@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 = {},
doi = {10.1093/biostatistics/kxaf018},
pmid = {40544344},
issn = {1468-4357},
support = {//National Institute of Allergy and Infectious Diseases/ ; R37AI054165/NH/NIH HHS/United States ; /NH/NIH HHS/United States ; /VA/VA/United States ; //United States Government/ ; },
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.},
}

Humans
*Biomarkers
*Clinical Trials, Phase III as Topic/methods
*Endpoint Determination/methods
*Vaccines
Randomized Controlled Trials as Topic
Observational Studies as Topic
Biostatistics

@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; >500X and >1000X average depth for whole genome and fusion gene respectively) were recovered from samples with Ct ≤ 30 (∼594 and 2,004 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 to 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 FDA-reportable data for clinical trials of RSV antiviral products, with robust performance in global samples from as recently as the 2023/24 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.},
}

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

@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.},
}

Humans
*Genome-Wide Association Study
Polymorphism, Single Nucleotide
Male
*Lipids/blood/genetics
Female
*Gene-Environment Interaction
Adult
Genetic Loci
Middle Aged
Social Support

@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.},
}

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

@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 {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 {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 {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 {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 = {},
number = {},
pages = {},
doi = {10.1016/S2352-3026(25)00144-9},
pmid = {40532723},
issn = {2352-3026},
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 = {},
number = {},
pages = {},
doi = {10.1056/NEJMoa2415434},
pmid = {40532178},
issn = {1533-4406},
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},
doi = {10.1200/CCI-24-00292},
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.},
}

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

@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 {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.},
}

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

@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 = {P50 MH115837/MH/NIMH NIH HHS/United States ; R01 CA244171/CA/NCI NIH HHS/United States ; R01 LM012810/LM/NLM NIH HHS/United States ; TL1 TR002318/TR/NCATS 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.},
}

Animals
Mice
*Disease Models, Animal
Mice, Transgenic
*Neoplasms/immunology/pathology
*Immune Tolerance
Humans
Genes, Reporter/immunology
Luminescent Proteins/immunology/genetics

@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},
doi = {10.1016/j.ebiom.2025.105804},
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: Consensus Response Criteria for TA-TMA.},
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 three 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 {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},
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 {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 non-covalent, 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 non-covalent 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 = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2025.05.011},
pmid = {40513563},
issn = {1537-6605},
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 (HCT): 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 = {BACKGROUND: 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.

OBJECTIVES: 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.

STUDY DESIGN: 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; FACT-BMT), symptom burden (ESAS), anxiety and depression symptoms (HADS and PHQ-9), and posttraumatic stress symptoms (PCL) were measured at time of admission (i.e., 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 length of stay groups in time to readmission or death in the first year post-HCT.

RESULTS: 606 patients (mean age=55.7 years [18.3-78.0 years]; 56.6% male; 81.5% White; 53.1% allogeneic HCT) were included. Patients with PLOS were younger (mean 53.3 vs 56.6 years, p=0.004), in complete remission prior to HCT (52.8% vs 46.3%, p=0.02), diagnosed with acute leukemia (34.2% vs 26.1%, p<0.001), and underwent allogeneic HCT (62.1% vs 49.9%, p<0.0001). In multivariate analyses, worse pre-HCT QOL (OR 0.99, p=0.003), symptom burden (OR 1.02, p=0.01) and depressive symptoms (OR 1.07, p=0.01) were associated with higher risk of PLOS. Patients with PLOS reported worse QOL at two weeks (∆ = -12.3, p<0.0001), three months (∆ = -6.9, p=0.002), and six months post-HCT (∆ =-4.8, p=0.02) compared to those without PLOS. Patients with PLOS reported greater symptom burden at two weeks (∆ =10.2, p<0.0001) and three months (∆ = 3.9, p=0.04), but not six months post-HCT (∆ = 0.5, p=0.79). Patients with PLOS reported higher depression burden at two weeks (∆ = 2.5, p<0.0001) and three months (∆ = 1.1, p=0.03), but not six months post-HCT (∆ = 0.6, p=0.19). Patients with PLOS experienced shorter time to death or re-admission in the first year post-HCT (median 221 days vs not reached, HR 1.7; CI 1.3-2.2, p<0.001).

CONCLUSIONS: 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 {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},
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},
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 {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 = {310030_188547/SNSF_/Swiss National Science Foundation/Switzerland ; R01 AI146028/SNSF_/Swiss National Science Foundation/Switzerland ; NSF PHY-2309135/GF/NIH HHS/United States ; //Kavli Institute for Theoretical Physics/ ; 2919.02//National Science Foundation/ ; //Gordon and Betty Moore Foundation/ ; /HHMI/Howard Hughes Medical Institute/United States ; S10OD028685/RI/ORIP NIH HHS/United States ; //Schmidt Sciences/ ; //LLC/ ; //National Defense Science and Engineering/ ; BAA 200-2021-11554/CC/CDC HHS/United States ; 75D30124C20302/CC/CDC HHS/United States ; //James S. McDonnell Foundation/ ; /HHMI/Howard Hughes Medical Institute/United States ; },
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.},
}

*SARS-CoV-2/genetics
*Genome, Viral
*RNA, Viral/genetics/chemistry
*Mutation Rate
Nucleic Acid Conformation
COVID-19/virology
Humans
Evolution, Molecular
Mutation
Silent Mutation

@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.

OBJECTIVE: 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 (WHI) enrolled in a 2-week 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 (PLFAs) 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 (ANOVA) 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 non-users (p < 0.001). Users of omega-3 fatty acid dietary supplements had geometric mean serum phospholipid DHA+EPA that were 38-46% higher than non-users (p < 0.0001). In contrast, use of lutein + zeaxanthin containing supplements was not associated with serum lutein + zeaxanthin (p = 0.72). Users of two 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. 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.},
}

Humans
*Adenomatous Polyposis Coli/epidemiology/complications/diagnosis/therapy
*Stomach Neoplasms/epidemiology/diagnosis/therapy/etiology
Risk Factors
Disease Management
Adenomatous Polyps

@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},
doi = {10.1016/j.esmoop.2025.105312},
pmid = {40499462},
issn = {2059-7029},
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 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 {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},
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 {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},
doi = {10.1182/bloodadvances.2025015850},
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},
doi = {10.1148/radiol.242423},
pmid = {40492914},
issn = {1527-1315},
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.},
}

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

@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.},
}

Humans
*HIV Infections/immunology/prevention & control
*Randomized Controlled Trials as Topic/methods/statistics & numerical data
Infant
Models, Statistical
Computer Simulation
Infant, Newborn
Female

@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.},
}

*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

@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.},
}

Humans
*Hematopoietic Stem Cell Transplantation/adverse effects
*Survivors
*Graft vs Host Disease/etiology/prevention & control/therapy

@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},
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 {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.},
}

*Graft vs Host Disease/therapy/diagnosis/immunology/etiology
Humans
*Hematopoietic Stem Cell Transplantation/adverse effects
Animals
Disease Management

@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.},
}

*Phylogeny
*SARS-CoV-2/genetics/classification
COVID-19/virology
Humans
Genome, Viral

@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 = {},
doi = {10.1093/abm/kaaf012},
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.},
}

Humans
Adolescent
*Neoplasms/psychology
Young Adult
Female
Male
*Behavior Therapy/methods
*Adaptation, Psychological
Child
Pilot Projects
*Social Support
Adult
*Stress, Psychological/therapy

@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.},
}

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

@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 = {},
number = {},
pages = {},
doi = {10.1101/gr.280357.124},
pmid = {40480832},
issn = {1549-5469},
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 performed 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.},
}

Humans
*Genetic Therapy/methods
Clinical Trials as Topic
*Neoplasms/therapy/immunology/genetics
*Cell- and Tissue-Based Therapy/methods
Gene Editing
*Immunotherapy, Adoptive/methods

@article {pmid40480553,
year = {2025},
author = {Petrykey, K and Chen, Y and Neupane, A and French, J 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 St. Jude Lifetime Cohort, (SJLIFE, model-development; n=3,479; median age 32.3 years, IQR 24.4-40.9) and Childhood Cancer Survivor Study (CCSS, model-validation; n=6,875; median age 33.2 years, IQR 27.9-38.9) 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 (CTCAE 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 a 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 to 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.},
}

Humans
*Genetic Variation/genetics
Surveys and Questionnaires
Male
Female
Genetic Testing
Adult

@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 {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.},
}

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

@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},
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.},
}