear/virology ; Viral Load ; Young Adult ; Tenofovir/therapeutic use ; Middle Aged ; Retrospective Studies ; Diketopiperazines ; }, abstract = {We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected
PATIENTS AND METHODS: Twenty-one patients with ROR1+ tumors received CAR-T cells at one of four dose levels: 3.3 × 105, 1 × 106, 3.3 × 106, and 1 × 107 cells/kg body weight, administered after lymphodepletion with cyclophosphamide/fludarabine or oxaliplatin/cyclophosphamide. Cohort A included patients with chronic lymphocytic leukemia (CLL, n = 3); cohort B included patients with triple-negative breast cancer (TNBC, n = 10) or non-small cell lung cancer (NSCLC, n = 8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.
RESULTS: Treatment was well tolerated, apart from one dose-limiting toxicity at dose level 4 in a patient with advanced NSCLC. Two of the three (67%) patients with CLL showed robust CAR-T-cell expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR-T cells expanded to variable levels and infiltrated tumors poorly and 1 of 18 patients (5.5%) achieved partial response by RECIST 1.1.
CONCLUSIONS: ROR1 CAR-T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations. See related commentary by Kobold, p. 437.}, }
@article {pmid39465550, year = {2025}, author = {O'Donnell, PH and Loriot, Y and Csoszi, T and Matsubara, N and Shin, SJ and Park, SH and Atduev, V and Gumus, M and Karaca, SB and Grivas, P and de Wit, R and Castellano, DE and Powles, T and Vuky, J and Zhao, Y and O'Hara, K and Okpara, CE and Franco, S and Homet Moreno, B and Żołnierek, J and Siefker-Radtke, AO}, title = {Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.}, journal = {Cancer}, volume = {131}, number = {1}, pages = {e35601}, pmid = {39465550}, issn = {1097-0142}, support = {//Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. (Rahway, New Jersey, USA)/ ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Urologic Neoplasms/drug therapy/pathology ; Carcinoma, Transitional Cell/drug therapy/pathology ; Adult ; Progression-Free Survival ; Urinary Bladder Neoplasms/drug therapy/pathology ; }, abstract = {BACKGROUND: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility.
METHODS: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety.
RESULTS: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n = 370) and LEAP-011 (n = 242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups.
CONCLUSIONS: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.}, }
@article {pmid39464162, year = {2024}, author = {Russell, ML and Trofimov, A and Bradley, P and Matsen, FA}, title = {Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464162}, issn = {2692-8205}, support = {S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology--short stretches of sequence homology between gene ends--can bias the recombination process, the extent of microhomology's impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCRα repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process.}, }
@article {pmid39464114, year = {2024}, author = {Bridge, J and Johnson, MJ and Kim, J and Wenthe, S and Krueger, J and Wick, B and Kluesner, M and Crane, AT and Bell, J and Skeate, JG and Moriarity, BS and Webber, BR}, title = {Efficient multiplex non-viral engineering and expansion of polyclonal γδ CAR-T cells for immunotherapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464114}, issn = {2692-8205}, support = {R01 AI161017/AI/NIAID NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; U24 OD026641/OD/NIH HHS/United States ; R21 CA237789/CA/NCI NIH HHS/United States ; U54 CA232561/CA/NCI NIH HHS/United States ; R21 AI163731/AI/NIAID NIH HHS/United States ; P01 CA254849/CA/NCI NIH HHS/United States ; R01 AI146009/AI/NIAID NIH HHS/United States ; U54 CA268069/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Gamma delta (γδ) T cells are defined by their unique ability to recognize a limited repertoire of non-peptide, non-MHC-associated antigens on transformed and pathogen-infected cells. In addition to their lack of alloreactivity, γδ T cells exhibit properties distinct from other lymphocyte subsets, prompting significant interest in their development as an off-the-shelf cellular immunotherapeutic. However, their low abundance in circulation, heterogeneity, limited methods for ex vivo expansion, and under-developed methodologies for genetic modification have hindered basic study and clinical application of γδ T cells. Here, we implement a feeder-free, scalable approach for ex vivo manufacture of polyclonal, non-virally modified, gene edited chimeric antigen receptor (CAR)-γδ T cells in support of therapeutic application. Engineered CAR-γδ T cells demonstrate high function in vitro and and in vivo. Longitudinal in vivo pharmacokinetic profiling of adoptively transferred polyclonal CAR-γδ T cells uncover subset-specific responses to IL-15 cytokine armoring and multiplex base editing. Our results present a robust platform for genetic modification of polyclonal CAR-γδ T cells and present unique opportunities to further define synergy and the contribution of discrete, engineered CAR-γδ T cell subsets to therapeutic efficacy in vivo.}, }
@article {pmid39462857, year = {2024}, author = {Panch, SR and Vassallo, RR and Adams, S and Borge, DP and Gammon, R and Gandhi, MJ and Philogene, M and Sullivan, HC and Wu, Y and Kopko, P}, title = {Management of human leukocyte antigen-mediated platelet transfusion refractoriness: Brief synopsis and recent literature review.}, journal = {Transfusion}, volume = {64}, number = {12}, pages = {2380-2390}, doi = {10.1111/trf.18036}, pmid = {39462857}, issn = {1537-2995}, }
@article {pmid39456570, year = {2024}, author = {Lim, SYT and Huo, J and Laszlo, GS and Cole, FM and Kehret, AR and Li, J and Lunn-Halbert, MC and Persicke, JL and Rupert, PB and Strong, RK and Walter, RB}, title = {Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders.}, journal = {Cancers}, volume = {16}, number = {20}, pages = {}, pmid = {39456570}, issn = {2072-6694}, support = {R21-AI150566//National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8[V-set]-directed T cell-engaging BiAbs and Siglec-8[V-set]-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8[C2-set] mAbs, Siglec-8[C2-set]-directed T cell-engaging BiAbs, and Siglec-8[C2-set]-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders.}, }
@article {pmid39454280, year = {2025}, author = {Pidala, J and Kim, J and Kalos, D and Cutler, C and DeFilipp, Z and Flowers, MED and Hamilton, BK and Chin, KK and Rotta, M and El Jurdi, N and Hamadani, M and Ahmed, G and Kitko, C and Ponce, D and Sung, A and Tang, H and Farhadfar, N and Nemecek, E and Pusic, I and Qayed, M and Rangarajan, H and Hogan, W and Etra, A and Jaglowski, S}, title = {Ibrutinib for therapy of steroid-refractory chronic graft-versus-host disease: a multicenter real-world analysis.}, journal = {Blood advances}, volume = {9}, number = {5}, pages = {1040-1048}, pmid = {39454280}, issn = {2473-9537}, mesh = {Humans ; *Graft vs Host Disease/drug therapy/mortality/etiology ; Male ; Female ; Middle Aged ; *Piperidines/therapeutic use ; Adult ; Chronic Disease ; *Adenine/analogs & derivatives/therapeutic use ; Retrospective Studies ; Aged ; *Pyrimidines/therapeutic use ; Treatment Outcome ; Hematopoietic Stem Cell Transplantation/adverse effects ; Young Adult ; }, abstract = {To examine the activity of ibrutinib in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) after the US Food and Drug Administration approval, we conducted a multicenter retrospective study. Data were standardly collected (N = 270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), gastrointestinal (GI) (26%), lung (27%), liver (19%), genital (7%), and others (4.4%). The National Institutes of Health (NIH) severity was mild in 5.7%, moderate 42%, and severe 53%. Thirty-nine percent had overlap subtype. Karnofsky performance status (KPS) was ≥80% in 72%. The median prednisone was 0.21 mg/kg (0-2.27). Ibrutinib was started at a median of 18.2 months after cGVHD onset and in earlier lines of therapy (second line, 26%; third, 30%; fourth, 21%; fifth, 9.6%; sixth, 10%; seventh or higher, 1.2%). Among evaluable patients, the 6-month NIH overall response rate (ORR; complete response [CR]/partial response [PR]) was 45% (PR 42%; CR 3%). The median duration of response was 15 months (range, 1-46). Liver involvement had association with 6-month ORR (multivariate [MVA] odds ratio, 5.49; 95% confidence interval [CI], 2.3-14.2; P < .001). The best overall response was 56%, with most (86%) achieving by 1 to 3 months. With a median follow-up for survivors of 30.5 months, failure-free survival (FFS) was 59% (53%-65%) at 6 months and 41% (36%-48%) at 12 months. On MVA, increased age (hazard ratio [HR], 1.01; 95% CI, 1.0-1.02; P = .033), higher baseline prednisone (HR, 1.92; 95% CI, 1.09-3.38; P = .032), and lung involvement (HR, 1.58; 95% CI, 1.1-2.28; P = .016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.}, }
@article {pmid39454232, year = {2024}, author = {, }, title = {Global, regional, and national burden of injuries, and burden attributable to injuries risk factors, 1990 to 2019: results from the Global Burden of Disease study 2019.}, journal = {Public health}, volume = {237}, number = {}, pages = {212-231}, doi = {10.1016/j.puhe.2024.06.011}, pmid = {39454232}, issn = {1476-5616}, mesh = {Humans ; *Global Burden of Disease/trends ; *Wounds and Injuries/epidemiology/mortality ; Risk Factors ; Male ; Female ; *Global Health/statistics & numerical data ; Adult ; Middle Aged ; *Disability-Adjusted Life Years ; Adolescent ; Young Adult ; Aged ; Child, Preschool ; Infant ; Child ; Cause of Death ; Incidence ; Cost of Illness ; }, abstract = {OBJECTIVES: In this study, the trends and current situation of the injury burden as well as attributable burden to injury risk factors at global, regional, and national levels based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 are presented.
STUDY DESIGN: To assess the attributable burden of injury risk factors, the data of interest on data sources were retrieved from the Global Health Data Exchange (GHDx) and analyzed.
METHODS: Cause-specific death from injuries was estimated using the Cause of Death Ensemble model in the GBD 2019. The burden attributable to each injury risk factor was incorporated in the population attributable fraction to estimate the total attributable deaths and disability-adjusted life years. The Socio-demographic Index (SDI) was used to evaluate countries' developmental status.
RESULTS: Globally, there were 713.9 million (95% uncertainty interval [UI]: 663.8 to 766.9) injuries incidence and 4.3 million (UI: 3.9 to 4.6) deaths caused by injuries in 2019. There was an inverse relationship between age-standardized disability-adjusted life year rate and SDI quintiles in 2019. Overall, low bone mineral density was the leading risk factor of injury deaths in 2019, with a contribution of 10.5% (UI: 9.0 to 11.6) of total injuries and age-standardized deaths, followed by occupational risks (7.0% [UI: 6.3-7.9]) and alcohol use (6.8% [UI: 5.2 to 8.5]).
CONCLUSION: Various risks were responsible for the imposed burden of injuries. This study highlighted the small but persistent share of injuries in the global burden of diseases and injuries to provide beneficial data to produce proper policies to reach an effective global injury prevention plan.}, }
@article {pmid39454203, year = {2025}, author = {Farhadfar, N and Lee, SJ}, title = {Racial and socioeconomic status diversity and GVHD outcomes.}, journal = {Blood advances}, volume = {9}, number = {3}, pages = {644}, pmid = {39454203}, issn = {2473-9537}, }
@article {pmid39454125, year = {2025}, author = {Mosher, CE and Lee, S and Addington, EL and Park, S and Lewson, AB and Snyder, S and Hirsh, AT and Bricker, JB and Miller, KD and Ballinger, TJ and Schneider, BP and Storniolo, AM and Newton, EV and Champion, VL and Johns, SA}, title = {Randomized Controlled Trial of Acceptance and Commitment Therapy for Fatigue Interference With Functioning in Metastatic Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {6}, pages = {662-671}, doi = {10.1200/JCO.24.00965}, pmid = {39454125}, issn = {1527-7755}, support = {R01 CA230542/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Fatigue/therapy/etiology/psychology ; *Breast Neoplasms/pathology/psychology/complications/therapy ; Middle Aged ; Quality of Life ; *Acceptance and Commitment Therapy/methods ; Aged ; Adult ; Activities of Daily Living ; Treatment Outcome ; Neoplasm Metastasis ; }, abstract = {PURPOSE: Fatigue is a highly prevalent and disabling symptom for patients with metastatic breast cancer (MBC). Evidence-based interventions for managing fatigue in advanced cancer populations are lacking. This phase II randomized controlled trial tested the effect of acceptance and commitment therapy (ACT) on fatigue interference with functioning in patients with MBC.
METHODS: Eligible patients were women with stage IV breast cancer who had moderate to severe fatigue interference. Patients completed a baseline assessment that included self-report measures of fatigue interference with activities, mood, and cognition (primary outcome) and sleep interference with functioning, engagement in daily activities, and quality of life (QOL; secondary outcomes). Then patients were randomly assigned to six weekly telephone-delivered sessions of either ACT (n = 116) or education/support (n = 120). Follow-up assessments occurred at 2 weeks, 3 months, and 6 months postintervention (means, 9.69, 20.51, and 33.59 weeks postbaseline, respectively).
RESULTS: Linear mixed model analyses showed that compared with patients in the education/support condition, patients in the ACT condition reported significantly less fatigue interference (P = .018). These results were significant at 2 weeks and 6 months postintervention. ACT's effect on sleep interference was not statistically significant after the Sidak adjustment for multiple comparisons (P = .037). ACT patients showed a steady decline in sleep interference, a trend that was not found for education/support patients. Engagement in daily activities and QOL did not significantly differ between study groups, except for functional QOL (P = .006). Compared with education/support patients, ACT patients showed significantly better functional QOL at 2 weeks and 6 months postintervention.
CONCLUSION: Results suggest that a brief, telephone-delivered ACT intervention can reduce fatigue interference with functioning in patients with MBC.}, }
@article {pmid39453463, year = {2025}, author = {Collienne, L and Barker, M and Suchard, MA and Matsen, FA}, title = {Phylogenetic Tree Instability After Taxon Addition: Empirical Frequency, Predictability, and Consequences For Online Inference.}, journal = {Systematic biology}, volume = {74}, number = {1}, pages = {101-111}, pmid = {39453463}, issn = {1076-836X}, mesh = {*Phylogeny ; *Classification/methods ; Likelihood Functions ; }, abstract = {Online phylogenetic inference methods add sequentially arriving sequences to an inferred phylogeny without the need to recompute the entire tree from scratch. Some online method implementations exist already, but there remains concern that additional sequences may change the topological relationship among the original set of taxa. We call such a change in tree topology a lack of stability for the inferred tree. In this article, we analyze the stability of single taxon addition in a Maximum Likelihood framework across 1000 empirical datasets. We find that instability occurs in almost 90% of our examples, although observed topological differences do not always reach significance under the approximately unbiased (AU) test. Changes in tree topology after addition of a taxon rarely occur close to its attachment location, and are more frequently observed in more distant tree locations carrying low bootstrap support. To investigate whether instability is predictable, we hypothesize sources of instability and design summary statistics addressing these hypotheses. Using these summary statistics as input features for machine learning under random forests, we are able to predict instability and can identify the most influential features. In summary, it does not appear that a strict insertion-only online inference method will deliver globally optimal trees, although relaxing insertion strictness by allowing for a small number of final tree rearrangements or accepting slightly suboptimal solutions appears feasible.}, }
@article {pmid39453271, year = {2024}, author = {Shaik, F and Uldrick, TS and Mazinu, M and Gwebushe, N and Mosam, A}, title = {Early Changes in Health-Related Quality of Life as a Biomarker of Survival in African Patients with HIV-Associated Kaposi Sarcoma.}, journal = {Tropical medicine and infectious disease}, volume = {9}, number = {10}, pages = {}, pmid = {39453271}, issn = {2414-6366}, support = {SELF-INITIATED RESEARCH (SIR) GRANT//South African Medical Research Council/ ; }, abstract = {Sub-Saharan Africa bears the largest public health burden of Kaposi sarcoma (KS), a leading cause of cancer mortality. Quality of life (QOL) assessments in cancer patients can provide information on prognosis beyond traditional biomarkers or biological measures. The prognostic value of QOL measures in patients with HIV-KS was evaluated. Prognostic associations of baseline QOL scores (by quartiles or thresholds for clinical importance) and changes in QOL scores (using minimum important difference) over the first 3 months of therapy were evaluated in 112 participants with HIV-KS randomised to receive ART, with or without chemotherapy. Cox's regression analysis assessed the prognostic contribution of QOL scores from the EORTC QLQ-C30 questionnaire. Survival curves were generated using the Kaplan-Meier method. Baseline QOL scores did not predict overall survival. The change in the 3-month QOL scores for the global health scale, fatigue, and pain domains was prognostic; the hazard ratios were 3.88 (95% CI 1.32-11.38, p = 0.01), 3.72 (95% CI 1.61-8.62, p = 0.00) and 5.96 (95% CI 2.46-14.43, p = 0.00), respectively. QOL assessments can provide useful prognostic information in patients with HIV-KS. Patients lacking meaningful improvement early into treatment represent a population at high risk of death.}, }
@article {pmid39450393, year = {2024}, author = {Sanchez, E and Krantz, EM and Escobar, ZK and Tverdek, F and Rosen, EA and Oshima, MU and Carpenter, PA and Pergam, SA and Liu, C}, title = {Epidemiology and Outcomes of Recurrent C Difficile Infection Among Hematopoietic Cell Transplant Recipients: A Single-center, Retrospective 10-year Study.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae570}, pmid = {39450393}, issn = {2328-8957}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: There are limited data on the contemporary epidemiology of recurrent Clostridioides difficile infection (CDI) among hematopoietic cell transplant (HCT) recipients. We aimed to determine the incidence, risk factors, and outcomes for recurrent CDI among HCT recipients.
METHODS: We conducted a retrospective study of adult HCT recipients between 2012 and 2021 diagnosed with index CDI between HCT day -7 and +100. Recurrent CDI was defined as new symptoms and a positive test within 12 weeks after treatment for index CDI. Cox proportional hazards models were used to investigate associations between prespecified variables (age, neutropenia, exposure to antibiotics with antianaerobic coverage, cytomegalovirus viremia/disease, and metronidazole monotherapy) and recurrent infection, presented as hazard ratios with 95% confidence intervals (CI).
RESULTS: Of 3479 HCT recipients, 416 (12%) had index CDI and were treated with oral vancomycin (31%), metronidazole (41%), oral vancomycin and metronidazole (29%). Of 381 patients eligible for recurrent CDI analysis, 35 had recurrent infection; cumulative incidence was 10% (95% CI, 7-13) at 12 weeks. In the 14 days after recurrence, 2/25 (8%) patients required hospital admission; none died within 30 days. Metronidazole monotherapy for treatment of index CDI was associated with an increased rate of recurrence (adjusted hazard ratio, 2.0; 95% CI, 1.0-4.0; P = .048).
CONCLUSIONS: Recurrent CDI occurred in 10% of HCT recipients in the early posttransplant period and was associated with use of metronidazole. Further study is needed to characterize risk factors for recurrent CDI among HCT recipients to guide use of agents aimed at preventing recurrence.}, }
@article {pmid39449055, year = {2024}, author = {Behera, S and Belyeu, JR and Chen, X and Paulin, LF and Nguyen, NQH and Newman, E and Mahmoud, M and Menon, VK and Qi, Q and Joshi, P and Marcovina, S and Rossi, M and Roller, E and Han, J and Onuchic, V and Avery, CL and Ballantyne, CM and Rodriguez, CJ and Kaplan, RC and Muzny, DM and Metcalf, GA and Gibbs, RA and Yu, B and Boerwinkle, E and Eberle, MA and Sedlazeck, FJ}, title = {Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {255}, pmid = {39449055}, issn = {1755-8794}, mesh = {Humans ; *Cardiovascular Diseases/genetics ; *Alleles ; *Lipoprotein(a)/genetics/blood ; DNA Copy Number Variations ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.}, }
@article {pmid39448999, year = {2024}, author = {Thuo, N and Bardon, AR and Mogere, P and Kiptinness, C and Casmir, E and Wairimu, N and Owidi, E and Okello, P and Mugo, NR and Baeten, JM and Ngure, K and Ortblad, KF}, title = {Acceptability of six-monthly PrEP dispensing supported with interim HIV self-testing to simplify PrEP delivery in Kenya: findings from qualitative research.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1281}, pmid = {39448999}, issn = {1472-6963}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; R01 MH113572/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/methods ; Female ; Male ; *HIV Infections/prevention & control ; Adult ; *Qualitative Research ; *Self-Testing ; *Patient Acceptance of Health Care/statistics & numerical data ; Anti-HIV Agents/therapeutic use/administration & dosage ; Young Adult ; HIV Testing/methods ; Interviews as Topic ; }, abstract = {BACKGROUND: In Africa, dispensing oral HIV pre-exposure prophylaxis (PrEP) within already strained public health facilities has led to prolonged waiting periods and suboptimal experiences for clients. We sought to explore the acceptability of dispensing PrEP semiannually with interim HIV self-testing (HIVST) versus quarterly PrEP dispensing with clinic-based HIV testing to optimize clinic-delivered PrEP services.
METHODS: We conducted a qualitative study within a non-inferiority individual-level randomized controlled trial testing the effect of six-monthly PrEP dispensing with HIVST compared to the standard-of-care three-monthly PrEP dispensing on PrEP clinical outcomes in Kenya (ClinicalTrials.gov: NCT03593629). Eligible participants were ≥ 18 years, refilling PrEP for the first time, and either in an HIV serodifferent relationship (men and women) or singly enrolled (women only). A subset of participants in the intervention group completed serial in-depth interviews (IDIs) at enrollment, six months, and 12 months. We utilized stratified purposive sampling to ensure representation across participant groups. We analyzed our qualitative data thematically using a combination of inductive and deductive approaches, the latter guided by the Theoretical Framework of Acceptability (TFA).
RESULTS: Between May 2018 and June 2021, we conducted 120 serial IDIs with 55 participants; 64% (35/55) were in a serodifferent relationship, 64% (35/55) were women, and the median age was 32 years (IQR 27-40). Overall, participants found this novel PrEP delivery model highly acceptable; it was well-liked, private (TFA construct: affective attitude), and less burdensome (TFA construct: burden) compared to standard PrEP delivery. Additionally, participants were confident in their ability to participate in the intervention (TFA construct: self-efficacy). Some participants, however, highlighted model disadvantages, including fewer opportunities for in-person counseling and potentially less accurate HIV testing (TFA construct: opportunity costs). Ultimately, most participants reported that the intervention allowed them to achieve their HIV prevention goals (TFA construct: perceived effectiveness) and that their confidence in at-home HIVST and PrEP continuation increased following each semiannual clinic visit.
CONCLUSIONS: Semiannual PrEP clinic visits supported with six-monthly drug dispensing and interim HIVST was acceptable among PrEP users who experienced the intervention in Kenya. More comprehensive pre-intervention counseling and training on HIVST may help alleviate the client concerns presented, which were often resolved over time with intervention experience.}, }
@article {pmid39447443, year = {2024}, author = {Ronsley, R and Cole, B and Ketterl, T and Wright, J and Ermoian, R and Hoffman, LM and Margol, AS and Leary, SES}, title = {Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review.}, journal = {Pediatric neurology}, volume = {161}, number = {}, pages = {237-246}, doi = {10.1016/j.pediatrneurol.2024.09.031}, pmid = {39447443}, issn = {1873-5150}, mesh = {Humans ; *Neoplasms, Germ Cell and Embryonal/therapy/diagnosis ; *Central Nervous System Neoplasms/therapy/diagnosis ; Child ; Survivorship ; Cancer Survivors ; }, abstract = {Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid. Diagnosis is made based on an integrated analysis of histologic and molecular features via tissue sampling. Risk stratification is based on integration of clinical staging and extent of resection with histologic and molecular risk factors. The therapeutic approach for these tumors is multimodal and includes surgery, chemotherapy, and radiation, tailored to the individual patient factors (including age) and specific tumor type. Comprehensive supportive care including management of nausea, nutrition support, pain, fertility preservation, and mitigation of therapy-related morbidity (including hearing protection) is imperative through treatment of CNS embryonal tumors. Despite advances in therapy and supportive care, the long-term consequences of current treatment strategies are substantial. Integration of less toxic, molecularly targeted therapies and a comprehensive, multidisciplinary approach to survivorship care are essential to improving survival and the overall quality of life for survivors.}, }
@article {pmid39447094, year = {2025}, author = {Sehn, LH and Bartlett, NL and Matasar, MJ and Schuster, SJ and Assouline, SE and Giri, P and Kuruvilla, J and Shadman, M and Cheah, CY and Dietrich, S and Fay, K and Ku, M and Nastoupil, LJ and Wei, MC and Yin, S and To, I and Kaufman, D and Kwan, A and Penuel, E and Bolen, CR and Budde, LE}, title = {Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies.}, journal = {Blood}, volume = {145}, number = {7}, pages = {708-719}, pmid = {39447094}, issn = {1528-0020}, mesh = {Humans ; *Lymphoma, Follicular/drug therapy/mortality/pathology ; Female ; Male ; Middle Aged ; Aged ; Follow-Up Studies ; Adult ; Aged, 80 and over ; *Antibodies, Bispecific/therapeutic use/adverse effects/administration & dosage ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Neoplasm Recurrence, Local/drug therapy ; Recurrence ; }, abstract = {Mosunetuzumab, a CD20×CD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7 to not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of CR was not reached (NR; 95% CI, 33.0 to NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE to NE). Median progression-free survival was 24.0 months (95% CI, 12.0 to NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) after 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions, and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe, and effective treatment for patients with R/R FL, including those with high-risk disease. This trial was registered at www.clinicaltrials.gov as #NCT02500407.}, }
@article {pmid39447043, year = {2024}, author = {McDougall, JA and Adler Jaffe, S and Jacobson, K and Shaver, TL and Wilson, JLF and Baca, K and Boyce, T and Tawfik, B and Page-Reeves, J}, title = {Randomized pilot trial of an unconditional cash transfer intervention to address food insecurity in oncology.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {6}, pages = {}, pmid = {39447043}, issn = {2515-5091}, support = {UG1 CA189824/CA/NCI NIH HHS/United States ; 2UG1CA189824//Wake Forest NCI Community Oncology Research Program/ ; }, mesh = {Humans ; Female ; Pilot Projects ; *Food Insecurity ; *Cancer Survivors ; *Quality of Life ; Middle Aged ; *Breast Neoplasms ; *Genital Neoplasms, Female/therapy ; Diet/economics ; Aged ; Adult ; Social Determinants of Health ; Food Supply/economics/statistics & numerical data ; }, abstract = {Screening for food insecurity and other social determinants of health is being integrated into oncology practice. We performed a pilot randomized trial to investigate whether an unconditional cash transfer (UCT) could be used to address food insecurity among female breast and gynecological cancer survivors. Food-insecure cancer survivors completed a baseline survey and were randomly assigned to receive $100/month for 3 months (UCT) or usual care (UC). Participants (n = 14) completed a follow-up survey after 3 months, and we compared changes in health-related quality of life, indicators of food insecurity, diet quality, and whether a participant had to forgo, delay, or make changes to medical care because of cost. The UCT was associated with higher physical health scores, fewer indicators of food insecurity, better diet quality, and a lower likelihood of forgoing medical care than those who received UC. Our results suggest that UCTs can improve outcomes for food-insecure cancer survivors.}, }
@article {pmid39446892, year = {2024}, author = {Schaefer, R and Donaldson, L and Leus, M and Osakwe, CE and Chimukangara, B and Dalal, S and Duerr, A and Gao, F and Glidden, DV and Grinsztejn, B and Justman, J and Kumwenda, G and Laeyendecker, O and Lee, HY and Maldarelli, F and Mayer, KH and Murray, J and Parekh, BS and Rice, B and Robertson, MN and Saito, S and Vannappagari, V and Warren, M and Zeballos, D and Zinserling, J and Miller, V}, title = {Promising results of HIV prevention trials highlight the benefits of collaboration in global health: The perspective of the Forum HIV Recency Assay Working Group.}, journal = {PLOS global public health}, volume = {4}, number = {10}, pages = {e0003878}, pmid = {39446892}, issn = {2767-3375}, support = {001/WHO_/World Health Organization/International ; R01 AI095066/AI/NIAID NIH HHS/United States ; }, }
@article {pmid39446266, year = {2025}, author = {Gichane, MW and Velloza, J and Hosek, S and Beauchamp, G and Anderson, P and Delany-Moretlwe, S and Celum, C and , }, title = {Hoping to Adhere? Examining the Relationship Between Hope and Pre-exposure Prophylaxis Willingness, Adherence, and Persistence Among Young Women in South Africa and Zimbabwe (HPTN 082).}, journal = {AIDS and behavior}, volume = {29}, number = {2}, pages = {527-534}, pmid = {39446266}, issn = {1573-3254}, support = {UM1AI068617//National Institute of Allergy and Infectious Diseases/ ; K01 MH134775/MH/NIMH NIH HHS/United States ; UM1AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1AI068613//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; K01MH134775/MH/NIMH NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Zimbabwe/epidemiology ; South Africa/epidemiology ; *Pre-Exposure Prophylaxis ; *HIV Infections/prevention & control/psychology ; Adult ; *Anti-HIV Agents/therapeutic use/administration & dosage ; Adolescent ; Young Adult ; *Medication Adherence/psychology ; *Hope ; Tenofovir/administration & dosage/therapeutic use ; Organophosphates/blood/administration & dosage ; Adenine/analogs & derivatives ; }, abstract = {Hope is a powerful psychological construct which is linked to positive health. Greater hope is associated with improved antiretroviral therapy adherence; however, less is known about the impact of hope on oral pre-exposure prophylaxis (PrEP) outcomes. HIV Prevention Trials Network 082, was an open-label PrEP study among young women (ages 16-25) in South Africa and Zimbabwe. Hope was measured at baseline and follow-up using a subset of the Hope for the Future Scale (score range 6-24) and PrEP willingness was measured using a subscale of the HIV Prevention Readiness Measure (score range 6-30). Intracellular tenofovir-diphosphate (TFV-DP) concentrations were obtained from dried blood spot samples at weeks 13, 26, and 52; high PrEP adherence was defined as TFV-DP concentrations ≥ 700 fmol/punch. Persistence was defined as TFV-DP > 16 fmol/punch at weeks 26 and 52. Linear regression and generalized estimating equations were used to assess the relationship between hope and PrEP willingness, adherence, and persistence. The median age of participants (n = 432) was 21 years (interquartile range [IQR]: 19-22). The mean hope score at baseline was 21.0 (SD = 3.4). Although hope was positively associated with PrEP willingness (β = 0.22, 95% CI 0.15, 0.37), it was not associated with high PrEP adherence (aRR = 1.00, 95% CI 0.96, 1.05), or persistence at follow-up (aRR = 1.02, 95% CI 0.99, 1.05). While cultivating hope may be an important strategy in building willingness to take oral PrEP, it may not be enough to sustain PrEP adherence or persistence.}, }
@article {pmid39445720, year = {2025}, author = {Compton, ZT and Mellon, W and Harris, VK and Rupp, S and Mallo, D and Kapsetaki, SE and Wilmot, M and Kennington, R and Noble, K and Baciu, C and Ramirez, LN and Peraza, A and Martins, B and Sudhakar, S and Aksoy, S and Furukawa, G and Vincze, O and Giraudeau, M and Duke, EG and Spiro, S and Flach, E and Davidson, H and Li, CI and Zehnder, A and Graham, TA and Troan, BV and Harrison, TM and Tollis, M and Schiffman, JD and Aktipis, CA and Abegglen, LM and Maley, CC and Boddy, AM}, title = {Cancer Prevalence across Vertebrates.}, journal = {Cancer discovery}, volume = {15}, number = {1}, pages = {227-244}, pmid = {39445720}, issn = {2159-8290}, support = {T32 CA272303/CA/NCI NIH HHS/United States ; P01 CA091955/CA/NCI NIH HHS/United States ; OTKA K143421//Agence Nationale de la Recherche (ANR)/ ; COVER ANR-23-CE02-0019//Agence Nationale de la Recherche (ANR)/ ; U54 CA217376/CA/NCI NIH HHS/United States ; ADHS18-198847//Arizona Biomedical Research Commission (ABRC)/ ; U2C CA233254/CA/NCI NIH HHS/United States ; //Hyundai Hope On Wheels (Hope On Wheels)/ ; BC132057//Congressionally Directed Medical Research Programs (CDMRP)/ ; R01 CA140657/CA/NCI NIH HHS/United States ; R21 CA257980/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Neoplasms/epidemiology/genetics/veterinary ; Prevalence ; *Vertebrates ; Humans ; }, abstract = {Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes. See related commentary by Metzger, p. 14.}, }
@article {pmid39442617, year = {2025}, author = {Hortobagyi, GN and Lacko, A and Sohn, J and Cruz, F and Ruiz Borrego, M and Manikhas, A and Hee Park, Y and Stroyakovskiy, D and Yardley, DA and Huang, CS and Fasching, PA and Crown, J and Bardia, A and Chia, S and Im, SA and Martin, M and Loi, S and Xu, B and Hurvitz, S and Barrios, C and Untch, M and Moroose, R and Visco, F and Parnizari, F and Zarate, JP and Li, Z and Waters, S and Chakravartty, A and Slamon, D}, title = {A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {2}, pages = {149-157}, doi = {10.1016/j.annonc.2024.10.015}, pmid = {39442617}, issn = {1569-8041}, mesh = {Humans ; Female ; *Purines/administration & dosage/adverse effects/therapeutic use ; *Aminopyridines/administration & dosage/adverse effects/therapeutic use ; *Breast Neoplasms/drug therapy/pathology/mortality ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Receptor, ErbB-2/metabolism ; Adult ; Receptors, Progesterone/metabolism ; Male ; Aged ; Receptors, Estrogen/metabolism ; Disease-Free Survival ; Chemotherapy, Adjuvant ; Letrozole/administration & dosage ; Anastrozole/administration & dosage ; Aromatase Inhibitors/administration & dosage/therapeutic use ; Goserelin/administration & dosage ; Antineoplastic Agents, Hormonal ; }, abstract = {BACKGROUND: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS).
PATIENTS AND METHODS: Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n = 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n = 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after ∼500 events.
RESULTS: At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P = 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed.
CONCLUSIONS: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.}, }
@article {pmid39442371, year = {2024}, author = {Yonemori, K and Boni, V and Min, KG and Meniawy, TM and Lombard, J and Kaufman, PA and Richardson, DL and Bender, L and Okera, M and Matsumoto, K and Giridhar, KV and García-Sáenz, JA and Prenen, H and de Speville Uribe, BD and Dizon, DS and Garcia-Corbacho, J and Van Nieuwenhuysen, E and Li, Y and Estrem, ST and Nguyen, B and Bacchion, F and Ismail-Khan, R and Jhaveri, K and Banda, K}, title = {Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study.}, journal = {Gynecologic oncology}, volume = {191}, number = {}, pages = {172-181}, doi = {10.1016/j.ygyno.2024.10.006}, pmid = {39442371}, issn = {1095-6859}, mesh = {Humans ; Female ; *Aminopyridines/administration & dosage/adverse effects/pharmacokinetics ; Middle Aged ; *Benzimidazoles/administration & dosage/adverse effects/pharmacokinetics ; Aged ; *Endometrial Neoplasms/drug therapy/pathology/metabolism ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use/administration & dosage ; Adult ; Neoplasm Recurrence, Local/drug therapy ; Carcinoma, Endometrioid/drug therapy/pathology/metabolism ; Receptors, Estrogen/metabolism ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC.
METHODS: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity.
RESULTS: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12).
CONCLUSION: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.}, }
@article {pmid39441907, year = {2024}, author = {Oshima, MU and Higgins, J and Jenkins, I and Randolph, T and Smith, T and Valentine, C and Salk, J and Yeung, C and Beppu, L and Campbell, J and Carpenter, PA and Lee, SJ and Flowers, ME and Radich, JP and Storb, R}, title = {Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.}, journal = {Science translational medicine}, volume = {16}, number = {770}, pages = {eado5108}, pmid = {39441907}, issn = {1946-6242}, support = {UG1 CA233338/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA175008/CA/NCI NIH HHS/United States ; R44 CA233381/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Tissue Donors ; Adult ; Middle Aged ; Male ; Mutation/genetics ; Female ; Young Adult ; Child ; Clonal Hematopoiesis/genetics ; Transplant Recipients ; Adolescent ; }, abstract = {After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.}, }
@article {pmid39441819, year = {2024}, author = {Owens, L and Brahme, O and Gulati, R and Etzioni, R}, title = {Trends in age and prostate-specific antigen at prostate cancer diagnosis between 2010 and 2019.}, journal = {JNCI cancer spectrum}, volume = {8}, number = {6}, pages = {}, pmid = {39441819}, issn = {2515-5091}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; U01CA253915/CA/NCI NIH HHS/United States ; //Rosalie and Harold Rea Brown Endowed Chair/ ; }, mesh = {Aged ; Aged, 80 and over ; Humans ; Male ; Middle Aged ; Age Factors ; Black or African American ; Delayed Diagnosis/statistics & numerical data ; Early Detection of Cancer ; Incidence ; *Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/blood/diagnosis/pathology ; *SEER Program ; United States/epidemiology ; White ; }, abstract = {Recent studies have shown that de novo metastatic prostate cancer incidence in the United States increased from 2010 to 2019. Plausible explanations include delayed detection after recommendations against prostate cancer screening or upstaging associated with use of more sensitive imaging technologies. Using Surveillance, Epidemiology, and End Results patient cases and controlling for aging of the population, we found the median age and prostate-specific antigen (PSA) level at prostate cancer diagnosis increased by 1.4 years of age (95% CI = 1.3 to 1.5 years) and 1.4 ng/mL (95% CI = 1.4 to 1.5 ng/mL) over this period, consistent with the delayed detection hypothesis. Racial differences were noted, with 75th percentiles of PSA at diagnosis increasing by 4.3 ng/mL (95% CI = 3.7 to 4.8 ng/mL) over this time period for non-Hispanic Black men compared with 3.0 ng/mL (95% CI = 2.8 to 3.2 ng/mL) for non-Hispanic White men. Overall, patient characteristics at diagnosis suggest that delayed detection contributed at least in part to increases in de novo metastatic disease.}, }
@article {pmid39439295, year = {2024}, author = {Colonne, CK and Kimble, EL and Turtle, CJ}, title = {Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.}, journal = {Expert review of hematology}, volume = {17}, number = {11}, pages = {797-818}, doi = {10.1080/17474086.2024.2420614}, pmid = {39439295}, issn = {1747-4094}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/immunology ; *Immunotherapy, Adoptive/methods ; *Tumor Microenvironment/immunology ; *Receptors, Chimeric Antigen/immunology/therapeutic use/metabolism ; Antigens, Neoplasm/immunology ; T-Lymphocytes/immunology/metabolism/transplantation ; Clinical Trials as Topic ; Treatment Outcome ; }, abstract = {INTRODUCTION: Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.
AREAS COVERED: In analyses of clinical trials of CAR-T cell therapy for R/R AML, complete responses without measurable residual disease have been reported, but the durability of those responses remains unclear. Significant barriers to successful CAR-T cell therapy in AML include the scarcity of suitable tumor-target antigens (TTA), inherent T cell functional deficits, and the immunoinhibitory and hostile tumor microenvironment (TME). This review will focus on these barriers to successful CAR-T cell therapy in AML, and discuss scientific advancements and evolving strategies to overcome them.
EXPERT OPINION: Achieving durable remissions in R/R AML will likely require a multifaceted approach that integrates advancements in TTA selection, enhancement of the intrinsic quality of CAR-T cells, and development of strategies to overcome inhibitory mechanisms in the AML TME.}, }
@article {pmid39437647, year = {2024}, author = {Wickline, MM and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Vaccine hesitancy and routine revaccination among adult HCT survivors in the United States: A convergent mixed methods analysis.}, journal = {Vaccine}, volume = {42}, number = {26}, pages = {126374}, doi = {10.1016/j.vaccine.2024.126374}, pmid = {39437647}, issn = {1873-2518}, mesh = {Humans ; Male ; Female ; Middle Aged ; United States ; Cross-Sectional Studies ; *Hematopoietic Stem Cell Transplantation/psychology ; *Vaccination Hesitancy/psychology/statistics & numerical data ; *Immunization, Secondary ; Adult ; Aged ; Surveys and Questionnaires ; COVID-19 Vaccines/administration & dosage ; COVID-19/prevention & control ; Survivors/psychology ; Vaccination/psychology ; }, abstract = {Revaccination to restore immunity to vaccine-preventable diseases (VPDs) is essential risk mitigation in the prevention of infectious morbidity and mortality after hematopoietic cell transplantation (HCT). However, revaccination rates have been shown to be insufficient and to what extent vaccine hesitancy contributes to survivors not becoming fully revaccinated is unknown. We performed a cross-sectional, mixed methods survey-based study to explore how vaccine hesitancy influences revaccination among US adult HCT survivors who were 2 to 8 years after transplant. Participants were asked to complete the Vaccination Confidence Scale (VCS) and open-ended survey items regarding vaccine confidence. The survey response rate was 30 %; among 332 respondents, vaccine confidence was high in 69 %, medium in 20 %, and low in 11 %. On multivariable analysis, four factors associated with high vaccine confidence were: predominantly Democrat zip codes (per 2020 election results), ability to pay for revaccination out of pocket, receipt of pre-HCT adult vaccines, and receipt of COVID-19 vaccines. From 189 participants who also answered open-ended items, 14 themes associated with vaccine confidence were identified and collapsed into 4 categories based on the VCS: Benefits, Harms, Trust, and Other. Merged analysis showed congruence between VCS scores and open-ended survey responses and created a narrative about the relative importance of the constructs when approaching revaccination by vaccine confidence level. These findings significantly expand our knowledge of how vaccine hesitancy influences revaccination uptake among US adult HCT survivors. Population-specific interventions to approach vaccine-hesitant survivors should be developed and tested.}, }
@article {pmid39436293, year = {2024}, author = {Partridge, SC and Xu, J}, title = {Cellular Characterization of Breast Cancer Using Microstructural Diffusion MRI.}, journal = {Radiology}, volume = {313}, number = {1}, pages = {e242268}, pmid = {39436293}, issn = {1527-1315}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; R01 CA269620/CA/NCI NIH HHS/United States ; R21 CA270731/CA/NCI NIH HHS/United States ; }, }
@article {pmid39433652, year = {2025}, author = {Adesina, OO and Jenkins, IC and Galvão, F and de Moura, AC and Fertrin, KY and Zemel, BS and Saad, STO}, title = {Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.}, journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA}, volume = {36}, number = {1}, pages = {93-102}, pmid = {39433652}, issn = {1433-2965}, support = {K23 HL148310/HL/NHLBI NIH HHS/United States ; CSDA 2020095/DDCF/Doris Duke Charitable Foundation/United States ; 5K23HL148310-02/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Alendronate/therapeutic use/pharmacology ; Male ; *Bone Density/drug effects ; Female ; *Bone Density Conservation Agents/therapeutic use/pharmacology ; Retrospective Studies ; Adult ; *Anemia, Sickle Cell/physiopathology/drug therapy/complications ; Middle Aged ; *Absorptiometry, Photon/methods ; *Osteoporosis/physiopathology/chemically induced/drug therapy ; *Lumbar Vertebrae/physiopathology ; *Femur Neck/physiopathology ; }, abstract = {UNLABELLED: Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited.
PURPOSE: To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis.
METHODS: We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype.
RESULTS: Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9 years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm[2]) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357 g/cm[2] (p = 0.028) in those on alendronate for > 5 years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4 years.
CONCLUSION: In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48 months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5 years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.}, }
@article {pmid39432443, year = {2024}, author = {Molstad, AJ and Cai, Y and Reiner, AP and Kooperberg, C and Sun, W and Hsu, L}, title = {Heterogeneity-aware integrative regression for ancestry-specific association studies.}, journal = {Biometrics}, volume = {80}, number = {4}, pages = {}, pmid = {39432443}, issn = {1541-0420}, support = {75N92021D00001/HL/NHLBI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL145806/NH/NIH HHS/United States ; //WHI/ ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; Genome-Wide Association Study/statistics & numerical data ; Regression Analysis ; Likelihood Functions ; Black People/genetics/statistics & numerical data ; Proteome ; Computer Simulation ; Models, Statistical ; Biometry/methods ; }, abstract = {Ancestry-specific proteome-wide association studies (PWAS) based on genetically predicted protein expression can reveal complex disease etiology specific to certain ancestral groups. These studies require ancestry-specific models for protein expression as a function of SNP genotypes. In order to improve protein expression prediction in ancestral populations historically underrepresented in genomic studies, we propose a new penalized maximum likelihood estimator for fitting ancestry-specific joint protein quantitative trait loci models. Our estimator borrows information across ancestral groups, while simultaneously allowing for heterogeneous error variances and regression coefficients. We propose an alternative parameterization of our model that makes the objective function convex and the penalty scale invariant. To improve computational efficiency, we propose an approximate version of our method and study its theoretical properties. Our method provides a substantial improvement in protein expression prediction accuracy in individuals of African ancestry, and in a downstream PWAS analysis, leads to the discovery of multiple associations between protein expression and blood lipid traits in the African ancestry population.}, }
@article {pmid39431098, year = {2024}, author = {Rodarte, J and Baehr, C and Hicks, D and McGovern, M and Zhang, Y and Silva-Ortiz, P and Hannon, B and Duddu, S and Pancera, M and Pravetoni, M}, title = {Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil.}, journal = {ACS omega}, volume = {9}, number = {41}, pages = {42506-42519}, pmid = {39431098}, issn = {2470-1343}, support = {U01 DA051658/DA/NIDA NIH HHS/United States ; UG3 DA057850/DA/NIDA NIH HHS/United States ; }, abstract = {The opioid overdose epidemic is a growing and evolving public health crisis fueled by the widespread presence of fentanyl and fentanyl analogues (F/FAs) in both street mixtures and counterfeit pills. To expand current treatment options, drug-targeting monoclonal antibodies (mAbs) offer a viable therapeutic for both pre- and postexposure clinical scenarios. This study reports the isolation, in vitro characterization, and in vivo efficacy of two murine mAb families targeting fentanyl, carfentanil, or both. Because humanization of the mAbs by CDR grafting negatively impacted affinity for both fentanyl and carfentanil, crystal structures of mAbs in complex with fentanyl or carfentanil were analyzed to identify key residues involved in ligand binding in murine versus humanized structures, and site-directed mutagenesis was used to verify their functional importance. The structural analysis identified a framework residue, Tyr36, present in the murine germline sequence of two mAbs, which was critical for binding to fentanyl and carfentanil. These studies emphasize the importance of structural considerations in mAb engineering to optimize mAbs targeting small molecules including opioids and other drugs of public health interest.}, }
@article {pmid39430319, year = {2024}, author = {Ye, L and Ryu, H and Granadier, D and Nguyen, LT and Simoni, Y and Dick, I and Firth, T and Rouse, E and Chiang, P and Lee, YCG and Robinson, BW and Creaney, J and Newell, EW and Redwood, AJ}, title = {Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.}, journal = {Translational lung cancer research}, volume = {13}, number = {9}, pages = {2352-2372}, pmid = {39430319}, issn = {2218-6751}, support = {R01 AI176563/AI/NIAID NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8[+] T cells include less differentiated stem-like exhausted T (Tex[stem]) cells and terminally exhausted T (Tex[term]) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.
METHODS: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex[stem] and Tex[term] CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.
RESULTS: Higher frequency of Tex[stem] was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex[term] was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Tex[stem], median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Tex[stem] cells also contained 'bystander' virus-specific T cells.
CONCLUSIONS: This study demonstrates that PE CD8 Tex[stem] cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.}, }
@article {pmid39429723, year = {2024}, author = {Georgakopoulou, A and Li, C and Kiem, HP and Lieber, A}, title = {In vitro and in vivo expansion of CD33/HBG promoter-edited HSPCs with Mylotarg.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {4}, pages = {101343}, pmid = {39429723}, issn = {2329-0501}, abstract = {We developed an in vivo HSC gene therapy approach that consists of HSC mobilization and intravenous injection of HSC-tropic HDAd vectors. To achieve therapeutically relevant numbers of corrected cells, we incorporated in vivo expansion of transduced cells. We used an HDAd vector for a multiplex adenine base editing approach to (1) remove the region within CD33 that is recognized by gemtuzumab ozogamicin (GO) (Mylotarg), and (2) create therapeutic edits within the HBG1/2 promoters to reactivate γ-globin/HbF. In vitro studies with HDAd-transduced human CD34[+] cells showed editing of both targeted sites and a 2- to 3-fold GO-mediated expansion of edited erythroid/myeloid progenitors. After erythroid in vitro differentiation, up to 40% of erythrocytes were HbF positive. For in vivo studies, mice were transplanted with human CD34[+] cells. After engraftment, HSCs were mobilized with G-CSF/AMD3100 followed by an intravenous HDAd injection and GO-mediated in vivo selection. Two months later, editing in human cells within the bone marrow was significantly higher in GO-treated mice. The percentage of HbF[+] human erythroid cells was 2.5-fold greater compared with untreated mice. These data indicate that in vivo GO selection can increase edited erythroid cells.}, }
@article {pmid39428758, year = {2024}, author = {Minot, SS and Mayer-Blackwell, K and Fiore-Gartland, A and Johnson, A and Self, S and Bhatti, P and Yao, L and Liu, L and Sun, X and Jinfa, Y and Kublin, J}, title = {Species- and subspecies-level characterization of health-associated bacterial consortia that colonize the human gut during infancy.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2414975}, pmid = {39428758}, issn = {1949-0984}, support = {R01 AI127100/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Infant ; *Feces/microbiology ; *Bacteria/classification/genetics/isolation & purification ; Male ; Female ; Metagenomics ; Microbial Consortia ; Metagenome ; Infant, Newborn ; Cohort Studies ; Cystic Fibrosis/microbiology ; }, abstract = {BACKGROUND: The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.
RESULTS: Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a published cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual.
CONCLUSION: By augmenting published metagenomic datasets with data from a newly established cohort, we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.}, }
@article {pmid39428129, year = {2024}, author = {Samorodnitsky, S and Wu, MC}, title = {Statistical analysis of multiple regions-of-interest in multiplexed spatial proteomics data.}, journal = {Briefings in bioinformatics}, volume = {25}, number = {6}, pages = {}, pmid = {39428129}, issn = {1477-4054}, support = {U10 CA180819/GF/NIH HHS/United States ; //Hope Foundation for Cancer Research/ ; }, mesh = {Humans ; *Proteomics/methods ; Neoplasms/metabolism/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology/genetics ; Triple Negative Breast Neoplasms/pathology/metabolism/genetics ; Colorectal Neoplasms/metabolism/pathology/genetics ; Lung Neoplasms/metabolism/pathology/genetics ; Data Interpretation, Statistical ; Algorithms ; }, abstract = {Multiplexed spatial proteomics reveals the spatial organization of cells in tumors, which is associated with important clinical outcomes such as survival and treatment response. This spatial organization is often summarized using spatial summary statistics, including Ripley's K and Besag's L. However, if multiple regions of the same tumor are imaged, it is unclear how to synthesize the relationship with a single patient-level endpoint. We evaluate extant approaches for accommodating multiple images within the context of associating summary statistics with outcomes. First, we consider averaging-based approaches wherein multiple summaries for a single sample are combined in a weighted mean. We then propose a novel class of ensemble testing approaches in which we simulate random weights used to aggregate summaries, test for an association with outcomes, and combine the $P$-values. We systematically evaluate the performance of these approaches via simulation and application to data from non-small cell lung cancer, colorectal cancer, and triple negative breast cancer. We find that the optimal strategy varies, but a simple weighted average of the summary statistics based on the number of cells in each image often offers the highest power and controls type I error effectively. When the size of the imaged regions varies, incorporating this variation into the weighted aggregation may yield additional power in cases where the varying size is informative. Ensemble testing (but not resampling) offered high power and type I error control across conditions in our simulated data sets.}, }
@article {pmid39424451, year = {2025}, author = {Li, T and Isautier, J and Lee, JM and Marinovich, ML and Houssami, N}, title = {Performance of Digital Breast Tomosynthesis Versus Digital Mammography in Women With a Family History of Breast Cancer: A Systematic Review.}, journal = {Clinical breast cancer}, volume = {25}, number = {2}, pages = {e103-e112}, doi = {10.1016/j.clbc.2024.09.013}, pmid = {39424451}, issn = {1938-0666}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/genetics/diagnosis ; *Mammography/methods ; *Early Detection of Cancer/methods/statistics & numerical data ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: There is limited evidence on the performance of digital breast tomosynthesis (DBT) in populations at increased risk of breast cancer. Our objective was to systematically review evidence on the performance of DBT versus digital mammography (DM) in women with a family history of breast cancer (FHBC).
METHODS: We searched 5 databases (2011-January 2024) for studies comparing DBT and DM in women with a FHBC that reported any measure of cancer detection, recall, sensitivity and specificity. Findings were presented using a descriptive and narrative approach. Risk of bias was assessed using QUADAS-2/C.
RESULTS: Five (4 screening, 1 diagnostic) studies were included (total 3089 DBT, 3024 DM) with most (4/5) being prospective including 1 RCT. All studies were assessed as being at high risk of bias or applicability concern. Four screening studies reported recall rate (range: DBT: 2.7%-4.5%, DM: 2.8%-11.5%) with 3 reporting DBT had lower rates than DM. Cancer detection rates (CDR) were reported in the same studies (DBT: 5.1-11.6 per 1000, DM: 3.8-8.3); 3 reported higher CDR for DBT (vs. DM), and 1 reported same CDR for both. Compared with DM, higher values for sensitivity, specificity and PPV for DBT were reported in 2 studies.
CONCLUSION: This review provides early evidence that DBT may outperform DM for screening women with a FHBC. Our findings support further evaluation of DBT in this population. However, summarized findings were based on few studies and participants, and high-quality studies with improved methodology are needed to address biases identified in our review.}, }
@article {pmid39424273, year = {2025}, author = {Liese, AD and Julceus, EF and Brown, AD and Pihoker, C and Frongillo, EA and Sauder, KA and Malik, FS and Bellatorre, A and Reboussin, BA and Mendoza, JA}, title = {Reassessing the Burden of Food Insecurity in Youth and Young Adults With Youth-onset Diabetes: The Importance of Marginal Food Security.}, journal = {Canadian journal of diabetes}, volume = {49}, number = {1}, pages = {29-36.e1}, pmid = {39424273}, issn = {2352-3840}, support = {R01 DK117461/DK/NIDDK NIH HHS/United States ; T32 GM081740/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Adolescent ; *Food Insecurity ; Young Adult ; *Diabetes Mellitus, Type 1/epidemiology ; *Diabetes Mellitus, Type 2/epidemiology ; Canada/epidemiology ; *Food Security/statistics & numerical data ; Adult ; Prevalence ; Child ; Follow-Up Studies ; *Food Supply ; Cohort Studies ; *Cost of Illness ; }, abstract = {INTRODUCTION: Whereas marginal food insecurity (FI) has been recognized as important in Canadian food security policy, the category of marginal food security (MFS) is often ignored in US food security research.
METHODS: Prevalence of FI was estimated according to the conventional and an alternate classification of MFS with FI among 938 youth and young adults (YYA) with youth-onset type 1 diabetes (T1D) and 156 with youth-onset type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study (2018-2021). Multivariable regression was used to estimate the association of MFS and conventionally defined FI ascertained with diabetes-related outcomes, including acute diabetes complications, health-care utilization, and diabetes self-management among YYA with T1D.
RESULTS: MFS affected 10% of participants with T1D and 20% of participants with T2D. Classifying MFS with FI increased FI prevalence from 18.0% to 27.8% in participants with T1D and 34.6% to 55.1% in participants with T2D. Compared to T1D with high food security, YYA with T1D who were experiencing FI had higher odds of hypoglycemia (2.1, 95% confidence interval [CI] 1.2 to 3.6) and ketoacidosis (1.6, 95% CI 1.0 to 2.6), but no association was seen in MFS. The FI group also had higher odds of emergency department use and hospitalization (2.3, 95% CI 1.5 to 3.4; 2.4, 95% CI 1.5 to 3.9) and lower odds of technology use and checking glucose (0.6, 95% CI 0.4 to 0.9; 0.3, 95% CI 0.1 to 0.6). The MFS group exhibited associations of similar directions.
CONCLUSION: Health-care providers should consider care of individuals with T1D and MFS in the same way as care for those with FI.}, }
@article {pmid39422615, year = {2024}, author = {Lazarchuk, P and Nguyen, MM and Curca, CM and Pavlova, MN and Oshima, J and Sidorova, JM}, title = {Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells.}, journal = {Aging}, volume = {16}, number = {20}, pages = {12977-13011}, pmid = {39422615}, issn = {1945-4589}, support = {R01 CA210916/CA/NCI NIH HHS/United States ; R01 GM115482/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Werner Syndrome Helicase/metabolism/genetics ; *Heterochromatin/metabolism ; *Werner Syndrome/genetics/metabolism ; *Fibroblasts/metabolism ; *Cell Proliferation ; Chromobox Protein Homolog 5/metabolism ; Histone Deacetylase 2/metabolism/genetics ; DNA Replication ; Cellular Senescence ; RecQ Helicases/metabolism/genetics ; }, abstract = {Werner syndrome of premature aging is caused by mutations in the WRN RECQ helicase/exonuclease, which functions in DNA replication, repair, transcription, and telomere maintenance. How the loss of WRN accelerates aging is not understood in full. Here we show that WRN is necessary for optimal constitutive heterochromatin levels in proliferating human fibroblasts. Locally, WRN deficiency derepresses SATII pericentromeric satellite repeats but does not reduce replication fork progression on SATII repeats. Globally, WRN loss reduces a subset of protein-protein interactions responsible for the organization of constitutive heterochromatin in the nucleus, namely, the interactions involving Lamin B1 and Lamin B receptor, LBR. Both the mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and unlike the former, the latter phenotype does not require WRN catalytic activities. The phenotypes of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence. WRN interacts with histone deacetylase 2, HDAC2; WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1α, and WRN complexes with HP1α and HDAC2 are downregulated in senescing cells. The data suggest that the effect of WRN loss on heterochromatin is separable from senescence program, but mimics at least some of the heterochromatin changes associated with it.}, }
@article {pmid39422601, year = {2024}, author = {Samorodnitsky, S and Othus, M and LeBlanc, M and Wu, MC}, title = {Reverse Selection Designs for Accommodating Multiple Control Arms.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {24}, pages = {5535-5539}, pmid = {39422601}, issn = {1557-3265}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; //Hope Foundation for Cancer Research/ ; }, mesh = {Humans ; *Research Design ; *Randomized Controlled Trials as Topic ; Sample Size ; }, abstract = {Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual-yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.}, }
@article {pmid39420548, year = {2024}, author = {Kelly, JP and Runco, DV and Slaven, JE and Niehaus, JZ}, title = {Healthcare Utilization in Pediatric Cancer Patients Near the End-of-Life.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091241294055}, doi = {10.1177/10499091241294055}, pmid = {39420548}, issn = {1938-2715}, abstract = {Objective: Describe the healthcare utilization in the last 60 days of life in pediatric patients with cancer who died at home under hospice care and those that died in the hospital. Methods: Retrospective chart review of the medical records of those children with cancer diagnosis with palliative care consult and died either under hospice care at home or in the hospital. Results: Patients dying under hospice care spent a median of 44 days at home. Patients dying in the hospital spent a median of 30.5 days in the hospital, 10.5 days in the intensive care unit, and underwent 3.5 procedures requiring anesthesia. 45% of those that died in the hospital were compassionately extubated. Conclusion: For those dying with a cancer diagnosis, hospice care can allow for significant time at home with minimal healthcare while those dying in the hospital do spend a significant time in the hospital. This provides more information to both providers and families about end-of-life healthcare utilization.}, }
@article {pmid39420192, year = {2025}, author = {Wallis, W and Gulbis, AM and Wang, T and Lee, CJ and Sharma, A and Williams, KM and Nishihori, T and Prestidge, T and Gowda, L and Byrne, M and Krem, MM and MacMillan, ML and Kitko, CL and Pidala, J and Spellman, SR and Lee, SJ and Alousi, AM}, title = {Incidence of bacterial blood stream infections in patients with acute GVHD.}, journal = {Bone marrow transplantation}, volume = {60}, number = {1}, pages = {52-57}, pmid = {39420192}, issn = {1476-5365}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/mortality/complications ; Male ; Female ; Middle Aged ; Adult ; Incidence ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Acute Disease ; Adolescent ; Aged ; *Bacterial Infections/etiology ; *Bacteremia/etiology ; Young Adult ; Registries ; }, abstract = {Bacterial bloodstream infections (BSI) can be a substantial contributor to complications of GVHD treatment. The aim of this study was to determine the risk for BSI from neutrophil engraftment through day 100 post transplant in patients with acute GVHD (AGVHD) based on organ involvement and severity. Patients (n = 4064) who underwent an allogeneic hematopoietic stem cell transplant (HCT) reported to the CIBMTR registry were analyzed. Grade II-IV AGVHD occurred in 1607 (39.5%) patients and was associated with a greater day-100 incidence of post engraftment BSI than with grade 0/I (24.9 vs. 15.3%). Patients with grade III/IV AGVHD had the highest BSI risk (HR 2.45; 95% CI 1.99-3.0; p < 0.0001). Lower GI involvement increased BSI risk (HR 1.54; 95% CI 1.17-2.02; p = 0.0019). BSI post-engraftment through day 100 was associated with worse survival (HR 1.64, 95% CI 1.43-1.87; p < 0.001) and higher non-relapse mortality (NRM), (HR 2.22; 95% CI 1.91-2.59; p < 0.001). Those with stage III/IV GI involvement are at highest risk for BSI. Future studies evaluating novel methods for preventing BSI in these high risk populations are needed to reduce mortality associated with AGVHD.}, }
@article {pmid39419747, year = {2024}, author = {Lehrbach, N}, title = {Anything you can do, glycans do better: deglycosylation and noncanonical ubiquitination vie to rule the proteasome.}, journal = {Trends in biochemical sciences}, volume = {49}, number = {12}, pages = {1033-1035}, pmid = {39419747}, issn = {0968-0004}, support = {R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {*Ubiquitination ; *Proteasome Endopeptidase Complex/metabolism ; Glycosylation ; Humans ; *Polysaccharides/metabolism/chemistry ; Animals ; Nuclear Respiratory Factor 1/metabolism ; }, abstract = {The Nrf1/Nfe2L1 transcription factor is a master regulator of proteasome biogenesis. New work by Yoshida and colleagues reveals a surprising mechanism by which ubiquitination of N-glycosylated Nrf1 controls its function.}, }
@article {pmid39418644, year = {2024}, author = {Uy, GL and Pullarkat, V and Baratam, P and Stuart, RK and Walter, RB and Winer, ES and Wang, Q and Faderl, S and Chakravarthy, D and Menno, D and Cheung, RS and Lin, TL}, title = {Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy.}, journal = {Blood advances}, volume = {8}, number = {24}, pages = {6248-6256}, pmid = {39418644}, issn = {2473-9537}, mesh = {Humans ; *Sulfonamides/therapeutic use/administration & dosage ; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration & dosage ; *Leukemia, Myeloid, Acute/drug therapy ; *Daunorubicin/administration & dosage/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Middle Aged ; Female ; Male ; *Cytarabine/administration & dosage/therapeutic use ; Aged ; Adult ; Treatment Outcome ; }, abstract = {Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX-351 IV on days 1 and 3 plus venetoclax 400 mg orally on days 2 to 21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary end points were the RP2D and safety of CPX-351 combined with venetoclax. Secondary end points included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17 of 35 patients (49%), all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1 of 8 patients (13%) with a mutation in TP53, and CR/CRi was achieved by 15 of 26 patients (58%) with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.ClinicalTrials.gov as #NCT04038437.}, }
@article {pmid39416221, year = {2024}, author = {Geiger, RA and Khera, D and Tenthorey, JL and Kochs, G and Graf, L and Emerman, M and Malik, HS}, title = {Heterozygous and generalist MxA super-restrictors overcome breadth-specificity tradeoffs in antiviral restriction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416221}, issn = {2692-8205}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit a broad range of viruses. However, they face the challenge of maintaining this breadth as viruses evolve to escape their defense. Viral escape drives restriction factors to evolve rapidly, selecting for amino acid changes at their virus-binding interfaces to regain defense. How do restriction factors balance the breadth of antiviral functions against the need to evolve specificity against individual escaping viruses? We explored this question in human MxA, which uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as THOV and IAV. Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 revealed variants with a ten-fold increase in potency against THOV. However, this strategy did not yield improved IAV restriction, suggesting a strong tradeoff between antiviral specificity and breadth. Here, using a modified combinatorial mutagenesis strategy, we find 'super-restrictor' MxA variants with over ten-fold enhanced restriction of the avian IAV strain H5N1 but reduced THOV restriction. Analysis of super-restrictor MxA variants reveals that the identity of residue 561 explains most of MxA's breadth-specificity tradeoff in H5N1 versus THOV restriction. However, rare 'generalist' super-restrictors with enhanced restriction of both viruses allow MxA to overcome the breadth-specificity tradeoff. Finally, we show that a heterozygous combination of two 'specialist' super-restrictors, one against THOV and the other against IAV, enhances restriction against both viruses. Thus, two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity tradeoffs that may be pervasive in host-virus conflicts.}, }
@article {pmid39416011, year = {2025}, author = {Haack, AJ and Brown, LG and Goldstein, AJ and Mulimani, P and Berthier, J and Viswanathan, AR and Kopyeva, I and Whitten, JM and Lin, A and Nguyen, SH and Leahy, TP and Bouker, EE and Padgett, RM and Mazzawi, NA and Tokihiro, JC and Bretherton, RC and Wu, A and Tapscott, SJ and DeForest, CA and Popowics, TE and Berthier, E and Sniadecki, NJ and Theberge, AB}, title = {Suspended Tissue Open Microfluidic Patterning (STOMP).}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416011}, issn = {2692-8205}, support = {F30 HL158030/HL/NHLBI NIH HHS/United States ; R01 HL149734/HL/NHLBI NIH HHS/United States ; R90 DE023059/DE/NIDCR NIH HHS/United States ; R35 GM128648/GM/NIGMS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R03 DE029827/DE/NIDCR NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, abstract = {Free-standing tissue structures tethered between pillars are powerful mechanobiology tools for studying cell contraction. To model interfaces ubiquitous in natural tissues and upgrade existing single-region suspended constructs, we developed Suspended Tissue Open Microfluidic Patterning (STOMP), a method to create multiregional suspended tissues. STOMP uses open microfluidics and capillary pinning to pattern subregions within free-standing tissues, facilitating the study of complex tissue interfaces, such as diseased-healthy boundaries (e.g., fibrotic-healthy) and tissue-type interfaces (e.g., bone-ligament). We observed altered contractile dynamics in fibrotic-healthy engineered heart tissues compared to single-region tissues and differing contractility in bone-ligament enthesis constructs compared to single-tissue periodontal ligament models. STOMP is a versatile platform - surface tension-driven patterning removes material requirements common with other patterning methods (e.g., shear-thinning, photopolymerizable) allowing tissue generation in multiple geometries with native extracellular matrices and advanced 4D materials. STOMP combines the contractile functionality of suspended tissues with precise patterning, enabling dynamic and spatially controlled studies.}, }
@article {pmid39415317, year = {2025}, author = {Purice, MD and Lago-Baldaia, I and Fernandes, VM and Singhvi, A}, title = {Molecular profiling of invertebrate glia.}, journal = {Glia}, volume = {73}, number = {3}, pages = {632-656}, pmid = {39415317}, issn = {1098-1136}, support = {227823//Esther A. and Joseph Klingenstein Fund/ ; 225986/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; NS114222/NH/NIH HHS/United States ; 5T32CA080416-25/NH/NIH HHS/United States ; R01 NS114222/NS/NINDS NIH HHS/United States ; BRFSG-2023-10//Brain Research Foundation/ ; //Washington Research Foundation/ ; /WT_/Wellcome Trust/United Kingdom ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Neuroglia/metabolism/physiology ; Caenorhabditis elegans ; Drosophila melanogaster ; }, abstract = {Caenorhabditis elegans and Drosophila melanogaster are powerful experimental models for uncovering fundamental tenets of nervous system organization and function. Findings over the last two decades show that molecular and cellular features are broadly conserved between invertebrates and vertebrates, indicating that insights derived from invertebrate models can broadly inform our understanding of glial operating principles across diverse species. In recent years, these model systems have led to exciting discoveries in glial biology and mechanisms of glia-neuron interactions. Here, we summarize studies that have applied current state-of-the-art "-omics" techniques to C. elegans and D. melanogaster glia. Coupled with the remarkable acceleration in the pace of mechanistic studies of glia biology in recent years, these indicate that invertebrate glia also exhibit striking molecular complexity, specificity, and heterogeneity. We provide an overview of these studies and discuss their implications as well as emerging questions where C. elegans and D. melanogaster are well-poised to fill critical knowledge gaps in our understanding of glial biology.}, }
@article {pmid39414943, year = {2024}, author = {Wang, T and Roach, MJ and Harvey, K and Morlanes, JE and Kiedik, B and Al-Eryani, G and Greenwald, A and Kalavros, N and Dezem, FS and Ma, Y and Pita-Juarez, YH and Wise, K and Degletagne, C and Elz, A and Hadadianpour, A and Johanneson, J and Pakiam, F and Ryu, H and Newell, EW and Tonon, L and Kohlway, A and Drennon, T and Abousoud, J and Stott, R and Lund, P and Durruthy, J and Vallejo, AF and Li, W and Salomon, R and Kaczorowski, D and Warren, J and Butler, LM and O'Toole, S and Plummer, J and Vlachos, IS and Lundeberg, J and Swarbrick, A and Martelotto, LG}, title = {snPATHO-seq, a versatile FFPE single-nucleus RNA sequencing method to unlock pathology archives.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {1340}, pmid = {39414943}, issn = {2399-3642}, support = {APP2004774//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {*Paraffin Embedding/methods ; Humans ; *Sequence Analysis, RNA/methods ; *Tissue Fixation/methods ; *Single-Cell Analysis/methods ; Formaldehyde/chemistry ; Transcriptome ; Gene Expression Profiling/methods ; Workflow ; }, abstract = {Formalin-fixed paraffin-embedded (FFPE) samples are valuable but underutilized in single-cell omics research due to their low RNA quality. In this study, leveraging a recent advance in single-cell genomic technology, we introduce snPATHO-seq, a versatile method to derive high-quality single-nucleus transcriptomic data from FFPE samples. We benchmarked the performance of the snPATHO-seq workflow against existing 10x 3' and Flex assays designed for frozen or fresh samples and highlighted the consistency in snRNA-seq data produced by all workflows. The snPATHO-seq workflow also demonstrated high robustness when tested across a wide range of healthy and diseased FFPE tissue samples. When combined with FFPE spatial transcriptomic technologies such as FFPE Visium, the snPATHO-seq provides a multi-modal sampling approach for FFPE samples, allowing more comprehensive transcriptomic characterization.}, }
@article {pmid39414769, year = {2024}, author = {Fortuna, GG and Banerjee, R and Savid-Frontera, C and Song, J and Morán-Segura, CM and Nguyen, JV and Lekakis, L and Fernandez-Pol, S and Samraj, AN and Naresh, KN and Vazquez-Martinez, M and Baz, RC and Spiegel, JY and Mikkilineni, L and Gubatan, JM and Sidana, S and de Menezes Silva Corraes, A and Kalariya, NM and Patel, KK and Shim, KG and Fonseca, R and Ferreri, C and Voorhees, PM and Richard, S and Valdes, CR and Sireesha Asoori, and Wolf, JL and Cowan, AJ and Sborov, DW and Locke, FL and Lin, Y and Wang, Y and Hansen, DK}, title = {Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {180}, pmid = {39414769}, issn = {2044-5385}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/immunology/drug therapy ; *Enterocolitis/etiology/therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; *Immunotherapy, Adoptive/adverse effects ; Adult ; Receptors, Chimeric Antigen/therapeutic use/immunology ; }, abstract = {We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.}, }
@article {pmid39414027, year = {2024}, author = {Wong, WW and Speakman, JR and Ainslie, PN and Anderson, LJ and Arab, L and Baddou, I and Bedu-Addo, K and Blaak, EE and Blanc, S and Bonomi, AG and Bouten, CV and Bovet, P and Buchowski, MS and Butte, NF and Camps, SG and Casper, R and Close, GL and Colbert, LH and Cooper, JA and Das, SK and Davies, PS and Eaton, S and Ekelund, U and Hambly, C and El Hamdouchi, A and Entringer, S and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and Hoos, MB and Hu, S and Joosen, A and Katzmarzyk, PT and Kempen, KP and Kimura, M and Kraus, WE and Kushner, RF and Larsson, CL and Morehen, JC and Morton, JP and Neuhouser, ML and Nicklas, TA and Ojiambo, RM and Pietilainen, KH and Pitsiladis, YP and Plasqui, G and Prentice, RL and Rabinovich, R and Racette, SB and Raichen, DA and Redman, L and Ravussin, E and Reilly, JJ and Roberts, S and Scuitt, AJ and Sjödin, AM and Stice, E and Urlacher, SS and Valenti, G and van Etten, LM and Van Mil, EA and Verbunt, JA and Wells, JC and Wilson, G and Yoshida, T and Zhang, X and Loechl, CU and Luke, A and Murphy-Alford, AJ and Pontzer, H and Sagayama, H and Rood, JC and Schoeller, DA and Westerterp, KR and Yamada, Y and , }, title = {Decline in Isotope Dilution Space Ratio Above Age 60 Could Affect Energy Estimates Using the Doubly Labeled Water Method.}, journal = {The Journal of nutrition}, volume = {154}, number = {12}, pages = {3824-3831}, pmid = {39414027}, issn = {1541-6100}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Body Composition ; *Energy Metabolism ; Aged ; Adult ; *Oxygen Isotopes ; Deuterium ; Indicator Dilution Techniques ; Water ; Young Adult ; Age Factors ; Aged, 80 and over ; Deuterium Oxide ; Anthropometry ; }, abstract = {BACKGROUND: Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR.
OBJECTIVES: We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR.
METHODS: We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR.
RESULTS: From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 ± 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001).
CONCLUSIONS: Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding.}, }
@article {pmid39413835, year = {2024}, author = {Liu, J and Berchuck, A and Backes, FJ and Cohen, J and Grisham, R and Leath, CA and Martin, L and Matei, D and Miller, DS and Robertson, S and Barroilhet, L and Uppal, S and Hendrickson, AW and Gershenson, DM and Gray, HJ and Hakam, A and Jain, A and Konecny, GE and Moroney, J and Ratner, E and Schorge, J and Thaker, PH and Werner, TL and Zsiros, E and Behbakht, K and Chen, LM and DeRosa, M and Eisenhauer, EL and Leiserowitz, G and Litkouhi, B and McHale, M and Percac-Lima, S and Rodabaugh, K and Vargas, R and Jones, F and Kovach, E and Hang, L and Ramakrishnan, S and Alvarez, RD and Armstrong, DK}, title = {NCCN Guidelines® Insights: Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer, Version 3.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {512-519}, doi = {10.6004/jnccn.2024.0052}, pmid = {39413835}, issn = {1540-1413}, mesh = {Humans ; Female ; *Ovarian Neoplasms/diagnosis/therapy/pathology ; *Peritoneal Neoplasms/therapy/diagnosis ; *Fallopian Tube Neoplasms/diagnosis/therapy/pathology ; Medical Oncology/standards/methods ; Neoplasm Staging ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; }, abstract = {The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.}, }
@article {pmid39413812, year = {2024}, author = {Shah, B and Mattison, RJ and Abboud, R and Abdelmessieh, P and Aldoss, I and Burke, PW and DeAngelo, DJ and Dinner, S and Fathi, AT and Gauthier, J and Haddadin, M and Jain, N and Jonas, B and Kirby, S and Liedtke, M and Litzow, M and Logan, A and Long, M and Luger, S and Mangan, JK and Massaro, S and May, W and Oluwole, O and Park, J and Przespolewski, A and Rangaraju, S and Saygin, C and Schwartz, M and Shami, P and Tomlinson, B and Webster, J and Awotiwon, A and Stehman, K}, title = {Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {563-576}, doi = {10.6004/jnccn.2024.0051}, pmid = {39413812}, issn = {1540-1413}, mesh = {Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/diagnosis ; Medical Oncology/standards/methods ; Adult ; Philadelphia Chromosome ; Adolescent ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.}, }
@article {pmid39413375, year = {2024}, author = {Herrera, AF and LeBlanc, M and Castellino, SM and Li, H and Rutherford, SC and Evens, AM and Davison, K and Punnett, A and Parsons, SK and Ahmed, S and Casulo, C and Bartlett, NL and Tuscano, JM and Mei, MG and Hess, BT and Jacobs, R and Saeed, H and Torka, P and Hu, B and Moskowitz, C and Kaur, S and Goyal, G and Forlenza, C and Doan, A and Lamble, A and Kumar, P and Chowdhury, S and Brinker, B and Sharma, N and Singh, A and Blum, KA and Perry, AM and Kovach, AE and Hodgson, D and Constine, LS and Shields, LK and Prica, A and Dillon, H and Little, RF and Shipp, MA and Crump, M and Kahl, B and Leonard, JP and Smith, SM and Song, JY and Kelly, KM and Friedberg, JW}, title = {Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.}, journal = {The New England journal of medicine}, volume = {391}, number = {15}, pages = {1379-1389}, pmid = {39413375}, issn = {1533-4406}, support = {UG1CA189955/NH/NIH HHS/United States ; UG1 CA233330/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10CA180819/NH/NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; U10CA180863/NH/NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10CA180821/NH/NIH HHS/United States ; U10CA180820/NH/NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects ; *Brentuximab Vedotin/administration & dosage/adverse effects ; *Dacarbazine/administration & dosage/adverse effects ; *Doxorubicin/administration & dosage/adverse effects ; *Hodgkin Disease/drug therapy/mortality/radiotherapy/pathology ; Intention to Treat Analysis ; Kaplan-Meier Estimate ; Neoplasm Staging ; *Nivolumab/administration & dosage/adverse effects ; Progression-Free Survival ; *Vinblastine/administration & dosage/adverse effects ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients.
METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.
RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.
CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).}, }
@article {pmid39412842, year = {2024}, author = {Fabens, I and Makhele, C and Igaba, NK and Hlongwane, S and Phohole, M and Waweru, E and Oni, F and Khwepeya, M and Sardini, M and Moyo, K and Tweya, H and Wafula, MB and Pienaar, J and Ndebele, F and Setswe, G and Dong, TQ and Feldacker, C}, title = {WhatsApp Versus SMS for 2-Way, Text-Based Follow-Up After Voluntary Medical Male Circumcision in South Africa: Exploration of Messaging Platform Choice.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e62762}, pmid = {39412842}, issn = {2561-326X}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; Male ; *Circumcision, Male/psychology ; *Text Messaging ; South Africa ; Adult ; Adolescent ; *Mobile Applications ; Telemedicine ; Young Adult ; Patient Satisfaction ; Middle Aged ; Aftercare/methods ; }, abstract = {BACKGROUND: Telehealth is growing, especially in areas where access to health facilities is difficult. We previously used 2-way texting (2wT) via SMS to improve the quality of postoperative care after voluntary medical male circumcision in South Africa. In this study, we offered males aged 15 years and older WhatsApp or SMS as their message delivery and interaction platform to explore user preferences and behaviors.
OBJECTIVE: The objectives of this process evaluation embedded within a larger 2wT expansion trial were to (1) explore 2wT client preferences, including client satisfaction, with WhatsApp or SMS; (2) examine response rates (participation) by SMS and WhatsApp; and (3) gather feedback from the 2wT implementation team on the WhatsApp approach.
METHODS: Males aged 15 years and older undergoing voluntary medical male circumcision in program sites could choose their follow-up approach, selecting 2wT via SMS or WhatsApp or routine care (in-person postoperative visits). The 2wT system provided 1-way educational messages and an open 2-way communication channel between providers and clients. We analyzed quantitative data from the 2wT database on message delivery platforms (WhatsApp vs SMS), response rates, and user behaviors using chi-square tests, z tests, and t tests. The team conducted short phone calls with WhatsApp and SMS clients about their perceptions of this 2wT platform using a short, structured interview guide. We consider informal reflections from the technical team members on the use of WhatsApp. We applied an implementation science lens using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to focus results on practice and policy improvement.
RESULTS: Over a 2-month period-from August to October, 2023-337 males enrolled in 2wT and were offered WhatsApp or SMS and were included in the analysis. For 2wT reach, 177 (53%) participants chose WhatsApp as their platform (P=.38). Mean client age was 30 years, and 253 (75%) participants chose English for automated messages. From quality assurance calls, almost all respondents (87/89, 98%) were happy with the way they were followed up. For effectiveness, on average for the days on which responses were requested, 58 (33%) WhatsApp clients and 44 (28%) SMS clients responded (P=.50). All 2wT team members believed WhatsApp limited the automated message content, language choices, and inclusivity as compared with the SMS-based 2wT approach.
CONCLUSIONS: When presented with a choice of 2wT communication platform, clients appear evenly split between SMS and WhatsApp. However, WhatsApp requires a smartphone and data plan, potentially reducing reach at scale. Clients using both platforms responded to 2wT interactive prompts, demonstrating similar effectiveness in engaging clients in follow-up. For telehealth interventions, digital health designers should maintain an SMS-based platform and carefully consider adding WhatsApp as an option for clients, using an implementation science approach to present evidence that guides the best implementation approach for their setting.}, }
@article {pmid39410956, year = {2024}, author = {Parker, SA and Weygand, J and Bernat, BG and Jackson, AM and Mawlawi, O and Barreto, I and Hao, Y and Khan, R and Yorke, AA and Swanson, W and Huq, MS and Lief, E and Biancia, CD and Njeh, CF and Al-Basheer, A and Chau, OW and Avery, S and Ngwa, W and Sandwall, PA}, title = {Assessing Radiology and Radiation Therapy Needs for Cancer Care in Low-and-Middle-Income Countries: Insight From a Global Survey of Departmental and Institutional Leaders.}, journal = {Advances in radiation oncology}, volume = {9}, number = {11}, pages = {101615}, pmid = {39410956}, issn = {2452-1094}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: The global cancer burden and mortality rates are increasing, with significant disparities in access to care in low- and middle-income countries (LMICs). This study aimed to identify radiology and radiation therapy needs in LMICs from the perspective of departmental and institutional leaders.
METHODS AND MATERIALS: A survey was developed and conducted by the American Association of Physicists in Medicine Global Needs Assessment Committee and the American Association of Physicists in Medicine International Council. The survey, organized into 5 sections (Introduction, Infrastructure Needs, Education Needs, Research Needs, and General Information), was open to respondents from March 1, to August 16, 2022.
RESULTS: A total of 175 responses were received from 6 global regions: Africa (31.4%), the Americas (17.7%), the Eastern Mediterranean (14.3%), Europe (9.1%), Southeast Asia (23.4%), and the Western Pacific (4.0%). The greatest reported need was for new or updated equipment, particularly positron emission tomography/computed tomography imaging technology. There was also a high demand for clinical and equipment training. Approximately 25% of institutions reported a lack of radiology-based cancer screening programs because of high health care costs and a shortage of specialized equipment. Many institutions that expressed interest in research face funding and grant challenges.
CONCLUSIONS: The findings highlight critical areas where organizations can support LMICs in enhancing radiology and radiation therapy services to mitigate the growing cancer burden.}, }
@article {pmid39406835, year = {2024}, author = {Li, Z and Li, R and Ganan-Gomez, I and Abbas, HA and Garcia-Manero, G and Sun, W}, title = {Accurate identification of locally aneuploid cells by incorporating cytogenetic information in single cell data analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24152}, pmid = {39406835}, issn = {2045-2322}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; U24 CA274212/CA/NCI NIH HHS/United States ; R03CA270725/NH/NIH HHS/United States ; R01GM105785/NH/NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Aneuploidy ; *Algorithms ; Cytogenetic Analysis/methods ; Markov Chains ; Sequence Analysis, RNA/methods ; Leukemia, Myeloid, Acute/genetics/pathology ; Data Analysis ; }, abstract = {Single-cell RNA sequencing is a powerful tool to investigate the cellular makeup of tumor samples. However, due to the sparse data and the complex tumor microenvironment, it can be challenging to identify neoplastic cells that play important roles in tumor growth and disease progression. This is especially relevant for blood cancers, where neoplastic cells may be highly similar to normal cells. To address this challenge, we have developed partCNV and partCNVH, two methods for rapid and accurate detection of aneuploid cells with local copy number deletion or amplification. PartCNV uses an expectation-maximization (EM) algorithm with mixtures of Poisson distributions and incorporates cytogenetic information to guide the classification. PartCNVH further improves partCNV by integrating a hidden Markov model for feature selection. We have thoroughly evaluated the performance of partCNV and partCNVH through simulation studies and real data analysis using three scRNA-seq datasets from blood cancer patients. Our results show that partCNV and partCNVH have favorable accuracy and provide more interpretable results compared to existing methods. In the real data analysis, we have identified multiple biological processes involved in the oncogenesis of myelodysplastic syndromes and acute myeloid leukemia.}, }
@article {pmid39405343, year = {2024}, author = {Hamilton, E and Galsky, MD and Ochsenreither, S and Del Conte, G and Martín, M and De Miguel, MJ and Yu, EY and Williams, A and Gion, M and Tan, AR and Agrawal, L and Rutten, A and Machiels, JP and Cresta, S and Debruyne, PR and Hennequin, A and Moreno, V and Minchom, A and Valdes-Albini, F and Petrylak, D and Li, L and Tsuchihashi, Z and Suto, F and Cheng, FC and Kandil, M and Barrios, D and Hurvitz, S}, title = {Trastuzumab Deruxtecan with Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {30}, number = {24}, pages = {5548-5558}, pmid = {39405343}, issn = {1557-3265}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; //AstraZeneca (AstraZeneca PLC)/ ; //Daiichi Sankyo Inc./ ; }, mesh = {Humans ; Female ; *Trastuzumab/administration & dosage/adverse effects/therapeutic use ; *Receptor, ErbB-2/metabolism/genetics ; Aged ; Middle Aged ; *Breast Neoplasms/drug therapy/pathology/genetics/metabolism ; *Nivolumab/administration & dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Male ; Adult ; Urologic Neoplasms/drug therapy/pathology/genetics ; Aged, 80 and over ; Immunoconjugates/adverse effects/administration & dosage/therapeutic use ; Neoplasm Metastasis ; Camptothecin/analogs & derivatives ; }, abstract = {PURPOSE: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).
PATIENTS AND METHODS: Part 1 determined the recommended dose for expansion of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate by independent central review.
RESULTS: In part 1, seven patients with mBC were enrolled and received T-DXd 3.2 mg/kg (four patients) or 5.4 mg/kg (three patients) plus nivolumab. The recommended dose for expansion for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously every 3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of three administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and four with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the confirmed objective response rates (95% confidence interval) for cohorts 1 to 4 were 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. The median treatment duration (range) with T-DXd in cohorts 1 to 4 was 8.9 (1-23) months, 6.9 (1-21) months, 3.9 (1-21) months, and not assessed, respectively; the most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, and 75.0%, respectively). Adjudicated drug-related interstitial lung disease/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0%, respectively (one grade 5 each, cohorts 1 and 3).
CONCLUSIONS: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T-DXd. Interstitial lung disease/pneumonitis is an important risk and requires careful monitoring and prompt intervention.}, }
@article {pmid39404767, year = {2024}, author = {Li, Y and Lee, T and Marin, K and Hua, X and Srinivasan, S and Fredricks, DN and Lee, JR and Ling, W}, title = {SurvBal: compositional microbiome balances for survival outcomes.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {10}, pages = {}, pmid = {39404767}, issn = {1367-4811}, support = {R01 GM155734/GM/NIGMS NIH HHS/United States ; R01 GM129512/GM/NIGMS NIH HHS/United States ; }, mesh = {*Microbiota ; *Software ; Humans ; Proportional Hazards Models ; Survival Analysis ; Bacteria/classification ; }, abstract = {SUMMARY: Identification of balances of bacterial taxa in relation to continuous and dichotomous outcomes is an increasingly frequent analytic objective in microbiome profiling experiments. SurvBal enables the selection of balances in relation to censored survival or time-to-event outcomes which are of considerable interest in many biomedical studies. The most commonly used survival models-the Cox proportional hazards and parametric survival models are included in the package, which are used in combination with step-wise selection procedures to identify the optimal associated balance of microbiome, i.e. the ratio of the geometric means of two groups of taxa's relative abundances.
The SurvBal R package and Shiny app can be accessed at https://github.com/yinglia/SurvBal and https://yinglistats.shinyapps.io/shinyapp-survbal/.}, }
@article {pmid39403956, year = {2024}, author = {Young, CL and Beichman, AC and Mas-Ponte, D and Hemker, SL and Zhu, L and Kitzman, JO and Shirts, BH and Harris, K}, title = {A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.}, journal = {Genetics}, volume = {228}, number = {4}, pages = {}, pmid = {39403956}, issn = {1943-2631}, support = {R01 GM129123/GM/NIGMS NIH HHS/United States ; R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; }, abstract = {Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.}, }
@article {pmid39403932, year = {2024}, author = {Zhang, P and Minnie, SA and Hill, GR}, title = {Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. Reply.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {20}, pages = {}, pmid = {39403932}, issn = {1558-8238}, mesh = {Animals ; Humans ; Mice ; Calcineurin/metabolism/immunology/genetics ; *Calcineurin Inhibitors ; Chronic Disease ; *Graft vs Host Disease/immunology/pathology ; Immunologic Memory ; *Isoantigens/immunology ; Memory T Cells/immunology ; T-Lymphocyte Subsets/immunology/metabolism ; }, }
@article {pmid39402405, year = {2024}, author = {Bologna, E and Licari, LC and Badani, KK and Razdan, S and Psutka, SP and Ditonno, F and Ramos-Carpinteyro, R and Soputro, NA and Jackson, JC and Nelson, R and Rais-Bahrami, S and White, WM and Djaladat, H and Pierorazio, PM and Eun, DD and Kutikov, A and Margulis, V and Kovac, E and Kim, IY and Anele, UA and Mehrazin, R and Ben-David, R and Viers, BR and Su, LM and Rogers, CG and Abdollah, F and Ghazi, A and Cherullo, EE and Vourganti, S and Coogan, CL and Raman, JD and Sundaram, CP and Stifelman, M and Link, RE and Kaouk, J and Crivellaro, S and Autorino, R}, title = {The impact of single-port robotic surgery: a survey among urology residents and fellows in the United States.}, journal = {Journal of robotic surgery}, volume = {18}, number = {1}, pages = {369}, pmid = {39402405}, issn = {1863-2491}, mesh = {*Robotic Surgical Procedures/education/statistics & numerical data ; *Internship and Residency ; United States ; Humans ; Surveys and Questionnaires ; *Urology/education ; *Fellowships and Scholarships ; Urologic Surgical Procedures/education ; Male ; Female ; Clinical Competence ; }, abstract = {Our aim was to investigate the perception and future expectations of Single-Port (SP) surgery among urology trainees in the United States. A 34-item online survey was distributed to urological residency and fellowship programs across the US, covering demographic profiles, SP training opportunities, perceived educational impact, and future perspectives. Descriptive analysis and multivariable linear regression were used to assess predictors of SP adoption. 201 surveys were completed (28.6% completion rate). Among institutions with an SP platform, about 50% have used it regularly for over 2 years, though often in less than 50% of procedures. While robotic simulators are commonly available, only 17% offer both multi-port and SP simulators, and structured pre-clinical SP training is limited. Approximately 30% of respondents expressed concerns over limited hands-on experience and a steeper learning curve with SP. Around 40% felt that their robotic surgery exposure was negatively impacted by SP's introduction. SP surgery's benefits are seen mostly in the immediate post-operative period and a significant number of respondents foresee a major role for SP in urology. However, proficiency in SP surgery is not seen as crucial for career advancement or job opportunities. Academic job aspirations, SP platform availability, and SP surgery workload are predictors of future SP implementation. Trainees increasingly recognize the clinical benefits of SP procedures but express concerns about the potential negative impact on hands-on experience. Training programs should more systematically integrate SP technology into curricula. There is a correlation between training in high-volume SP centers and future SP adoption.}, }
@article {pmid39401968, year = {2024}, author = {Pulliam, T and Jani, S and Goff, PH and Bhakuni, R and Tabachnick-Cherny, S and Smythe, K and Seaton, BW and Tachiki, L and Kulikauskas, R and Church, C and Koelle, DM and Nghiem, P and Bhatia, S}, title = {Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {10}, pages = {}, pmid = {39401968}, issn = {2051-1426}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; F30 CA254168/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/immunology ; *Membrane Proteins/metabolism ; Skin Neoplasms/drug therapy/immunology/pathology ; Biomarkers, Tumor/metabolism ; Male ; B7-H1 Antigen/metabolism ; Aged ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions.
METHODS: We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines.
RESULTS: We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient's tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient's tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors.
CONCLUSIONS: Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.}, }
@article {pmid39398350, year = {2024}, author = {Chen, Z and Li, X and Zhang, B}, title = {The role of randomization inference in unraveling individual treatment effects in early phase vaccine trials.}, journal = {Statistical communications in infectious diseases}, volume = {16}, number = {1}, pages = {}, pmid = {39398350}, issn = {2194-6310}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Randomization inference is a powerful tool in early phase vaccine trials when estimating the causal effect of a regimen against a placebo or another regimen. Randomization-based inference often focuses on testing either Fisher's sharp null hypothesis of no treatment effect for any participant or Neyman's weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results to a special case where naïve participants are expected not to exhibit responses to highly specific endpoints. These methods are suitable for completely randomized trials, stratified completely randomized trials, and a matched study comparing two non-randomized arms from possibly different trials. We evaluate the usefulness of these methods using synthetic data in simulation studies. Finally, we apply these methods to HIV Vaccine Trials Network Study 086 (HVTN 086) and HVTN 205 and showcase a wide range of application scenarios of the methods. R code that replicates all analyses in this article can be found in first author's GitHub page at https://github.com/Zhe-Chen-1999/ITE-Inference.}, }
@article {pmid39396254, year = {2024}, author = {Petersdorf, EW}, title = {HLA structure and function in hematopoietic-cell transplantation.}, journal = {Best practice & research. Clinical haematology}, volume = {37}, number = {3}, pages = {101564}, doi = {10.1016/j.beha.2024.101564}, pmid = {39396254}, issn = {1532-1924}, support = {U01 AI069197/AI/NIAID NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *HLA Antigens/immunology/genetics ; Killer Cells, Natural/immunology ; Polymorphism, Genetic ; Donor Selection ; Allografts ; Histocompatibility Testing ; Transplantation, Homologous ; }, abstract = {The degree of HLA compatibility between a patient and donor has formed the basis of donor selection since the development of allogeneic hematopoietic cell transplantation over 50 years ago and has advanced understanding of the basic immunobiology of HLA. New evidence supports a role for germline variation in the patient and the donor that do not require HLA matching for their effects to have clinical consequences. The discovery of novel non-coding polymorphisms, structural features of HLA molecules, and expression provide new models for donor selection and inspire the development of tools for clinical translation. Pairwise effects of HLA ligand/donor NK receptors may play an important role in transplant outcomes and showcase the value of understanding the role played by each constituent of the NK pathway in modulating donor responses to target antigens.}, }
@article {pmid39396092, year = {2024}, author = {Denos, M and Sun, YQ and Brumpton, BM and Li, Y and Albanes, D and Burnett-Hartman, A and Campbell, PT and Küry, S and Li, CI and White, E and Samadder, JN and Jenkins, MA and Mai, XM}, title = {Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23891}, pmid = {39396092}, issn = {2045-2322}, support = {R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Female ; *Mendelian Randomization Analysis ; *Lung Neoplasms/genetics/epidemiology ; *Genome-Wide Association Study ; *Gonadal Steroid Hormones/metabolism ; Sex Hormone-Binding Globulin/genetics/metabolism ; Risk Factors ; Testosterone/blood ; Polymorphism, Single Nucleotide ; Middle Aged ; White People/genetics ; }, abstract = {The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.}, }
@article {pmid39396053, year = {2024}, author = {Marcink, TC and Zipursky, G and Sobolik, EB and Golub, K and Herman, E and Stearns, K and Greninger, AL and Porotto, M and Moscona, A}, title = {How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8831}, pmid = {39396053}, issn = {2041-1723}, support = {R01 AI160953/AI/NIAID NIH HHS/United States ; R01 AI114736/AI/NIAID NIH HHS/United States ; U19 AI181984/AI/NIAID NIH HHS/United States ; AI121349//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI160961/AI/NIAID NIH HHS/United States ; AI160961//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160953//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI152275//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI114736//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; F32 AI152275/AI/NIAID NIH HHS/United States ; R01 AI121349/AI/NIAID NIH HHS/United States ; }, mesh = {*Antibodies, Neutralizing/immunology ; *Viral Fusion Proteins/immunology/metabolism/chemistry ; Humans ; *Virus Internalization ; *Parainfluenza Virus 3, Human/immunology ; Antibodies, Viral/immunology ; Cryoelectron Microscopy ; HN Protein/metabolism/immunology/chemistry/genetics ; Antibodies, Monoclonal/immunology ; Animals ; Mutation ; Models, Molecular ; }, abstract = {Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.}, }
@article {pmid39395534, year = {2024}, author = {Henry, NL and Unger, JM and Vaidya, R and Darke, AK and Skaar, TC and Fisch, MJ and Hershman, DL}, title = {Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107712}, pmid = {39395534}, issn = {1559-2030}, support = {R01 CA266012/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; *Antineoplastic Agents, Hormonal/therapeutic use/administration & dosage/adverse effects ; Anxiety ; *Aromatase Inhibitors/therapeutic use/adverse effects/administration & dosage ; Arthralgia ; *Breast Neoplasms/drug therapy ; Chemotherapy, Adjuvant/methods ; Estradiol/administration & dosage ; Hot Flashes/chemically induced ; Medication Adherence ; Patient Education as Topic ; *Premenopause ; Quality of Life ; Self Efficacy ; *Tamoxifen/therapeutic use/administration & dosage/adverse effects ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Premenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET.
METHODS: Pre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24 weeks, then every 4 weeks for 48 weeks. All participants will complete a battery of questionnaires every 12 weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72 weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72 weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression.
CONCLUSION: We expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence.
CLINICALTRIALS: govNCT05568472.}, }
@article {pmid39395448, year = {2024}, author = {Zhu, A and Psutka, SP}, title = {Editorial Comment on "Comparing Frailty Indices for Risk Stratifi cation in Urologic Oncology: Which Index to Choose?".}, journal = {Urology}, volume = {194}, number = {}, pages = {163-164}, doi = {10.1016/j.urology.2024.10.009}, pmid = {39395448}, issn = {1527-9995}, }
@article {pmid39387238, year = {2024}, author = {Khanijow, K and Rosendale, N and Wright, S and Lee, RS and Nass, S and Keniston, A and Dalal, M and Jager, LR and Anstett, T}, title = {Characterizing hospitalists' comfort and familiarity with LGBTQ clinical topics.}, journal = {Hospital practice (1995)}, volume = {}, number = {}, pages = {}, pmid = {39387238}, issn = {2154-8331}, support = {UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {OBJECTIVES: Evidence has shown that lesbian, gay, bisexual, queer (LGBQ) and transgender patients (LGBTQ) experience disparities in health care delivery and clinical outcomes. As the predominant U.S. inpatient provider workforce, this paper's objective was to understand hospitalists' comfort with LGBTQ health.
METHODS: A 58-question anonymous online survey was distributed in 2019 to practicing hospitalists through the Society of Hospital Medicine regarding their experiences in caring for hospitalized LGBTQ patients.
RESULTS: Two hundred and eighteen hospitalist providers completed the entire survey. While hospitalists reported high levels of comfort in caring for these populations (LGBQ: 90.6%, Transgender: 77.8%), they acknowledged feeling less confident in their clinical competence (LGBQ: 71.6%, Transgender: 51.2%). Hospitalist providers who were themselves LGBQ reported more comfort with most aspects of LGBQ patient clinical care than heterosexual respondents (p < 0.05 for 4 of 6 comfort variables). Seventy-four percent of hospitalists wanted training to advance their knowledge and skills in working with LGBTQ patients.
CONCLUSIONS: Hospitalist clinicians are regularly exposed to LGBTQ patients yet their comfort and expertise in caring for this vulnerable population is highly variable. Educational interventions that include reflective practice may serve to optimize hospitalists' ability to more confidently and competently serve LGBTQ patients.}, }
@article {pmid39394376, year = {2024}, author = {Ogimi, C and Xie, H and Waghmare, A and Jerome, KR and Leisenring, WM and Ueda Oshima, M and Carpenter, PA and Englund, JA and Boeckh, M}, title = {Correction: Novel factors to predict respiratory viral disease progression in allogeneic hematopoietic cell transplant recipients.}, journal = {Bone marrow transplantation}, volume = {59}, number = {12}, pages = {1790}, doi = {10.1038/s41409-024-02418-9}, pmid = {39394376}, issn = {1476-5365}, }
@article {pmid39394013, year = {2025}, author = {Gillessen, S and Turco, F and Davis, ID and Efstathiou, JA and Fizazi, K and James, ND and Shore, N and Small, E and Smith, M and Sweeney, CJ and Tombal, B and Zilli, T and Agarwal, N and Antonarakis, ES and Aparicio, A and Armstrong, AJ and Bastos, DA and Attard, G and Axcrona, K and Ayadi, M and Beltran, H and Bjartell, A and Blanchard, P and Bourlon, MT and Briganti, A and Bulbul, M and Buttigliero, C and Caffo, O and Castellano, D and Castro, E and Cheng, HH and Chi, KN and Clarke, CS and Clarke, N and de Bono, JS and De Santis, M and Duran, I and Efstathiou, E and Ekeke, ON and El Nahas, TIH and Emmett, L and Fanti, S and Fatiregun, OA and Feng, FY and Fong, PCC and Fonteyne, V and Fossati, N and George, DJ and Gleave, ME and Gravis, G and Halabi, S and Heinrich, D and Herrmann, K and Hofman, MS and Hope, TA and Horvath, LG and Hussain, MHA and Jereczek-Fossa, BA and Jones, RJ and Joshua, AM and Kanesvaran, R and Keizman, D and Khauli, RB and Kramer, G and Loeb, S and Mahal, BA and Maluf, FC and Mateo, J and Matheson, D and Matikainen, MP and McDermott, R and McKay, RR and Mehra, N and Merseburger, AS and Morgans, AK and Morris, MJ and Mrabti, H and Mukherji, D and Murphy, DG and Murthy, V and Mutambirwa, SBA and Nguyen, PL and Oh, WK and Ost, P and O'Sullivan, JM and Padhani, AR and Parker, C and Poon, DMC and Pritchard, CC and Rabah, DM and Rathkopf, D and Reiter, RE and Renard-Penna, R and Ryan, CJ and Saad, F and Sade, JP and Sandhu, S and Sartor, OA and Schaeffer, E and Scher, HI and Sharifi, N and Skoneczna, IA and Soule, HR and Spratt, DE and Srinivas, S and Sternberg, CN and Suzuki, H and Taplin, ME and Thellenberg-Karlsson, C and Tilki, D and Türkeri, LN and Uemura, H and Ürün, Y and Vale, CL and Vapiwala, N and Walz, J and Yamoah, K and Ye, D and Yu, EY and Zapatero, A and Omlin, A}, title = {Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC).}, journal = {European urology}, volume = {87}, number = {2}, pages = {157-216}, doi = {10.1016/j.eururo.2024.09.017}, pmid = {39394013}, issn = {1873-7560}, mesh = {Humans ; Male ; *Prostatic Neoplasms/therapy/pathology ; Consensus ; Delphi Technique ; }, abstract = {BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024.
METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists").
KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis.
The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.}, }
@article {pmid39392812, year = {2025}, author = {Sharma, V and Fadel, A and Tollefson, MK and Psutka, SP and Blezek, DJ and Frank, I and Thapa, P and Tarrell, R and Viers, LD and Potretzke, AM and Hartman, RP and Boorjian, SA and Viers, BR}, title = {Artificial Intelligence-Based Assessment of Preoperative Body Composition Is Associated With Early Complications After Radical Cystectomy.}, journal = {The Journal of urology}, volume = {213}, number = {2}, pages = {228-237}, doi = {10.1097/JU.0000000000004292}, pmid = {39392812}, issn = {1527-3792}, mesh = {Humans ; Male ; *Cystectomy/adverse effects/methods ; Female ; *Postoperative Complications/epidemiology/etiology ; *Body Composition ; *Urinary Bladder Neoplasms/surgery ; Aged ; *Artificial Intelligence ; Middle Aged ; *Tomography, X-Ray Computed ; Retrospective Studies ; Preoperative Period ; }, abstract = {PURPOSE: We aimed to use a validated artificial intelligence (AI) algorithm to extract muscle and adipose areas from CT images before radical cystectomy (RCx) and then correlate these measures with 90-day post-RCx complications.
MATERIALS AND METHODS: A tertiary referral center's cystectomy registry was queried for patients who underwent RCx between 2009 and 2017 for bladder cancer. Eight hundred forty-three RCx patients with CT imaging within 90 days of preceding surgery were included, to allow for extraction of body composition parameters by AI. We assessed complications within 90 days of surgery including wound, infectious, and major complications; readmission; and death. Multivariable logistic regressions associated pre-RCx measures with post-RCx complications.
RESULTS: Increasing subcutaneous adipose tissue was associated with more wound complications, while patients with increasing visceral adipose tissue had greater odds of infectious-related complications. After adjusting for patient characteristics, every 10 cm[2] increases in fat mass index were associated with more infectious (odds ratio [OR], 1.04; P = .002) and wound (OR, 1.06; P < .001) complications. On multivariable analysis, a higher preoperative skeletal muscle index was associated with lower odds of major complications (OR, 0.75 for every 10 cm[2]; P = .008), while higher intramuscular adipose was associated with higher odds of major complications (OR, 1.93; P = .008).
CONCLUSIONS: Automated AI body composition measurements preoperatively are associated with post-RCx complications. These measurements, in addition to patient (Eastern Cooperative Oncology Group performance status and smoking status) and surgical (robotic approach and continent diversion) characteristics, can then be used to individualize patient counseling and facilitate triage of nutritional and rehabilitation efforts.}, }
@article {pmid39391570, year = {2024}, author = {Brown, MC and Snidarich, M and Budak, JZ and Murphy, N and Giustini, N and Romine, PE and Weiner, BJ and Caverly, T and Crothers, K and Triplette, M}, title = {Adaptation of a Tailored Lung Cancer Screening Decision Aid for People With HIV.}, journal = {CHEST pulmonary}, volume = {2}, number = {3}, pages = {}, pmid = {39391570}, issn = {2949-7892}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA244432/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: People with HIV are both at elevated risk of lung cancer and at high risk of multimorbidity, which makes shared decision-making (SDM) for lung cancer screening (LCS) in people with HIV complex. Currently no known tools have been adapted for SDM in people with HIV.
RESEARCH QUESTION: Can an SDM decision aid be adapted to include HIV-specific measures with input from both people with HIV and their providers?
STUDY DESIGN AND METHODS: This study used qualitative methods including focus groups of people with HIV and interviews with HIV care providers to adapt and iterate an SDM tool for people with HIV. Eligible participants were those with HIV enrolled in an HIV primary care clinic who met age and smoking eligibility criteria for LCS and HIV care providers at the clinic. Both the focus groups and interviews included semistructured discussions of SDM and decision aid elements for people with HIV. We used a framework-guided thematic analysis, mapping themes onto the Health Equity Implementation framework.
RESULTS: Forty-three people with HIV participated in eight focus groups; 10 providers were interviewed. Key themes from patients included broad interest in adapting LCS SDM specifically for people with HIV, a preference for clear LCS recommendations, and the need for positive framing emphasizing survival. Providers were enthusiastic about personalized LCS risk assessments and point-of-care tools. Both patients and providers gave mixed views on the usefulness of HIV-specific risk measures in patient-facing tools. Themes were used to adapt a personalized and flexible SDM tool for LCS in people with HIV.
INTERPRETATION: People with HIV and providers were enthusiastic about specific tools for SDM that are personalized and tailored for people with HIV, that make recommendations, and that inform LCS decision-making. Divergent views on presenting patient-facing quantitative risk assessments suggests that these elements could be optional but available for review. This tool may have usefulness in complex decision-making for LCS in this population and currently is being evaluated in a pilot prospective trial.}, }
@article {pmid39389851, year = {2024}, author = {Swank, Z and Borberg, E and Chen, Y and Senussi, Y and Chalise, S and Manickas-Hill, Z and Yu, XG and Li, JZ and Alter, G and Henrich, TJ and Kelly, JD and Hoh, R and Goldberg, SA and Deeks, SG and Martin, JN and Peluso, MJ and Talla, A and Li, X and Skene, P and Bumol, TF and Torgerson, TR and Czartoski, JL and McElrath, MJ and Karlson, EW and Walt, DR and , }, title = {Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study.}, journal = {Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases}, volume = {30}, number = {12}, pages = {1599-1605}, pmid = {39389851}, issn = {1469-0691}, support = {R01 AI158013/AI/NIAID NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; UM1 TR004409/TR/NCATS NIH HHS/United States ; R01 AI176287/AI/NIAID NIH HHS/United States ; UM1 TR004528/TR/NCATS NIH HHS/United States ; R01 NS136197/NS/NINDS NIH HHS/United States ; R01 AI141003/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/diagnosis/blood/immunology/epidemiology ; Male ; Female ; *SARS-CoV-2/immunology ; Middle Aged ; *Antigens, Viral/blood/immunology ; Adult ; *Spike Glycoprotein, Coronavirus/immunology ; Aged ; Coronavirus Nucleocapsid Proteins/immunology ; Cohort Studies ; Phosphoproteins/blood/immunology ; }, abstract = {OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.
METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records.
RESULTS: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2).
DISCUSSION: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.}, }
@article {pmid39388026, year = {2024}, author = {Chen, JG and Zhang, YH and Lu, JH and Kensler, TW}, title = {Liver Cancer Etiology: Old Issues and New Perspectives.}, journal = {Current oncology reports}, volume = {26}, number = {11}, pages = {1452-1468}, pmid = {39388026}, issn = {1534-6269}, mesh = {Humans ; Aflatoxins/adverse effects/toxicity ; Alcohol Drinking/adverse effects ; Diet/adverse effects ; Genetic Predisposition to Disease ; Life Style ; *Liver Neoplasms/epidemiology/etiology ; Risk Factors ; }, abstract = {PURPOSE OF REVIEW: This review aims to synthesize the old issues and current understandings of the etiology of liver cancer, focusing on the diverse causative factors influenced by geographical, socioeconomic, and lifestyle variations across different regions.
RECENT FINDINGS: We highlight significant geographic disparities in liver cancer risk factors. While hepatitis B and C viruses, aflatoxin exposure, and alcohol consumption remain globally established contributors; metabolic dysfunction-associated steatotic liver disease and metabolic syndromes are increasingly prominent in the West. Chronic HBV and aflatoxin continue to dominate as risk factors in Asia and Africa. Dietary factors, metabolic diseases like diabetes and obesity, genetic predispositions, environmental risk factors and lifestyle choices such as smoking and alcohol use play substantial roles in specific populations. Protective factors like coffee and tea consumption, along with aspirin use, vegetables and fruits have shown potential in reducing HCC risk, although findings vary by population and dietary habits. Liver cancer etiology is influenced by various factors that differ by region. Established risk factors include hepatitis B and C, aflatoxin, and alcohol. Emerging risks, such as metabolic dysfunction-associated steatotic liver disease, are more prevalent in Western countries, while aflatoxin and HBV remains significant in Asia and Africa. Diet, metabolic conditions like diabetes and obesity, genetic predispositions, and lifestyle choices also play crucial roles. Coffee, tea, aspirin, vegetables, and fruits may reduce HCC risk, but effectiveness varies. Future research should integrate epidemiology, genetics, and nutrition, with global cooperation and data sharing essential for effective cancer control strategies.}, }
@article {pmid39388304, year = {2025}, author = {Bryce, Y and Whitton, JA and Stratton, KL and Leisenring, WM and Chow, EJ and Armstrong, G and Weil, B and Dieffenbach, B and Howell, RM and Oeffinger, KC and Nathan, PC and Tonorezos, ES}, title = {Prevalence of carotid ultrasound screening in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {131}, number = {1}, pages = {e35591}, pmid = {39388304}, issn = {1097-0142}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; U24 CA55727//Childhood Cancer Survivor Study/ ; P30 CA 008748//Vickers/ ; }, mesh = {Humans ; Male ; Female ; *Cancer Survivors/statistics & numerical data ; Child ; Adult ; Prevalence ; Adolescent ; *Ultrasonography ; *Neoplasms/radiotherapy/epidemiology/diagnostic imaging ; Young Adult ; Carotid Arteries/diagnostic imaging/radiation effects ; Middle Aged ; Cardiovascular Diseases/epidemiology/diagnostic imaging/etiology ; Child, Preschool ; Ultrasonography, Carotid Arteries ; }, abstract = {INTRODUCTION: Many childhood cancer survivors are at risk for cardiovascular disease and stroke. The North American Children's Oncology Group long-term follow-up guidelines recommend carotid ultrasound in cancer survivors 10 years after neck radiation therapy (RT) ≥40 Gy. The use of carotid ultrasound in this population has not been described.
METHODS: Survivors of childhood cancer diagnosed 1970-1999 (N = 8693) and siblings (N = 1989) enrolled in the Childhood Cancer Survivor Study were asked if they had ever had a carotid ultrasound. Prevalence of carotid ultrasound was evaluated. Prevalence ratios (PR) and 95% confidence intervals (CIs) were evaluated in multivariate Poisson regression models.
RESULTS: Among participants with no reported cardiovascular condition, prevalence of carotid ultrasound among survivors with RT ≥40 Gy to the neck (N = 172) was 29.7% (95% CI, 22.5-36.8), significantly higher than those with <40 Gy (prevalence 10.7%; 95% CI, 9.9%-11.4%). Siblings without a cardiovascular condition (N = 1621) had the lowest prevalence of carotid ultrasound (4.7%; 95% CI, 3.6%-5.7%). In a multivariable models among survivors with no reported cardiovascular condition and RT ≥40 Gy to the neck, those who were over age 50 (vs. 18-49) at follow-up (PR = 1.82; 95% CI, 1.09-3.05), with a history of seeing a cancer specialist in the last 2 years (PR = 2.58; 95% CI, 1.53-4.33), or having a colonoscopy (PR = 2.02; 95% CI, 1.17-3.48) or echocardiogram (PR = 6.42; 95% CI, 1.54-26.85) were more likely to have had a carotid ultrasound.
CONCLUSION: Many survivors do not undergo carotid ultrasound despite meeting existing guidelines. Health care delivery features such as having seen a cancer specialist or having other testing are relevant.}, }
@article {pmid39386724, year = {2024}, author = {Alassaf, M and Rajan, A}, title = {Adipocyte metabolic state regulates glial phagocytic function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386724}, issn = {2692-8205}, support = {P40 OD018537/OD/NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, abstract = {Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders[1-4], yet the underlying mechanisms remain poorly understood. The adipocyte-brain axis is crucial for brain function, as adipocytes secrete signaling molecules, including lipids and adipokines, that impinge on neural circuits to regulate feeding and energy expenditure[5]. Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions[6], but the causal links are not fully understood. Neural debris accumulates with age and injury, and glial phagocytic function is crucial for clearing this debris and maintaining a healthy brain microenvironment[7-9]. Using adult Drosophila, we investigate how adipocyte metabolism influences glial phagocytic activity in the brain. We demonstrate that a prolonged obesogenic diet increases adipocyte fatty acid oxidation and ketogenesis. Genetic manipulations that mimic obesogenic diet-induced changes in adipocyte lipid and mitochondrial metabolism unexpectedly reduce the expression of the phagocytic receptor Draper in Drosophila microglia-like cells in the brain. We identify Apolpp-the Drosophila equivalent of human apolipoprotein B (ApoB)-as a critical adipocyte-derived signal that regulates glial phagocytosis. Additionally, we show that Lipoprotein Receptor 1 (LpR1), the LDL receptor on phagocytic glia, is required for glial capacity to clear injury-induced neuronal debris. Our findings establish that adipocyte-brain lipoprotein signaling regulates glial phagocytic function, revealing a novel pathway that links adipocyte metabolic disorders with neurodegeneration.}, }
@article {pmid39386474, year = {2024}, author = {Freie, B and Ibrahim, AH and Carroll, PA and Bronson, RT and Augert, A and MacPherson, D and Eisenman, RN}, title = {MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386474}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248762/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Delet-ing Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.}, }
@article {pmid39386462, year = {2024}, author = {Wellington, R and Cheng, X and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S}, title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386462}, issn = {2692-8205}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; R01 DK131162/DK/NIDDK NIH HHS/United States ; DP2 HL147126/HL/NHLBI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; }, abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE). In this process, HE cells undergo a unique fate change termed endothelial-to-hematopoietic transition, or EHT. While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, the generation of bona fide HSCs from iPSCs remains a challenge. Here, we map single cell dynamics of EHT during embryoid body differentiation from iPSCs and integrate it with human embryo datasets to identify key transcriptional differences between in vitro and in vivo cell states. We further map ligand-receptor interactions associated with differential expression of developmental programs in the iPSC system. We found that the expression of endothelial genes was incompletely repressed during iPSC EHT. Elevated FGF signaling by FGF23, an endothelial pathway ligand, was associated with differential gene expression between in vitro and in vivo EHT. Chemical inhibition of FGF signaling during EHT increased HSPC generation in the zebrafish, while an FGF agonist had the opposite effect. Consistently, chemical inhibition of FGF signaling increased hematopoietic output from iPSCs. In summary, we map the dynamics of EHT from iPSCs at single cell resolution and identify ligand-receptor interactions that can be modulated to improve iPSC differentiation protocols. We show, as proof of principle, that chemical inhibition of FGF signaling during EHT improves hematopoietic output in zebrafish and the iPSC system.}, }
@article {pmid39386436, year = {2024}, author = {Nguyen, TNH and Horowitz, LF and Nguyen, B and Lockhart, E and Zhu, S and Gujral, TS and Folch, A}, title = {Microfluidic Modulation of Microvasculature in Microdissected Tumors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386436}, issn = {2692-8205}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; }, abstract = {The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo (e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.}, }
@article {pmid39385741, year = {2025}, author = {Mosna, F and Borlenghi, E and Litzow, M and Byrd, JC and Papayannidis, C and Tecchio, C and Ferrara, F and Marcucci, G and Cairoli, R and Morgan, EA and Gurrieri, C and Yeung, CCS and Deeg, HJ and Capelli, D and Candoni, A and Gotlib, JR and Lunghi, M and Pullarkat, S and Lanza, F and Galimberti, S and Forghieri, F and Venditti, A and Festuccia, M and Audisio, E and Marvalle, D and Rigolin, GM and Roti, G and DiBona, E and Visani, G and Albano, F and Eisfeld, AK and Valent, P and Huls, G and Borthakur, G and Krampera, M and Martinelli, G and Kröger, N and Sperotto, A and Gottardi, M}, title = {Long-term survival can be achieved in a significant fraction of older patients with core-binding factor acute myeloid leukemia treated with intensive chemotherapy.}, journal = {Haematologica}, volume = {110}, number = {3}, pages = {608-620}, pmid = {39385741}, issn = {1592-8721}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA262496/CA/NCI NIH HHS/United States ; R01 CA283574/CA/NCI NIH HHS/United States ; R01 CA284595/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/mortality/drug therapy/genetics/therapy/diagnosis ; Male ; Aged ; Female ; *Core Binding Factors/genetics/metabolism ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Adult ; Hematopoietic Stem Cell Transplantation ; Age Factors ; Treatment Outcome ; }, abstract = {Acute myeloid leukemia (AML) is mainly a disease of the elderly: however, knowledge about the outcomes of treatment of core-binding factor (CBF) AML in an older population is limited. We retrospectively collected data on 229 patients with CBF-AML followed long-term in the last two decades. The 5-year overall survival was 44.2% (95% confidence interval [95% CI]: 39.9-47.5) and the 5-year event-free survival was 32.9% (95% CI: 25.5-40.1). In a subgroup of patients ≥70 years old who completed intensive therapy (induction + ≥3 courses of consolidation including autologous stem cell transplantation: 10 patients) the median event-free survival was 11.8 months (95% CI: 9.4-15.2) and overall survival was 40.0% (95% CI: 36.4- 44.1) at 5 years. In univariate analysis, age ≥70 years (hazard ratio [HR]=1.78, 95% CI: 1.15-2.54, P=0.008), failure to achieve remission following induction (HR=8.96, 95% CI: 5.5-13.8; P<0.0001), no consolidation therapy (HR=0.75, 95% CI: 0.47-1.84, P=0.04) and fewer than three cycles of consolidation (HR=1.48, 95% CI: 0.75-3.2; P=0.0004) predicted poorer event-free survival. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a complete remission seems to be the most important first step and at least three cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.}, }
@article {pmid39385266, year = {2024}, author = {Saldarriaga, EM and Chen, Y and Montaño, MA and Thuo, N and Kiptinness, C and Terris-Prestholt, F and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Preferences for pre-exposure prophylaxis delivery via online pharmacy among potential users in Kenya: a discrete choice experiment.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {10}, pages = {e26356}, pmid = {39385266}, issn = {1758-2652}, support = {INV-035932/GATES/Bill & Melinda Gates Foundation/United States ; INV-038498/GATES/Bill & Melinda Gates Foundation/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; INV 035424//Bill and Melinda Gates Foundation/ ; INV-037646/GATES/Bill & Melinda Gates Foundation/United States ; }, mesh = {Humans ; *Pre-Exposure Prophylaxis/methods ; Kenya ; Male ; Female ; *HIV Infections/prevention & control ; Adult ; Young Adult ; Adolescent ; Middle Aged ; Anti-HIV Agents/therapeutic use/administration & dosage ; Pharmaceutical Services, Online ; Patient Preference ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is highly effective, but coverage remains low in high HIV prevalence settings. Initiating and continuing PrEP remotely via online pharmacies is a promising strategy to expand PrEP uptake, but little is known about potential users' preferences.
METHODS: We conducted a discrete choice experiment (DCE) to assess preferences for online pharmacy PrEP services. We partnered with MYDAWA, an online pharmacy in Nairobi, Kenya. Eligibility criteria were: ≥18 years, not known HIV positive, interested in PrEP. The DCE contained four attributes: PrEP eligibility assessment (online self-assessed, guided), HIV test type (provider administered, oral HIV self-test [HIVST], blood-based HIVST), clinical consultation (remote, in-person) and user support options (text messages, phone/video call, email). Additionally, participants indicated whether they were willing to uptake their selected service. The survey was advertised on MYDAWA's website; interested participants met staff in-person at a convenient location to complete the survey from 1 June to 20 November 2022. We used conditional logit modelling with an interaction by current PrEP use to estimate overall preferences and latent class analysis (LCA) to assess preference heterogeneity.
RESULTS: Overall, 772 participants completed the DCE; the mean age was 25 years and 54% were female. Most participants indicated a willingness to acquire online PrEP services, with particularly high demand among PrEP-naive individuals. Overall, participants preferred remote clinical consultation, HIV self-testing, online self-assessment and phone call user support. The LCA identified three subgroups: the "prefer online PrEP with remote components" group (60.3% of the sample) whose preferences aligned with the main analysis, the "prefer online PrEP with in-person components" group (20.7%), who preferred in-person consultation, provider-administered HIV testing, and guided assessment, and the "prefer remote PrEP (18.9%)" group who preferred online PrEP services only if they were remote.
CONCLUSIONS: Online pharmacy PrEP is highly acceptable and may expand PrEP coverage to those interested in PrEP but not accessing services. Most participants valued privacy and autonomy, preferring HIVST and remote provider interactions. However, when needing support for questions regarding PrEP, participants preferred phone/SMS contact with a provider. One-fifth of participants preferred online PrEP with in-person components, suggesting that providing multiple options can increase uptake.}, }
@article {pmid39385257, year = {2024}, author = {Edwards, LA and Yang, C and Sharma, S and Chen, ZH and Gorantla, L and Joshi, SA and Longhi, NJ and Worku, N and Yang, JS and Martinez Di Pietro, B and Armenian, S and Bhat, A and Border, W and Buddhe, S and Blythe, N and Stratton, K and Leger, KJ and Leisenring, WM and Meacham, LR and Nathan, PC and Narasimhan, S and Sachdeva, R and Sadak, K and Chow, EJ and Boyle, PM}, title = {Building a machine learning-assisted echocardiography prediction tool for children at risk for cancer therapy-related cardiomyopathy.}, journal = {Cardio-oncology (London, England)}, volume = {10}, number = {1}, pages = {66}, pmid = {39385257}, issn = {2057-3804}, support = {R21 CA277746/CA/NCI NIH HHS/United States ; CA277746//National Cancer Institute of the National Institutes of Health/ ; }, abstract = {BACKGROUND: Despite routine echocardiographic surveillance for childhood cancer survivors, the ability to predict cardiomyopathy risk in individual patients is limited. We explored the feasibility and optimal processes for machine learning-enhanced cardiomyopathy prediction in survivors using serial echocardiograms from five centers.
METHODS: We designed a series of deep convolutional neural networks (DCNNs) for prediction of cardiomyopathy (shortening fraction ≤ 28% or ejection fraction ≤ 50% on two occasions) for at-risk survivors ≥ 1-year post initial cancer therapy. We built DCNNs with four subsets of echocardiographic data differing in timing relative to case (survivor who developed cardiomyopathy) index diagnosis and two input formats (montages) with differing image selections. We used holdout subsets in a 10-fold cross-validation framework and standard metrics to assess model performance (e.g., F1-score, area under the precision-recall curve [AUPRC]). Performance of the input formats was compared using a combined 5 × 2 cross-validation F-test.
RESULTS: The dataset included 542 pairs of montages: 171 montage pairs from 45 cases at time of cardiomyopathy diagnosis or pre-diagnosis and 371 pairs from 70 at-risk survivors who didn't develop cardiomyopathy during follow-up (non-case). The DCNN trained to distinguish between non-case and time of cardiomyopathy diagnosis or pre-diagnosis case montages achieved an AUROC of 0.89 ± 0.02, AUPRC 0.83 ± 0.03, and F1-score: 0.76 ± 0.04. When limited to smaller subsets of case data (e.g., ≥ 1 or 2 years pre-diagnosis), performance worsened. Model input format did not impact performance accuracy across models.
CONCLUSIONS: This methodology is a promising first step toward development of a DCNN capable of accurately differentiating pre-diagnosis versus non-case echocardiograms to predict survivors more likely to develop cardiomyopathy.}, }
@article {pmid39384953, year = {2024}, author = {Appelbaum, FR}, title = {Offering patients a second chance: what is the minimum cure rate needed to justify allogeneic hematopoietic cell transplantation?.}, journal = {Leukemia}, volume = {38}, number = {12}, pages = {2515-2516}, pmid = {39384953}, issn = {1476-5551}, }
@article {pmid39384951, year = {2024}, author = {Anczukow, O and Allain, FH and Angarola, BL and Black, DL and Brooks, AN and Cheng, C and Conesa, A and Crosse, EI and Eyras, E and Guccione, E and Lu, SX and Neugebauer, KM and Sehgal, P and Song, X and Tothova, Z and Valcárcel, J and Weeks, KM and Yeo, GW and Thomas-Tikhonenko, A}, title = {Steering research on mRNA splicing in cancer towards clinical translation.}, journal = {Nature reviews. Cancer}, volume = {24}, number = {12}, pages = {887-905}, pmid = {39384951}, issn = {1474-1768}, support = {K08 CA245242/CA/NCI NIH HHS/United States ; R01 CA249204/CA/NCI NIH HHS/United States ; U01 CA232563/CA/NCI NIH HHS/United States ; R01 HL167071/HL/NHLBI NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; R01 CA248317/CA/NCI NIH HHS/United States ; R35 GM131876/GM/NIGMS NIH HHS/United States ; R35 GM136426/GM/NIGMS NIH HHS/United States ; R01 GM138541/GM/NIGMS NIH HHS/United States ; R01 GM140735/GM/NIGMS NIH HHS/United States ; P30 CA196521/CA/NCI NIH HHS/United States ; R21 AG080243/AG/NIA NIH HHS/United States ; R01 CA182467/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/genetics ; *RNA Splicing ; RNA, Messenger/genetics ; Spliceosomes/genetics ; Translational Research, Biomedical ; }, abstract = {Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens.}, }
@article {pmid39384807, year = {2024}, author = {Minot, SS and Li, N and Srinivasan, H and Ayers, JL and Yu, M and Koester, ST and Stangis, MM and Dominitz, JA and Halberg, RB and Grady, WM and Dey, N}, title = {Colorectal cancer-associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23646}, pmid = {39384807}, issn = {2045-2322}, support = {K08 DK111941/DK/NIDDK NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; R50CA233042//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {*Colorectal Neoplasms/microbiology/genetics ; *Gastrointestinal Microbiome/genetics ; Animals ; Humans ; Mice ; *Bacteria/genetics/classification ; *Precancerous Conditions/microbiology ; Metagenomics/methods ; }, abstract = {The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23-40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of "known unknowns" of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.}, }
@article {pmid39384761, year = {2024}, author = {Rocheleau, G and Clarke, SL and Auguste, G and Hasbani, NR and Morrison, AC and Heath, AS and Bielak, LF and Iyer, KR and Young, EP and Stitziel, NO and Jun, G and Laurie, C and Broome, JG and Khan, AT and Arnett, DK and Becker, LC and Bis, JC and Boerwinkle, E and Bowden, DW and Carson, AP and Ellinor, PT and Fornage, M and Franceschini, N and Freedman, BI and Heard-Costa, NL and Hou, L and Chen, YI and Kenny, EE and Kooperberg, C and Kral, BG and Loos, RJF and Lutz, SM and Manson, JE and Martin, LW and Mitchell, BD and Nassir, R and Palmer, ND and Post, WS and Preuss, MH and Psaty, BM and Raffield, LM and Regan, EA and Rich, SS and Smith, JA and Taylor, KD and Yanek, LR and Young, KA and , and Hilliard, AT and Tcheandjieu, C and Peyser, PA and Vasan, RS and Rotter, JI and Miller, CL and Assimes, TL and de Vries, PS and Do, R}, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8741}, pmid = {39384761}, issn = {2041-1723}, support = {R01 HL139731/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R35 GM124836/GM/NIGMS NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; P30 AG028747/AG/NIA NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R35-GM124836//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL146860/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 HL157635/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; HHSN268201100037C/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL121007/HL/NHLBI NIH HHS/United States ; R01-HL139865, R01-HL155915//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL139865/HL/NHLBI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; UM1 HG008853/HG/NHGRI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 HL164577/HL/NHLBI NIH HHS/United States ; HHSN268201600033C/ES/NIEHS NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R01 HL148239/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL155915/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Coronary Artery Disease/genetics ; *Genetic Predisposition to Disease ; *Linkage Disequilibrium ; *Polymorphism, Single Nucleotide ; Male ; Female ; Gene Frequency ; Genome-Wide Association Study ; White People/genetics ; Case-Control Studies ; Whole Genome Sequencing ; Genetic Variation ; Middle Aged ; }, abstract = {Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.}, }
@article {pmid39384759, year = {2024}, author = {Crook, ZR and Sevilla, GP and Young, P and Girard, EJ and Phi, TD and Howard, ML and Price, J and Olson, JM and Nairn, NW}, title = {CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8731}, pmid = {39384759}, issn = {2041-1723}, support = {R01 CA223674/CA/NCI NIH HHS/United States ; R01-CA223674//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Proteolysis/drug effects ; *Receptors, Transferrin/metabolism ; Animals ; Cell Line, Tumor ; *ErbB Receptors/metabolism ; *Lysosomes/metabolism ; Mice ; Carcinoma, Non-Small-Cell Lung/metabolism/drug therapy/genetics/pathology ; Hydrogen-Ion Concentration ; B7-H1 Antigen/metabolism ; Female ; Lung Neoplasms/metabolism/drug therapy/genetics ; Catalysis ; Endosomes/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.}, }
@article {pmid39383036, year = {2024}, author = {Scharffenberger, SC and Wan, YH and Homad, LJ and Kher, G and Haynes, AM and Poudel, B and Sinha, IR and Aldridge, N and Pai, A and Bibby, M and Chhan, CB and Davis, AR and Moodie, Z and Palacio, MB and Escolano, A and McElrath, MJ and Boonyaratanakornkit, J and Pancera, M and McGuire, AT}, title = {Targeting RSV-neutralizing B cell receptors with anti-idiotypic antibodies.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114811}, pmid = {39383036}, issn = {2211-1247}, support = {R21 AI156063/AI/NIAID NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; }, mesh = {*Antibodies, Neutralizing/immunology ; Animals ; *Receptors, Antigen, B-Cell/immunology/metabolism ; Humans ; *Antibodies, Anti-Idiotypic/immunology/pharmacology ; Mice ; B-Lymphocytes/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Viruses/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Viral/immunology ; Female ; Respiratory Syncytial Virus, Human/immunology ; Mice, Inbred BALB C ; }, abstract = {Respiratory syncytial virus (RSV) causes lower respiratory tract infections with significant morbidity and mortality at the extremes of age. Vaccines based on the viral fusion protein are approved for adults over 60, but infant protection relies on passive immunity via antibody transfer or maternal vaccination. An infant vaccine that rapidly elicits protective antibodies would fulfill a critical unmet need. Antibodies arising from the VH3-21/VL1-40 gene pairing can neutralize RSV without the need for affinity maturation, making them attractive to target through vaccination. Here, we develop an anti-idiotypic monoclonal antibody (ai-mAb) immunogen that is specific for unmutated VH3-21/VL1-40 B cell receptors (BCRs). The ai-mAb efficiently engages B cells with bona fide target BCRs and does not activate off-target non-neutralizing B cells, unlike recombinant pre-fusion (preF) protein used in current RSV vaccines. These results establish proof of concept for using an ai-mAb-derived vaccine to target B cells hardwired to produce RSV-neutralizing antibodies.}, }
@article {pmid39382296, year = {2024}, author = {Stearns, K and Lampe, G and Hanan, R and Marcink, T and Niewiesk, S and Sternberg, SH and Greninger, AL and Porotto, M and Moscona, A}, title = {Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.}, journal = {mBio}, volume = {15}, number = {11}, pages = {e0232724}, pmid = {39382296}, issn = {2150-7511}, support = {R01 AI114736/AI/NIAID NIH HHS/United States ; R01AI031971, R01AI114736, R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; F31 AI176760/AI/NIAID NIH HHS/United States ; R01 AI175362/AI/NIAID NIH HHS/United States ; //Sharon Golub Fund at Columbia University Vagelos College of Physicians & Surgeons/ ; R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI031971/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Virus Internalization ; *Viral Fusion Proteins/metabolism/genetics ; *Parainfluenza Virus 3, Human/genetics/physiology/metabolism ; HEK293 Cells ; Furin/metabolism/genetics ; HN Protein/metabolism/genetics ; Animals ; Cell Line ; Proteolysis ; }, abstract = {UNLABELLED: Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.
IMPORTANCE: Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.}, }
@article {pmid39381003, year = {2024}, author = {Fiore-Gartland, A and Srivastava, H and Seese, A and Day, T and Penn-Nicholson, A and Luabeya, AKK and Du Plessis, N and Loxton, AG and Bekker, LG and Diacon, A and Walzl, G and Sagawa, ZK and Reed, SG and Scriba, TJ and Hatherill, M and Coler, R}, title = {Co-regulation of innate and adaptive immune responses induced by ID93+GLA-SE vaccination in humans.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1441944}, pmid = {39381003}, issn = {1664-3224}, mesh = {Humans ; *Immunity, Innate ; *Adaptive Immunity ; Female ; Male ; *Tuberculosis Vaccines/immunology/administration & dosage ; *Vaccination ; Adult ; Tuberculosis/prevention & control/immunology ; Mycobacterium tuberculosis/immunology ; CD4-Positive T-Lymphocytes/immunology ; Antibodies, Bacterial/blood/immunology ; Vaccines, Subunit/immunology/administration & dosage ; }, abstract = {INTRODUCTION: Development of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood.
METHODS: In this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination.
RESULTS: Analyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response.
DISCUSSION: The results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.}, }
@article {pmid39380691, year = {2024}, author = {Parrish, AG and Arora, S and Thirimanne, HN and Rudoy, D and Schmid, S and Sievers, P and Sahm, F and Holland, EC and Szulzewsky, F}, title = {Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae148}, pmid = {39380691}, issn = {2632-2498}, abstract = {BACKGROUND: Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half of all meningiomas harbor inactivating mutations in NF2, leading to deregulation of oncogenic YAP1 activity. While benign NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. It is unclear if NF2 mutant meningiomas of different grades are equally reliant on YAP activity.
METHODS: We analyzed bulk and single-cell RNA-Seq data from a large cohort of human meningiomas for the expression of YAP1 target genes and Hippo effectors as well as in vitro cell line experiments.
RESULTS: Aggressive NF2 mutant meningiomas harbor decreased expression levels of YAP1 target genes and increased expression levels of the YAP1 antagonist VGLL4 and the upstream regulators FAT3/4 compared to their benign counterparts. Decreased expression of YAP1 target genes as well as high expression of VGLL4 and FAT3/4 is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas.
CONCLUSIONS: Our results shed new insight into the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.}, }
@article {pmid39379736, year = {2024}, author = {Bloom, A and Springer, R and Angier, H and Heintzman, J and Likumahuwa-Ackman, S and Huguet, N and Moreno, L and DeVoe, J}, title = {Association Between a Mother's Cervical Cancer Screening and Child's Human Papillomavirus (HPV) Vaccination Status.}, journal = {Maternal and child health journal}, volume = {28}, number = {12}, pages = {2137-2146}, pmid = {39379736}, issn = {1573-6628}, support = {R01 HS025962/HS/AHRQ HHS/United States ; R01HS025962//Agency for Healthcare Research and Quality/ ; }, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/prevention & control/diagnosis ; *Papillomavirus Vaccines/administration & dosage ; *Early Detection of Cancer/methods/statistics & numerical data ; *Papillomavirus Infections/prevention & control/diagnosis ; Child ; *Mothers/psychology/statistics & numerical data ; Adult ; Adolescent ; Vaccination/statistics & numerical data ; Male ; United States/epidemiology ; Mass Screening/methods/statistics & numerical data ; Cohort Studies ; Human Papillomavirus Viruses ; }, abstract = {OBJECTIVES: To investigate the association between maternal cervical cancer (CC) screening status and child human papillomavirus (HPV) vaccination uptake. To understand if child sex or social deprivation index (SDI) modify this association.
METHODS: We used a national cohort of children linked to at least one parent using electronic health record (EHR) data from a network of community health centers across the United States. We used SDI scores and child sex as moderating variables. We performed the analysis (1) for the whole sample (with SDI and child sex added as covariates), (2) stratified by SDI quartile (with child sex added as a covariate), and (3) stratified by SDI quartile and child sex, to examine whether associations vary by SDI quartile and by child sex.
RESULTS: N = 52,919 linked mother-child pairs. Mother's receipt of CC screening was positively associated with the linked child's odds of receiving HPV vaccination [adjusted odds ratio (AOR) 1.39, 95% confidence interval (CI) 1.32, 1.47]. Neither sex or SDI modified this association. There were no significant differences in odds of HPV vaccination in children between SDI quartiles or between male and female children.
CONCLUSIONS FOR PRACTICE: An effective way to improve rates of HPV vaccination among children and adolescents may be to target attention towards increasing CC screening rates among mothers. Further, focusing resources and efforts on CC screenings and care of both mothers and their children may be more worthwhile than isolated efforts targeting HPV vaccination for children and adolescents.}, }
@article {pmid39379678, year = {2025}, author = {Akhiwu, TO and Adewunmi, C and Bilalaga, M and Atarere, JO and Gaddipati, G and Chido-Amajuoyi, OG and Eziuche, DK and Onyeaka, H and Amonoo, HL}, title = {Clinical trial knowledge among cancer survivors in the United States: the role of health information technology.}, journal = {Cancer causes & control : CCC}, volume = {36}, number = {1}, pages = {93-100}, pmid = {39379678}, issn = {1573-7225}, support = {K08CA251654/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Cancer Survivors/statistics & numerical data/psychology ; Middle Aged ; United States/epidemiology ; Adult ; *Medical Informatics/statistics & numerical data/methods ; *Neoplasms/therapy/epidemiology ; Aged ; *Health Knowledge, Attitudes, Practice ; *Clinical Trials as Topic/statistics & numerical data ; Young Adult ; Surveys and Questionnaires ; }, abstract = {PURPOSE: Clinical trials are essential to the advancement of cancer care. However, clinical trial knowledge and participation remain critically low among adult patients with cancer. Health information technology (HIT) could play an important role in improving clinical trial knowledge and engagement among cancer survivors.
METHODS: We used data from 3,794 adults who completed the 2020 Health Information National Trends Survey, 626 (16.2%) of whom were cancer survivors. We examined the prevalence of HIT use in the study population and by cancer history using chi-squared tests. We used multivariable logistic regression models to examine the impact of HIT use on clinical trial knowledge for cancer survivors and respondents with no cancer history, respectively.
RESULTS: Approximately 63.8% of cancer survivors reported having some knowledge of clinical trials. Almost half of the cancer survivors used HIT to communicate with doctors (47.1%) and make health appointments (49.4%), 68.0% used HIT to look up health information online and 42.2% used it to check test results. In the adjusted models, the use of HIT in communicating with doctors [OR 2.79; 95% CI (1.41, 5.54)], looking up health information online [OR 2.84; 95% CI (1.04, 7.77)], and checking test results [OR 2.47; 95% CI (1.12, 5.43)] was associated with having some knowledge of clinical trials.
CONCLUSION: HIT use for engaging with the healthcare team and health information gathering is associated with higher clinical trial knowledge in cancer survivors. Given the rapid increase in mobile technology access globally and the increased use of HIT, digital technology can be leveraged to improve clinical trial knowledge and engagement among cancer survivors.}, }
@article {pmid39377755, year = {2024}, author = {Montaño, M and Shapiro, AE and Whitney, BM and Bamford, L and Burkholder, G and Cachay, ER and Christopoulos, KA and Crane, HM and Delaney, JAC and Eron, JJ and Fredericksen, RJ and Hunt, PW and Jacobson, JM and Keruly, JC and Kim, HN and Mayer, KH and Moore, RD and Napravnik, S and Pettit, A and Saag, MS and Yendewa, GA and Kitahata, MM and Bender Ignacio, RA}, title = {Mpox in People With Human Immunodeficiency Virus: Predictors of Diagnosis, Outcomes, and Vaccine Effectiveness in a Multisite Cohort.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae464}, pmid = {39377755}, issn = {1537-6591}, support = {P30 AI027763/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; P30 AI073961/AI/NIAID NIH HHS/United States ; //CFAR/ ; P30 AI110527/AI/NIAID NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; P30 AI50410//University of North Carolina Chapel Hill/ ; P30 AI094189/AI/NIAID NIH HHS/United States ; //University of Washington/ ; //Vanderbilt Univ/ ; P30 AI027767/AI/NIAID NIH HHS/United States ; P30 AI036214/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited.
METHODS: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt.
FINDINGS: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities.
INTERPRETATION: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.}, }
@article {pmid39377586, year = {2024}, author = {Belmont, L and Contreras, M and Cartwright-Acar, CH and Marceau, CD and Agrawal, A and Levoir, LM and Lubow, J and Goo, L}, title = {Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.}, journal = {Journal of virology}, volume = {98}, number = {11}, pages = {e0158224}, pmid = {39377586}, issn = {1098-5514}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; //Chan Zuckerberg Biohub - San Francisco/ ; T32 AI083203/AI/NIAID NIH HHS/United States ; //Fred Hutchinson Cancer Center Diverse Trainee Fund/ ; //Hypothesis Fund/ ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {*Dengue Virus/immunology/genetics/physiology ; Humans ; *Dengue/immunology/virology/genetics ; *GTPase-Activating Proteins/genetics/metabolism ; *Antibodies, Viral/immunology ; *Immunoglobulin G/immunology ; Receptors, IgG/metabolism/genetics/immunology ; Cell Line ; Genomics/methods ; Gene Knockout Techniques ; Animals ; Host-Pathogen Interactions/immunology/genetics ; Virus Internalization ; HEK293 Cells ; }, abstract = {Under some conditions, dengue virus (DENV) can hijack IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR)-a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this unusual IgG-mediated infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout (KO) screens in an in vitro system poorly permissive to infection in the absence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates the binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired the binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that promote efficient ADE of DENV infection. Our findings represent a first step toward advancing fundamental knowledge behind the biology of a non-canonical infection route implicated in disease.IMPORTANCEAntibodies can paradoxically enhance rather than inhibit dengue virus (DENV) infection in some cases. To advance knowledge of the functional requirements of antibody-dependent enhancement (ADE) of infection beyond existing descriptive studies, we performed a genome-scale CRISPR knockout (KO) screen in an optimized in vitro system permissive to efficient DENV infection only in the presence of IgG. In addition to FcgRIIa, a known receptor that facilitates IgG-mediated uptake of IgG-bound, but not naked DENV particles, our screens identified TBC1D24 and SV2B, cellular factors with no known role in DENV infection. We validated a functional role for TBC1D24 and SV2B in mediating ADE of all four DENV serotypes in different cell lines and using various antibodies. Thus, we identify cellular factors beyond Fc gamma receptors that promote ADE mechanisms. This study represents a first step toward advancing fundamental knowledge beyond a poorly understood non-canonical viral entry mechanism.}, }
@article {pmid39375704, year = {2024}, author = {Gabel, AM and Belleville, AE and Thomas, JD and Pineda, JMB and Bradley, RK}, title = {APC mutations dysregulate alternative polyadenylation in cancer.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {255}, pmid = {39375704}, issn = {1474-760X}, mesh = {*Polyadenylation ; Humans ; *Adenomatous Polyposis Coli Protein/genetics/metabolism ; *3' Untranslated Regions ; Mutation ; Colorectal Neoplasms/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Neoplasms/genetics/metabolism ; Poly A/metabolism ; Adenocarcinoma/genetics/metabolism/pathology ; }, abstract = {BACKGROUND: Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood.
RESULTS: We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3' UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations.
CONCLUSIONS: As APC has been previously identified as an RNA-binding protein that preferentially binds 3' UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.}, }
@article {pmid39375464, year = {2024}, author = {Crespillo-Casado, A and Pothukuchi, P and Naydenova, K and Yip, MCJ and Young, JM and Boulanger, J and Dharamdasani, V and Harper, C and Hammoudi, PM and Otten, EG and Boyle, K and Gogoi, M and Malik, HS and Randow, F}, title = {Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213.}, journal = {EMBO reports}, volume = {25}, number = {11}, pages = {4979-5005}, pmid = {39375464}, issn = {1469-3178}, support = {P400PB_191083//the Swiss National Science Foundation (SNSF)/ ; U54 AI170792 (PI: Nevan Krogan)//the National Institutes of Health/ ; BI31336//Diamond Light Source (Diamond)/ ; U105170648//UK Research and Innovation (UKRI)/ ; /WT_/Wellcome Trust/United Kingdom ; U54 AI170792/AI/NIAID NIH HHS/United States ; 222503/Z/21/Z//Wellcome Trust (WT)/ ; }, mesh = {*Ubiquitin-Protein Ligases/metabolism/genetics ; *Phylogeny ; Humans ; Toxoplasma/genetics/metabolism ; Listeria/genetics ; Cryoelectron Microscopy ; Salmonella/genetics/metabolism ; Protein Binding ; Immunity, Innate ; Adenosine Triphosphate/metabolism ; Host-Pathogen Interactions/genetics ; }, abstract = {Innate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond to phylogenetically distant pathogens, including Gram-negative Salmonella, Gram-positive Listeria, and eukaryotic Toxoplasma, remains unknown. Here we report that the evolutionary history of RNF213 is indicative of repeated adaptation to diverse pathogen target structures, especially in and around its newly identified CBM20 carbohydrate-binding domain, which we have resolved by cryo-EM. We find that RNF213 forms coats on phylogenetically distant pathogens. ATP hydrolysis by RNF213's dynein-like domain is essential for coat formation on all three pathogens studied as is RZ finger-mediated E3 ligase activity for bacteria. Coat formation is not diffusion-limited but instead relies on rate-limiting initiation events and subsequent cooperative incorporation of further RNF213 molecules. We conclude that RNF213 responds to evolutionarily distant pathogens through enzymatically amplified cooperative recruitment.}, }
@article {pmid39374582, year = {2025}, author = {Ali, N and Othus, M and Rodríguez-Arbolí, E and Orvain, C and Milano, F and Sandmaier, BM and Davis, C and Basom, RS and Appelbaum, FR and Walter, RB}, title = {Measurable residual disease as predictor of post-day +100 relapses after allografting in adult AML.}, journal = {Blood advances}, volume = {9}, number = {3}, pages = {558-570}, pmid = {39374582}, issn = {2473-9537}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasm, Residual/diagnosis ; *Leukemia, Myeloid, Acute/therapy/mortality/diagnosis/pathology ; Female ; Male ; *Hematopoietic Stem Cell Transplantation ; Middle Aged ; Adult ; Recurrence ; Transplantation, Homologous ; Aged ; Young Adult ; Prognosis ; Adolescent ; }, abstract = {Measurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.}, }
@article {pmid39374522, year = {2025}, author = {Coffey, DG and Ataca Atilla, P and Atilla, E and Landgren, O and Cowan, AJ and Simon, S and Pont, MJ and Comstock, ML and Hill, GR and Riddell, SR and Green, DJ}, title = {Single-cell analysis of the multiple myeloma microenvironment after γ-secretase inhibition and CAR T-cell therapy.}, journal = {Blood}, volume = {145}, number = {2}, pages = {220-233}, pmid = {39374522}, issn = {1528-0020}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/pathology/immunology/drug therapy/genetics ; *Tumor Microenvironment/immunology/drug effects ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors ; *Immunotherapy, Adoptive/methods ; *B-Cell Maturation Antigen/immunology/antagonists & inhibitors/genetics ; *Single-Cell Analysis ; Receptors, Chimeric Antigen/immunology ; Benzazepines ; Fluorocarbons ; }, abstract = {Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by γ-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the γ-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of nonclassical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions after exposure to GSI. Although many genes with altered expression are associated with γ-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (PFS; median PFS, 57 vs 861 days). GSIs are being explored in combination with the full spectrum of BCMA-targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.}, }
@article {pmid39374449, year = {2025}, author = {Dizman, N and Bakouny, Z and Haykal, T and Riano, I and Desai, A and Butt, A and Basu, A and Zhao, D and Saad, E and Saliby, RM and Gosain, R and Gosain, R and Ardeshir, F and Deng, L and Matt-Amaral, L and Arnaoutakis, K and Bekaii-Saab, T and Manochakian, R and Marshall, A and Forde, P and Murphy, M and Subbiah, V and Chavez-MacGregor, M and Owonikoko, TK and Lopes, G and Aggarwal, C and Lee, AI and Choueiri, TK}, title = {Guide to Understanding and Supporting International Medical Graduates in Hematology/Oncology by the ASCO International Medical Graduates Community of Practice.}, journal = {JCO oncology practice}, volume = {21}, number = {3}, pages = {292-299}, doi = {10.1200/OP-24-00565}, pmid = {39374449}, issn = {2688-1535}, mesh = {Humans ; *Medical Oncology/education ; *Hematology/education ; *Foreign Medical Graduates ; United States ; Societies, Medical ; Community of Practice ; }, abstract = {PURPOSE: International medical graduates (IMGs) are an essential component of the oncology workforce in the United States, comprising a third of all practicing oncologists and almost half of hematology/oncology fellows. In this article, we discuss the contributions of IMGs in the US oncology workforce, review unique challenges faced by IMGs, and propose potential solutions to overcome these challenges.
METHODS: ASCO's IMG Community of Practice was established with the mission to connect, mentor, guide, raise awareness, and overcome the challenges unique to IMGs interested in pursuing medical oncology in the United States. The content of this article is based on discussions at the IMG Community of Practice meetings at ASCO's 2023 and 2024 Annual Meetings.
RESULTS: IMGs bring an inherent diversity of thought and experience to the oncology workforce. They provide high-quality, culture- and language-concordant care to a diverse population of patients with cancer. However, IMGs in oncology face significant hardships throughout their careers, including visa-related restrictions, psychosocial and cultural struggles, as well as differential treatment while applying for residency and fellowship training, and early career positions. Greater awareness of these challenges among the members of the hematology/oncology community, along with institutional and individual efforts to support IMGs, is warranted.
CONCLUSION: We encourage oncology professionals and institutions to join our efforts in recognizing the unique paths of IMGs and providing support and advocacy to maximize the potential of IMGs in the US oncology workforce.}, }
@article {pmid39374015, year = {2024}, author = {Goldkorn, A and Tangen, C and Plets, M and Bsteh, D and Xu, T and Pinski, JK and Ingles, S and Triche, TJ and MacVicar, GR and Vaena, DA and Crispino, AW and McConkey, DJ and Lara, PN and Hussain, MHA and Quinn, DI and Dorff, TB and Lerner, SP and Thompson, I and Agarwal, N}, title = {Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2437871}, pmid = {39374015}, issn = {2574-3805}, support = {R01 CA172436/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; *Neoplastic Cells, Circulating ; Aged ; Prognosis ; Middle Aged ; Prospective Studies ; Prostatic Neoplasms/mortality/pathology/blood/drug therapy ; Prostatic Neoplasms, Castration-Resistant/blood/mortality/drug therapy/pathology ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Neoplasm Metastasis ; Prostate-Specific Antigen/blood ; }, abstract = {IMPORTANCE: In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC.
OBJECTIVE: To examine the prognostic value of CTC count in men with mHSPC.
In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023.
EXPOSURE: Metastatic hormone-sensitive prostate cancer.
MAIN OUTCOMES AND MEASURES: Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models.
RESULTS: Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84).
CONCLUSIONS AND RELEVANCE: In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.}, }
@article {pmid39373644, year = {2024}, author = {Wickline, M and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Barriers and facilitators to routine revaccination among adult Hematopoietic Cell Transplant survivors in the United States: A convergent mixed methods analysis.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {26}, number = {6}, pages = {e14388}, doi = {10.1111/tid.14388}, pmid = {39373644}, issn = {1399-3062}, support = {//Oncology Nursing Society Foundation/ ; //School of Nursing, University of Washington/ ; //Hester McLaws Nursing Scholarship/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Cross-Sectional Studies ; Male ; Female ; Adult ; Middle Aged ; United States/epidemiology ; *Immunization, Secondary ; Survivors ; Aged ; Young Adult ; Vaccination ; Vaccine-Preventable Diseases/prevention & control ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Hematopoietic cell transplant (HCT) survivorship care includes recommendations for post-HCT revaccination to restore immunity to vaccine-preventable diseases (VPDs). However, not all survivors agree to be vaccinated. No existing studies have comprehensively reported barriers and facilitators to adult HCT survivors completing revaccination.
METHODS: A cross-sectional survey of 194 adult HCT survivors was analyzed using convergent mixed methods. The analysis used various statistical methods to determine the prevalence of barriers and facilitators and the association between revaccination and the number and specific type of barriers and facilitators. Content analysis was applied to open-ended item responses. Integrated analysis merged quantitative and qualitative findings.
RESULTS: The most frequent barriers included the inability to receive live vaccines because of immunosuppression, identifying a suitable community location for administering childhood vaccines to adults, and delayed immune recovery. The most frequent facilitators were having healthcare insurance and a clear calendar of the revaccination schedule. Complete revaccination rates were lower with each additional reported barrier (OR = 0.58; 95% CI 0.459-0.722) and higher with each additional reported facilitator (OR = 1.31; 95% CI 1.05-1.63). Content analysis suggested that most barriers were practical issues. One significant facilitator highlighted by respondents was for the transplant center to coordinate and serve as the vaccination location for revaccination services. Merged analysis indicated convergence between quantitative and qualitative data.
CONCLUSION: Practical barriers and facilitators played a consequential role in revaccination uptake, and survivors would like to be revaccinated at the transplant center.}, }
@article {pmid39373623, year = {2025}, author = {Loroña, NC and Himbert, C and Ose, J and Cohen, SA and Strehli, I and Ulrich, CM and Cobos, S and Jean-Baptiste, E and Bloomer, AM and Figueiredo, JC and Gigic, B and Hardikar, S and Karchi, M and Mutch, M and Peoples, AR and Schneider, M and Shibata, D and Siegel, EM and Toriola, AT and Wood, EH and Li, CI}, title = {Alcohol Consumption and Smoking History at the Time of Diagnosis and the Risk of Colorectal Cancer Recurrence and Mortality: Results from the ColoCare Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {1}, pages = {59-66}, pmid = {39373623}, issn = {1538-7755}, support = {R01CA254108//National Cancer Institute (NCI)/ ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; U01CA206110//National Cancer Institute (NCI)/ ; R01 CA254108/CA/NCI NIH HHS/United States ; P30CA076292//National Cancer Institute (NCI)/ ; R01 AG083580/AG/NIA NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01CA189184//National Cancer Institute (NCI)/ ; T32 CA009168/CA/NCI NIH HHS/United States ; T32CA00916//National Cancer Institute (NCI)/ ; R01 CA207371/CA/NCI NIH HHS/United States ; K07 CA222060/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/mortality/pathology/epidemiology ; Male ; Female ; *Alcohol Drinking/adverse effects/epidemiology ; *Neoplasm Recurrence, Local/epidemiology ; Middle Aged ; Aged ; *Smoking/adverse effects/epidemiology ; Risk Factors ; Longitudinal Studies ; }, abstract = {BACKGROUND: Findings from studies investigating the impacts of alcohol use and smoking on colorectal cancer outcomes are inconclusive. This study aimed to investigate associations between alcohol use and smoking status at the time of diagnosis on recurrence and overall mortality among patients with colorectal cancer.
METHODS: The present study included 2,216 stage I-IV patients with colorectal cancer from the longitudinal multicenter ColoCare Study, with available data on recurrence and colorectal cancer-specific mortality. Cox proportional hazards models adjusted for age, sex, race, ethnicity, stage, tumor site, treatment, comorbidities, body mass index, and study site were fit, with imputations for missing data.
RESULTS: We observed 235 recurrences and 308 colorectal cancer-specific deaths over an average of 3 years of follow-up. After adjusting for confounders, current alcohol consumption and ever smoking, relative to not current consumption and never smoking, respectively, were not statistically significantly associated with colorectal cancer recurrence [alcohol-HR, 0.95. 95% confidence interval (CI), 0.71-1.29; ever smoking-HR, 0.98, 95% CI, 0.75-1.29] or colorectal cancer-specific mortality (alcohol-HR, 0.95. 95% CI, 0.74-1.22; ever smoking-HR, 0.98, 95% CI, 0.77-1.24).
CONCLUSIONS: No associations were observed between alcohol and smoking at diagnosis and clinical outcomes in this well-annotated longitudinal cohort.
IMPACT: Our cohort study reports no significant associations; however, limiting alcohol use and avoiding smoking are health behaviors recommended for colorectal cancer survivors for prevention of other cancers and chronic conditions.}, }
@article {pmid39373353, year = {2025}, author = {Amonoo, HL and Daskalakis, E and Lam, JA and Wolfe, ED and Guo, M and Onyeaka, HK and Newcomb, RA and Barata, A and Ghanime, PM and Keane, EP and Boardman, AC and Cutler, C and Pirl, WF and Peteet, JR and Gudenkauf, LM and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {Association between positive affect, flourishing, quality of life, and psychological distress in allogeneic hematopoietic stem cell transplantation.}, journal = {Journal of psychosocial oncology}, volume = {43}, number = {3}, pages = {373-388}, pmid = {39373353}, issn = {1540-7586}, support = {K08 CA251654/CA/NCI NIH HHS/United States ; R01 HL113272/HL/NHLBI NIH HHS/United States ; R37 CA288557/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Adult ; *Psychological Distress ; *Affect ; Transplantation, Homologous/psychology ; Depression/psychology ; Anxiety/psychology ; Aged ; *Survivors/psychology/statistics & numerical data ; }, abstract = {PURPOSE: To examine the associations between state positive psychological well-being (PPWB) constructs, mood, and quality of life (QOL) in hematopoietic stem cell transplantation (HSCT) survivors.
DESIGN: The study was a secondary analysis of cross-sectional data.
SAMPLE/METHODS: We analyzed self-report data assessing positive affect, flourishing, QOL, depression and anxiety, and PTSD symptoms from 158 allogeneic HSCT recipients at day-100 post-transplant enrolled in supportive care studies.
FINDINGS: Univariate analysis showed that factors associated with greater levels of various state PPWB constructs include older age, disability status, greater social support, and presence of graft-versus-host disease. Multivariate analysis showed that state PPWB constructs-greater levels of positive affect and flourishing-were significantly associated with better QOL and lower PTSD, anxiety, and depression symptomatology.
IMPLICATIONS: Our findings suggest that longitudinal studies are needed to examine the links between state PPWB constructs and HSCT outcomes, which may inform population specific interventions and opportunities to improve outcomes.}, }
@article {pmid39373106, year = {2024}, author = {Poston, JN and Brown, SP and Ginsburg, AS and Ilich, A and Herren, H and El Kassar, N and Triulzi, DJ and Key, NS and May, S and Gernsheimer, TB}, title = {Analysis of bleeding outcomes in patients with hypoproliferative thrombocytopenia in the A-TREAT clinical trial.}, journal = {Transfusion}, volume = {64}, number = {11}, pages = {2055-2062}, doi = {10.1111/trf.18028}, pmid = {39373106}, issn = {1537-2995}, support = {HL122272/HL/NHLBI NIH HHS/United States ; HL122894/HL/NHLBI NIH HHS/United States ; HL143403/HL/NHLBI NIH HHS/United States ; HL146226/HL/NHLBI NIH HHS/United States ; HL122272/HL/NHLBI NIH HHS/United States ; HL122894/HL/NHLBI NIH HHS/United States ; HL143403/HL/NHLBI NIH HHS/United States ; HL146226/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Thrombocytopenia/drug therapy/therapy ; Male ; Middle Aged ; *Hemorrhage/etiology ; Aged ; *Tranexamic Acid/therapeutic use ; Adult ; Platelet Transfusion ; Risk Factors ; Hematologic Neoplasms/complications/therapy ; Antifibrinolytic Agents/therapeutic use ; Platelet Count ; }, abstract = {BACKGROUND: Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) ≤ 25%, activated partial thromboplastin time ≥ 30 s, international normalized ratio ≥ 1.2, and platelets ≤ 5000/μL.
METHODS: We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo.
RESULTS: World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p = 0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets ≤5000/μL and HCT < 21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91).
DISCUSSION: The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets ≤5000/μL remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population.}, }
@article {pmid39371366, year = {2024}, author = {Krantz, EM and Mutyaba, I and Nankoma, J and Okuku, F and Casper, C and Orem, J and Swan, DA and Phipps, W and Schiffer, JT}, title = {Highly Heterogeneous Kaposi Sarcoma-Associated Herpesvirus Oral Shedding Kinetics Among People With and Without Kaposi Sarcoma and Human Immunodeficiency Virus Coinfection.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae548}, pmid = {39371366}, issn = {2328-8957}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: An improved understanding of oral Kaposi sarcoma-associated herpesvirus (KSHV) viral dynamics could provide insights into transmission risk and guide vaccine development.
METHODS: We evaluated KSHV oral shedding dynamics in Ugandan adults stratified by Kaposi sarcoma (KS) and human immunodeficiency virus (HIV) status. Participants were followed for ≥4 weeks, with daily home oral swab collection to quantify KSHV using polymerase chain reaction. Shedding rates were defined by number of days with KSHV DNA detected divided by total days with swabs and compared by group using hurdle models.
RESULTS: Two hundred ninety-five participants were enrolled; median age was 35 years (range, 18-71 years), and 134 (45%) were male. KSHV was detected more frequently among participants with KS (HIV positive [HIV[+]]/KS[+], 56/76 [74%]; HIV negative [HIV[-]]/KS[+], 9/18 [50%]) than those without KS (HIV[+]/KS[-], 36/125 [29%]; HIV[-]/KS[-], 16/76 [21%]); odds of shedding did not differ significantly by HIV status. Among participants with KSHV detected, shedding rates did not differ significantly by group. Median per-participant viral loads among positive samples were lowest in HIV[+]/KS[+] (3.1 log10 copies/mL) and HIV[-]/KS[+] (3.3 log10 copies/mL) participants relative to HIV[+]/KS[-] (3.8 log10 copies/mL) and HIV[-]/KS[-] (4.0 log10 copies/mL) participants. All groups had participants with low viral load intermittent shedding and participants with high viral load persistent shedding. Within each group, individual KSHV shedding rate positively correlated with median KSHV log10 copies/mL, and episode duration positively correlated with peak viral load.
CONCLUSIONS: Oral KSHV shedding is highly heterogeneous across Ugandan adults with and without KS and HIV. Persistent shedding is associated with higher median viral loads regardless of HIV and KS status.}, }
@article {pmid39371123, year = {2024}, author = {Dehn, JG and Logan, B and Shaw, BE and Devine, S and Ciurea, SO and Horowitz, M and He, N and Pusic, I and Srour, SA and Arai, S and Juckett, M and Uberti, J and Hill, L and Vasu, S and Hogan, WJ and Hayes-Lattin, B and Westervelt, P and Bashey, A and Farhadfar, N and Grunwald, MR and Leifer, E and Symons, H and Saad, A and Vogel, J and Erickson, C and Buck, K and Lee, SJ and Pidala, J}, title = {Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371123}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {IMPORTANCE: Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood.
OBJECTIVE: To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor.
DESIGN: This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.
SETTINGS: National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.
PARTICIPANTS: Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.
INTERVENTION: Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely