@article {pmid41042528,
year = {2025},
author = {Boiko, JR and Cooke, KR},
title = {Moving the needle on chronic GVHD of the lung.},
journal = {Blood advances},
volume = {9},
number = {19},
pages = {5038-5039},
doi = {10.1182/bloodadvances.2025017297},
pmid = {41042528},
issn = {2473-9537},
}

@article {pmid41042026,
year = {2025},
author = {Rafati, M and Wang, Y and Koppayi, AL and Savage, SA and Godley, LA and Williams, KM and Porter, C and Jones, K and Hicks, B and Spellman, SR and He, M and Atshan, R and Iwuagwu, C and Bolon, YT and Arrieta-Bolaños, E and Saultz, JN and Benjamin, CL and Lee, SJ and Saber, W and Gadalla, SM},
title = {Germline Pathogenic Variants in MUTYH Are Associated With Inferior Survival After Hematopoietic Cell Transplantation in Patients With Hematologic Malignancies or Disorders.},
journal = {American journal of hematology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ajh.70093},
pmid = {41042026},
issn = {1096-8652},
support = {W81XWH-19-1-0241/CP/NCI NIH HHS/United States ; 75N910D00024/CA/NCI NIH HHS/United States ; U24CA076518//U.S. Public Health Service/ ; //Congressionally Directed Medical Research Programs/ ; },
}

@article {pmid41039543,
year = {2025},
author = {Bouras, E and Papagiannopoulos, CK and Mustafa, R and Sobieski, D and Schmit, SL and Wu, AH and Brenner, H and Li, CI and Chan, AT and Pellatt, AJ and Zheng, W and Keku, TO and Moreno, V and Um, CY and Van Guelpen, B and Phipps, AI and Pai, RK and Lewis, SJ and Martin, RM and Gunter, MJ and Peters, U and Dehghan, A and Tsilidis, KK},
title = {Investigating the relationship of plasma microRNAs and colorectal cancer risk using genetic evidence.},
journal = {BMC medicine},
volume = {23},
number = {1},
pages = {532},
pmid = {41039543},
issn = {1741-7015},
support = {C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; *Colorectal Neoplasms/genetics/blood ; *MicroRNAs/blood/genetics ; Mendelian Randomization Analysis ; Male ; Genetic Predisposition to Disease ; Risk Factors ; Female ; Case-Control Studies ; Middle Aged ; },
abstract = {BACKGROUND: MicroRNAs (miRNAs) are short, single-stranded RNAs that function as post-transcriptional regulators of gene expression. Although circulating miRNAs have been linked to carcinogenesis, they have not yet been systematically investigated in relation to risk of colorectal cancer (CRC).

METHODS: We used Mendelian randomization (MR) and colocalization analyses to investigate the association of genetically predicted plasma miRNA concentrations (2083 miRNAs in 710 individuals) with risk of CRC (58,221 cases and 67,694 controls). For miRNAs associated with CRC risk, we also investigated their association with circulating plasma proteins (4907 proteins in 35,559 participants), bidirectionally, using MR. We performed pathway enrichment analysis (PEA) to explore downstream molecular pathways.

RESULTS: Associations of five miRNAs with CRC were found in MR and supported in colocalization analyses. Specifically, miR-146a-5p, miR-21-5p, and miR-4707-3p were positively, and miR-1908-5p and miR-6810-3p were inversely associated with CRC risk. Several protein associations were found for these miRNAs (range of proteins with P < 0.05: 78-796; 211 with FDR < 5%), and 11 pathways were identified in PEA, including regulation of Erb-B2 receptor tyrosine kinase 4 (miR-6810-3p) and insulin-like growth factor pathways (miR-1908-5p).

CONCLUSIONS: Our results support a potential implication of miR-146a-5p, miR-21-5p, miR-4707-3p, miR-1908-5p, and miR-6810-3p to CRC risk. However, their downstream effects should be elucidated before they can be utilized as preventive targets.},
}

Humans
*Colorectal Neoplasms/genetics/blood
*MicroRNAs/blood/genetics
Mendelian Randomization Analysis
Male
Genetic Predisposition to Disease
Risk Factors
Female
Case-Control Studies
Middle Aged

@article {pmid41038991,
year = {2025},
author = {Termini, CM},
title = {SLAM passes the haematopoietic stem cell identity test.},
journal = {Nature reviews. Molecular cell biology},
volume = {},
number = {},
pages = {},
pmid = {41038991},
issn = {1471-0080},
}

@article {pmid41037133,
year = {2025},
author = {Garzia, NA and Fest, S and Cushing-Haugen, K and Kensler, TW and Chavarro, JE and Tamimi, RM and Harris, HR},
title = {Childhood and adolescent dietary patterns and incidence of benign breast disease.},
journal = {Cancer causes & control : CCC},
volume = {},
number = {},
pages = {},
pmid = {41037133},
issn = {1573-7225},
support = {T32 CA094880/NH/NIH HHS/United States ; U01 HL145386/NH/NIH HHS/United States ; },
abstract = {PURPOSE: Childhood and adolescence may represent critical time windows for shaping future breast cancer risk. The association between early-life diet and breast cancer risk has been investigated, but few studies have examined the relation between adolescent diet and benign breast disease (BBD), an established breast cancer risk factor.

METHODS: Among 11,422 female Growing Up Today Study participants followed from 1996 to 2016 who completed food frequency questionnaires, we investigated the associations between adherence to three dietary patterns (Alternative Healthy Eating Index [AHEI], the Empirical Dietary Inflammatory Pattern [EDIP], and the Empirical Dietary Index for Hyperinsulinemia [EDIH]) at ages 10 and 14 years and self-reported BBD diagnosis. Cox proportional hazards models were used to estimates hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: Over 20 years of follow-up, 554 BBD cases were ascertained, with 259 biopsy-confirmed cases. Non-significant inverse associations were observed between greater adherence to the AHEI at age 10 and BBD risk (HR for fourth vs. first quartile = 0.74; 95% CI = 0.50-1.10; ptrend = 0.09), and between AHEI at age 14 and biopsy-confirmed BBD (HR for fourth vs. first quartile = 0.70; 95% CI = 0.48-1.03; ptrend = 0.10). Non-significant positive associations were observed between adherence to the EDIH at age 10 and (HR for fourth vs. first quartile = 1.49; 95% CI = 0.91-2.43; ptrend = 0.09) age 14 (HR for fourth vs. first quartile = 1.33; 95% CI = 0.97-1.82; ptrend = 0.09) and BBD risk. No associations were observed for EDIP. In secondary analyses, the association between EDIH at age 10 and BBD became statistically significant after accounting for change in dietary pattern quartile from age 10 to 14 (HR for fourth vs. first quartile = 2.14; 95% CI = 1.04-4.41). Adjustment for adult diet also strengthened associations between EDIH at age 10 and BBD risk (HR = 1.94; 95% CI = 1.12-3.37; ptrend = 0.007), and showed a significant inverse trend for AHEI (ptrend = 0.04).

CONCLUSION: These findings may suggest that greater early-life adherence to a healthier dietary pattern (AHEI) is associated with lower BBD risk, while consuming a more insulinemic dietary pattern (EDIH) may be associated with increased risk. Associations for EDIH at age 10 were statistically significant in secondary analyses accounting for dietary change and adult diet. Further research is needed to confirm these findings and clarify potential mechanisms.},
}

@article {pmid41036248,
year = {2025},
author = {Wallace, B and Dimitrov, D and Hébert-Dufresne, L and Berdahl, AM},
title = {Hotspot model shows how location-based superspreading accelerates and reshapes epidemics.},
journal = {PNAS nexus},
volume = {4},
number = {9},
pages = {pgaf299},
pmid = {41036248},
issn = {2752-6542},
abstract = {During outbreaks of many diseases, a small number of infected individuals are responsible for a disproportionately large number of new infections in what are called superspreading events (SSEs). SSEs broadly fall into four categories: (i) a single individual is more infectious due to biological differences in their infection or (ii) their greater degree of social connection; or (iii) the disease spreads more readily in certain high-risk facilities or (iv) "opportunistic" situations such as large gatherings. Existing modeling approaches work well to understand the first two of these but are not well suited to describe the dynamics in the latter two. Here, we introduce a simple agent-based model which captures the essential features of disease spreading more readily at high-risk locations or gatherings, which we call "hotspots." In our model, disease spreads and people recover as in a standard Susceptible, Infected, Recovered model, but agents are also characterized by individual probability of visiting the hotspot where disease spreads much more readily, providing an additional risk structure to the population. We use this model to investigate how an outbreak's probability, peak, and final size all vary under different risk heterogeneity assumptions. We show how some particular distributions of risk-taking behavior across the population heighten these effects. We complement our simulations with analytic results that provide theoretical bases for all of our numerical results and allow for robust interpretation and prediction.},
}

@article {pmid41035891,
year = {2025},
author = {Lawore, DC and Jena, S and Berard, AR and Birse, K and Lamont, A and Mackelprang, RD and Noel-Romas, L and Perner, M and Hou, X and Irungu, E and Mugo, N and Knodel, S and Muwonge, TR and Katabira, E and Hughes, SM and Levy, C and Calienes, FL and Hladik, F and Lingappa, JR and Burgener, AD and Green, LN and Brubaker, DK},
title = {Computational microbiome pharmacology analysis elucidates the anti-cancer potential of vaginal microbes and metabolites.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1602217},
pmid = {41035891},
issn = {1664-302X},
abstract = {The vaginal microbiome's role in risk, progression, and treatment of female cancers has been widely explored. Yet, there remains a need to develop methods to understand the interaction of microbiome factors with host cells and to characterize their potential therapeutic functions. To address this challenge, we developed a systems biology framework we term the Pharmacobiome for microbiome pharmacology analysis. The Pharmacobiome framework evaluates similarities between microbes, microbial byproducts, and known drugs based on their impact on host transcriptomic cellular signatures. Here, we apply our framework to characterization of the Anti-Gynecologic Cancer Vaginal Pharmacobiome. Using published vaginal microbiome multi-omics data from the Partners PrEP clinical trial, we constructed vaginal epithelial gene signatures associated with each profiled vaginal microbe and metabolite. We compared these microbiome-associated host gene signatures to post-drug perturbation host gene signatures related to 35 FDA-approved anti-cancer drugs from the Library of Integrated Network-based Cellular Signatures database to identify vaginal microbes and metabolites with high statistical and functional similarity to these drugs. We found that select lactobacilli particularly L. crispatus and their metabolites, such as taurine, can regulate host gene expression in ways similar to certain anti-cancer drugs. Additionally, we experimentally tested our model prediction that taurine, a metabolite produced by L. crispatus, kills cancerous breast and endometrial cancer cells. Our study shows that the Pharmacobiome is a robust framework for characterizing the anti-cancer therapeutic potential of vaginal microbiome factors with generalizability to other cancers, microbiomes, and diseases.},
}

@article {pmid41034423,
year = {2025},
author = {Setiawan, T and Muhammad, JA and Marcellina, N and Wirawan, LM and Jun, N and Sari, IN and Oehler, VG and Kim, DW and Kwon, HY},
title = {Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.},
journal = {Leukemia},
volume = {},
number = {},
pages = {},
pmid = {41034423},
issn = {1476-5551},
support = {2023R1A2C1003952//National Research Foundation of Korea (NRF)/ ; RS-2024-00437643//Korea Health Industry Development Institute (KHIDI)/ ; },
abstract = {Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.},
}

@article {pmid41034193,
year = {2025},
author = {Guo, B and Cai, Y and Kim, D and Smit, RAJ and Wang, Z and Iyer, KR and Hilliard, AT and Haessler, J and Tao, R and Broadaway, KA and Wang, Y and Pozdeyev, N and Stæger, FF and Yang, C and Vanderwerff, B and Patki, AD and Stalbow, L and Lin, M and Rafaels, N and Shortt, J and Wiley, L and Stanislawski, M and Pattee, J and Davis, L and Straub, PS and Shuey, MM and Cox, NJ and Lee, NR and Jørgensen, ME and Bjerregaard, P and Larsen, C and Hansen, T and Moltke, I and Meigs, JB and Stram, DO and Yin, X and Zhou, X and Chang, KM and Clarke, SL and Guarischi-Sousa, R and Lankester, J and Tsao, PS and Buyske, S and Graff, M and Raffield, LM and Sun, Q and Wilkens, LR and Carlson, CS and Easton, CB and Liu, S and Manson, JE and Marchand, LL and Haiman, CA and Mohlke, KL and Gordon-Larsen, P and Albrechtsen, A and Boehnke, M and Rich, SS and Manichaikul, A and Rotter, JI and Yousri, NA and Irvin, RM and , and , and Gignoux, C and North, KE and Loos, RJF and Assimes, TL and Peters, U and Kooperberg, C and Raghavan, S and Highland, HM and Darst, BF},
title = {Polygenic risk score for type 2 diabetes shows context-dependent effects across populations.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {8632},
pmid = {41034193},
issn = {2041-1723},
support = {R01HL143885//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HD30880//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL151152//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK139598//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL142302//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL143885//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL163262//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK122503//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL151152//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL156991//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01DK123019//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UM1DK078616//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R00CA246063//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R03CA287235//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01CA261339//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HL174378//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U54HG013243//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; PPM2-0226-170020//Qatar National Research Fund (QNRF)/ ; NPRP11S-0114-180299//Qatar National Research Fund (QNRF)/ ; NNF20OC0059313//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; NNF18CC0034900//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; P50CA097186//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA015704//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/epidemiology ; *Multifactorial Inheritance/genetics ; Male ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Genome-Wide Association Study ; Risk Factors ; Aged ; Adult ; Polymorphism, Single Nucleotide ; Case-Control Studies ; Genetic Risk Score ; },
abstract = {Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.},
}

Humans
*Diabetes Mellitus, Type 2/genetics/epidemiology
*Multifactorial Inheritance/genetics
Male
Female
*Genetic Predisposition to Disease
Middle Aged
Genome-Wide Association Study
Risk Factors
Aged
Adult
Polymorphism, Single Nucleotide
Case-Control Studies
Genetic Risk Score

@article {pmid41033921,
year = {2025},
author = {Kishan, AU and Juarez Casillas, JE and Sargos, P and Kalbasi, TR and Chabaud, S and Brihoum, M and Sachdeva, A and Nikitas, JN and Ma, TM and Karasik, D and Ballas, LK and Lock, D and Valle, L and Taparra, K and Reiter, RE and Saigal, C and Chamie, K and Donin, N and Chin, AI and Rettig, M and Nickols, NG and Sun, Y and Spratt, D and Lamb, JM and Cao, M and Pommier, P and Steinberg, ML},
title = {Stereotactic Intensity-modulated Radiotherapy After Radical Prostatectomy (SCIMITAR): 4-Year Outcomes of a Phase 2 Clinical Trial.},
journal = {European urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eururo.2025.09.4149},
pmid = {41033921},
issn = {1873-7560},
abstract = {In the phase 2 SCIMITAR trial, stereotactic body radiotherapy (SBRT; 30-34 Gy in 5 fractions) was delivered to the prostatic fossa after radical prostatectomy in 100 patients requiring postoperative RT, with or without nodal RT and androgen deprivation therapy (ADT). The primary endpoint was 4-yr biochemical recurrence (BCR)-free survival (BCR-FS), with events defined as BCR (prostate-specific antigen ≥0.2 ng/ml above nadir), salvage ADT, or death. Outcomes were compared to individual patient data (IPD) from a phase 3 trial of conventionally fractionated RT (CFRT) using inverse probability of treatment weighting and Fine-Gray models. At median follow-up of 53 mo, the 4-yr BCR-FS rate was 60% (95% confidence interval [CI] 50-70%). The IPD analysis revealed that for men not receiving ADT, the risk of BCR was lower with SBRT than with CFRT (subdistribution hazard ratio [sHR] 0.49, 95% CI 0.29-0.84; p = 0.008). For men receiving ADT, there was no significant difference in BCR risk between SBRT and CFRT (sHR 1.58, 95% CI 0.81-3.11; p = 0.18), although the asymmetrically broad 95%CI and directionality of the point estimate suggest that a higher BCR risk with SBRT cannot be ruled out. The 4-yr cumulative incidence rates for late grade ≥2 gastrointestinal and genitourinary toxicities were 6.6% and 32%, respectively. At 48 mo, the proportion of patients reporting a decline of more than two times the minimal clinically important difference in urinary incontinence, urinary irritative/obstructive, bowel, and sexual domains was 23%, 6.7%, 13%, and 9.7%, respectively. SBRT to the prostatic fossa appears to be safe and effective through 4 yr.},
}

@article {pmid41032739,
year = {2025},
author = {Owens, CA and Ludmir, EB and Liu, Q and Qiu, W and Gupta, AC and Smith, SA and Rigaud, B and Brock, KK and Bates, JE and Meyers, TG and Paulino, AC and Peterson, CB and Kry, SF and Teepen, JC and Ronckers, CM and Neglia, JP and Leisenring, WM and Oeffinger, KC and Nathan, PC and Turcotte, LM and Hodgson, DC and Hudson, MM and Robison, LL and Moskowitz, CS and Armstrong, GT and Henderson, TO and Yasui, Y and Howell, RM},
title = {Colorectal-Specific Radiation Dose and Chemotherapy Risk for Subsequent Colorectal Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study (CCSS) Report.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2500531},
doi = {10.1200/JCO-25-00531},
pmid = {41032739},
issn = {1527-7755},
abstract = {PURPOSE: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations.

METHODS: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (VX Gy) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models and excess rate ratio (ERR) models evaluated dose-response relationships for the incidence of colorectal SMNs. Reference groups were those not receiving the assessed treatment(s).

RESULTS: Among 25,723 survivors (median follow-up = 28.5 years; range = 5.0-48.9), 104 colorectal SMNs were identified. A dose-response relationship was observed between MCD and colorectal SMN rates; incidence rate ratios (IRRs) for 10 to <20 Gy and ≥20 Gy were 3.6 (95% CI, 1.9 to 6.9) and 8.3 (95% CI, 3.9 to 17.8), respectively. When ≥20% of the colorectum volume was irradiated, IRRs increased with increasing volume. The V20 Gy IRRs were 3.8 (95% CI, 1.9 to 7.6), 4.9 (95% CI, 2.0 to 12.0), and 8.7 (95% CI, 3.5 to 21.6) for irradiated volumes of 20% to <40%, 40% to <80%, and ≥80%, respectively. The IRR was 1.8 (95% CI, 1.0 to 3.0) for doxorubicin-equivalent dose ≥250 mg/m[2], 3.7 (95% CI, 2.2 to 6.4) for cyclophosphamide-equivalent dose ≥6,000 mg/m[2], and 4.5 (95% CI, 2.0 to 10.1) for platinum dose ≥450 mg/m[2]. For procarbazine dose, the IRR was 6.3 (95% CI, 3.0 to 13.2) for 4,200 to <7,036 mg/m[2] and 9.0 (95% CI, 4.3 to 18.9) for ≥7,036 mg/m[2]. In the absence of RT, colorectal SMN rates increased with exposure to any platinum-based agent (IRR, 3.8 [95% CI, 1.1 to 12.7]), alkylator (IRR, 4.8 [95% CI, 1.6 to 14.4]), or procarbazine (IRR, 16.9 [95% CI, 5.9 to 48.8]). Colorectal SMN rates increased linearly with procarbazine dose (ERR per 1,000 mg/m[2] = 73.0 [95% CI, 26.4% to 119.6%]) and MCD (ERR per 1 Gy = 20.8 [95% CI, 9.0% to 32.5%]). Quadratic ERR models did not improve data fit compared with linear ERR models.

CONCLUSION: These RT and chemotherapy dose-response relationships can better inform contemporary RT planning for pediatric patients and surveillance guidelines for high-risk survivors.},
}

@article {pmid41032722,
year = {2025},
author = {Curtis, DJ and Reynolds, J and Hill, GR},
title = {Cyclophosphamide and Cyclosporin for GVHD Prevention. Reply.},
journal = {The New England journal of medicine},
volume = {393},
number = {13},
pages = {1350-1351},
doi = {10.1056/NEJMc2511563},
pmid = {41032722},
issn = {1533-4406},
}

@article {pmid41032518,
year = {2025},
author = {Corey, L},
title = {Operation Warp Speed offers a roadmap for improving the efficiency of bench to bedside medical advances.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {40},
pages = {e2502975122},
doi = {10.1073/pnas.2502975122},
pmid = {41032518},
issn = {1091-6490},
support = {UM1 AI068614-14//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; },
}

@article {pmid41032288,
year = {2025},
author = {Blechter, B and Wang, X and Dai, J and Karsonaki, C and Shi, J and Shiraishi, K and Choi, J and Matsuo, K and Chen, TY and Hung, RJ and Chen, K and Shu, XO and Kim, YT and Choudhury, PP and Williams, J and Landi, MT and Lin, D and Zheng, W and Yin, Z and Zhou, B and Wang, J and Seow, WJ and Song, L and Chang, IS and Hu, W and Chien, LH and Cai, Q and Hong, YC and Kim, HN and Wu, YL and Wong, MP and Richardson, BD and Li, S and Zhang, T and Breeze, C and Wang, Z and Bassig, BA and Kim, JH and Albanes, D and Wong Sm, JY and Shin, MH and Chung, LP and Yang, Y and Zheng, H and Dai, H and Yatabe, Y and Zhang, XC and Kim, YC and Caporaso, NE and Chang, J and Ho, JCM and Daigo, Y and Momozawa, Y and Kamatani, Y and Kobayashi, M and Okubo, K and Honda, T and Hosgood, HD and Kunitoh, H and Watanabe, SI and Miyagi, Y and Matsumoto, S and Horinouchi, H and Tsuboi, M and Hamamoto, R and Goto, K and Takahashi, A and Goto, A and Minamiya, Y and Hara, M and Nishida, Y and Takeuchi, K and Wakai, K and Matsuda, K and Murakami, Y and Shimizu, K and Suzuki, H and Saito, M and Ohtaki, Y and Tanaka, K and Wu, T and Wei, F and Machiela, MJ and Kim, YH and Oh, IJ and Lee, VHF and Chang, GC and Chen, KY and Su, WC and Chen, YM and Seow, A and Park, JY and Kweon, SS and Gao, YT and Liu, J and Schwartz, AG and Houlston, R and Gorlov, IP and Wu, X and Yang, P and Lam, S and Tardon, A and Chen, C and Bojesen, SE and Johansson, M and Risch, A and Bickeböller, H and Ji, BT and Wichmann, HE and Christiani, DC and Rennert, G and Arnold, SM and Brennan, P and McKay, J and Field, JK and Davies, MPA and Shete, SS and Le Marchand, L and Liu, G and Andrew, AS and Kiemeney, LA and Zienolddiny-Narui, S and Grankvist, K and Cox, A and Taylor, F and Yuan, JM and Lazarus, P and Schabath, MB and Aldrich, MC and Jeon, HS and Jiang, SS and Chen, CH and Hsiao, CF and Hu, Z and Burdett, L and Yeager, M and Hutchinson, A and Hicks, B and Liu, J and Berndt, SI and Wu, W and Wang, J and Li, Y and Choi, JE and Park, KH and Sung, SW and Kang, CH and Wang, WC and Xu, J and Guan, P and Tan, W and Yu, CJ and Yang, G and Sihoe, ADL and Choi, YY and Park, IK and Hung, HH and Vermeulen, RCH and Cheng, I and Wu, J and Tsai, FY and Chan, JKC and Li, J and Lin, HC and Liu, J and Song, B and Sawada, N and Yamaji, T and Wyatt, K and Ma, H and Zhu, M and Wang, Y and Qi, T and Li, X and Ren, Y and Chao, A and Iwasaki, M and Zhu, J and Wu, G and Chen, CY and ScD, CC and Yang, PC and Stevens, VL and Fraumeni, JF and Lin, K and Walters, RG and Chen, Z and Chatterjee, N and Gorlova, OY and Amos, CI and Shen, H and Hsiung, CA and Chanock, SJ and Rothman, N and Kohno, T and Lan, Q and Zhang, H},
title = {Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djaf272},
pmid = {41032288},
issn = {1460-2105},
abstract = {BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction.

METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates.

RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier.

CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.},
}

@article {pmid41031719,
year = {2025},
author = {Nizam, A and Nguyen, CB and Li, J and Zabor, EC and Msaouel, P and Jiang, CY and Alhalabi, O and Oh, E and Davidsohn, MP and Epstein, IB and Bakaloudi, DR and Talukder, R and Jindal, T and Taylor, AK and Glover, MJ and Khaki, AR and Lemke, E and Mabey, H and Abuqayas, B and Jang, A and Brown, JR and Evans, ST and Pywell, C and Basu, A and Bilen, MA and Barata, PC and Zakharia, Y and Milowsky, MI and Kilari, D and Hoimes, CJ and Shah, SA and Emamekhoo, H and Davis, NB and Gupta, S and Grivas, P and Bellmunt, J and Campbell, MT and Alva, AS and Koshkin, VS},
title = {Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study.},
journal = {Cancer medicine},
volume = {14},
number = {19},
pages = {e71284},
pmid = {41031719},
issn = {2045-7634},
mesh = {Humans ; Male ; Female ; Aged ; Retrospective Studies ; Middle Aged ; *Antibodies, Monoclonal/adverse effects ; Aged, 80 and over ; *Immunoconjugates/adverse effects/therapeutic use/administration & dosage ; *Urologic Neoplasms/drug therapy/mortality/pathology ; *Carcinoma, Transitional Cell/drug therapy/mortality/pathology ; Treatment Outcome ; *Antineoplastic Agents, Immunological/adverse effects ; *Urinary Bladder Neoplasms/drug therapy/mortality/pathology ; },
abstract = {INTRODUCTION: Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data and no validated predictive biomarkers. Retrospective studies suggest higher objective response rates (ORR) among patients developing EV-related dermatologic toxicities, but survival implications remain unclear. This analysis assessed the safety of EV monotherapy and the impact of dermatologic and neurologic toxicities on efficacy outcomes in a multi-institutional cohort.

MATERIALS AND METHODS: UNITE is a multicenter, retrospective study across 16 US sites of patients with aUC treated with targeted agents, including EV. Primary endpoints were the incidence of EV treatment-related adverse events (TRAEs, any grade) and TRAE-related treatment modifications. Secondary endpoints included a comparison of ORR, progression-free survival (PFS), and overall survival (OS) between patients with and without dermatologic toxicities and neuropathy. To reduce immortal time bias, Cox regression models incorporated TRAEs as time-dependent covariates to adjust for EV treatment duration as well as Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, and liver metastases.

RESULTS: Between 2018 and 2023, 485 patients with aUC received > 1 dose of EV monotherapy. Most (67%) received > 2 prior therapy lines. Any grade TRAEs occurred in 77%, most frequently neuropathy (36%) and dermatologic toxicities (27%); 57% required treatment modification and 21% discontinued EV, primarily due to neuropathy (9%) and fatigue (3%). Patients with dermatologic toxicities and neuropathy had higher ORR (56% vs. 42%; p = 0.007 and 64% vs. 35%; p < 0.0001, respectively). Neuropathy was independently associated with improved OS (HR 0.66; 95% CI 0.50-0.87; p = 0.002); dermatologic TRAEs were not associated with PFS or OS benefit.

CONCLUSIONS: EV safety outside clinical trials was consistent with prior reports, with no new signals. Treatment modifications were most often due to neuropathy, dermatologic toxicities, and fatigue. Both dermatologic toxicities and neuropathy correlated with higher ORR, but only neuropathy was independently associated with improved OS.},
}

Humans
Male
Female
Aged
Retrospective Studies
Middle Aged
*Antibodies, Monoclonal/adverse effects
Aged, 80 and over
*Immunoconjugates/adverse effects/therapeutic use/administration & dosage
*Urologic Neoplasms/drug therapy/mortality/pathology
*Carcinoma, Transitional Cell/drug therapy/mortality/pathology
Treatment Outcome
*Antineoplastic Agents, Immunological/adverse effects
*Urinary Bladder Neoplasms/drug therapy/mortality/pathology

@article {pmid41031512,
year = {2025},
author = {Chalitsios, CV and Markozannes, G and Aglago, EK and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Dimou, N and Drew, DA and French, AJ and Georgeson, P and Giannakis, M and Gruber, SB and Gunter, MJ and Harrison, TA and Hoffmeister, M and Hsu, L and Huang, WY and Hullar, MA and Huyghe, JR and Lynch, BM and Moreno, V and Murphy, N and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Qu, C and Schmit, SL and Steinfelder, RS and Sun, W and Thomas, CE and Toland, AE and Trinh, QM and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Schoen, RE and Woods, MO and Brenner, H and Andreson, L and Pellatt, AJ and Peters, U and Phipps, AI and Tsilidis, KK},
title = {Physical activity and molecular subtypes of colorectal cancer: a pooled observational analysis and mendelian randomisation study.},
journal = {JNCI cancer spectrum},
volume = {},
number = {},
pages = {},
doi = {10.1093/jncics/pkaf095},
pmid = {41031512},
issn = {2515-5091},
abstract = {BACKGROUND: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.

METHODS: Pooled observational (ncases=5,386, ncontrols=6,798; nstudies=5) and genome-wide association data (ncases=8,178, ncontrols=10,472; nstudies=5) were utilised. We used multivariable logistic regression models and Mendelian randomisation (MR) to assess the association between physical activity and the risk of CRC subtypes defined by individual tumour markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests.

RESULTS: In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (ORObs-per 1SD=0.94, 95%CI 0.90-0.97), with an association that was stronger in males (ORObs-per 1SD=0.91, 95%CI 0.87-0.96) than in females (ORObs-per 1SD=0.97, 95%CI 0.91-1.03) (Pinteraction=0.04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or MR analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC.

CONCLUSIONS: Our findings suggest that physical activity is not differentially associated with the four major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.},
}

@article {pmid41028200,
year = {2025},
author = {Cheung, KJ and Horne-Badovinac, S},
title = {Publisher Correction: Collective cell migration modes in development, tissue repair and cancer.},
journal = {Nature reviews. Molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41580-025-00911-7},
pmid = {41028200},
issn = {1471-0080},
}

@article {pmid41028170,
year = {2025},
author = {Bot, A and Scharenberg, A and Friedman, K and Guey, L and Hofmeister, R and Andorko, JI and Klichinsky, M and Neumann, F and Shah, JV and Swayer, AJ and Trudeau, K and Weissman, D and Stephan, MT and Buchholz, CJ and June, CH},
title = {In vivo chimeric antigen receptor (CAR)-T cell therapy.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
pmid = {41028170},
issn = {1474-1784},
abstract = {Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient's body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies - including RNA delivered by lipid nanoparticles and engineered viral vectors - and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus.},
}

@article {pmid41027579,
year = {2025},
author = {Cheng, GS and Campbell, AP and Xie, H and Ogimi, C and Waghmare, A and Kuypers, J and Nichols, WG and Carpenter, P and Corey, L and Callais, C and Sandmaier, BM and Stevens-Ayers, T and Jerome, KR and Chien, JW and Leisenring, WM and Englund, JA and Boeckh, M},
title = {Respiratory Virus Infections and Pulmonary Impairment after Allogeneic Hematopoietic Cell Transplantation.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiaf503},
pmid = {41027579},
issn = {1537-6613},
abstract = {BACKGROUND: Respiratory virus infections (RVI) are common after hematopoietic cell transplantation (HCT), but their effect on pulmonary outcomes, including bronchiolitis obliterans syndrome (BOS), and mortality is poorly defined.

METHODS: Prospective cohort study of 471 allogeneic HCT recipients transplanted in the pre-COVID-19 pandemic era in an academic cancer center. Participants were prospectively followed for one year with serial handheld spirometry, symptom questionnaires, and multiplex 11-virus PCR. Pulmonary function testing occurred at recommended intervals. Cox proportional hazard and generalized estimating equation models were used to estimate associations between RVI and weekly spirometry with late airflow obstruction (AFO), BOS, and overall mortality.

RESULTS: The one-year cumulative incidence of at least one RVI was 62%; lower respiratory tract disease (LRTD) occurred in 7.6% of patients. Late AFO developed in 15.6% of patients and BOS in 3.9% of patients. Any symptomatic viral upper respiratory tract infections (URTI) were associated with AFO (adjusted HR [aHR] 1.87, 95% CI 1.11-3.16) and BOS (aHR 2.65, 95% CI 1.02-6.91). Individually, PIV-3 URTI were associated with AFO (aHR 2.83, 95% CI 1.01-7.97) and RSV URTI were associated with BOS (aHR 6.32, 95% CI 2.04-19.6). Short-term airflow decline was associated with AFO. Any LRTD (aHR 3.49, 95% CI 2.18-5.57), as well as symptomatic influenza URTI (aHR 2.68, 95% CI 1.52-4.72), were associated with mortality.

CONCLUSIONS: RVI after HCT, particularly those caused by RSV, PIV-3 and influenza, increase the risk of pulmonary impairment and mortality. These infections should be targeted for specific anti-viral approaches and intensified monitoring for late onset pulmonary disease.},
}

@article {pmid41027557,
year = {2025},
author = {Spellman, SR and Xu, K and Oloyede, T and Ahn, KW and Akhtar, OS and Bolon, YT and Broglie, L and Bloomquist, J and Bupp, C and Chen, M and Devine, SM and Jurdi, NE and Hamadani, M and Hengen, M and Huppler, AH and Jaglowski, S and Kuxhausen, M and Lee, SJ and Moskop, A and Page, KM and Pasquini, MC and Pérez, WS and Phelan, R and Rizzo, D and Saber, W and Stefanski, HE and Steinert, P and Tuschl, E and Visotcky, A and Vogel, R and Auletta, JJ and Shaw, BE and Allbee-Johnson, M},
title = {Corrigendum to: Current Activity Trends and Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy - A Report from the CIBMTR, Transplantation and Cellular Therapy, 31:8, August 2025, 505-532; Article Number: JTCT-S-25-00377.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2025.09.001},
pmid = {41027557},
issn = {2666-6367},
}

@article {pmid40924543,
year = {2025},
author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A},
title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.},
journal = {Bioinformatics (Oxford, England)},
volume = {41},
number = {10},
pages = {},
doi = {10.1093/bioinformatics/btaf488},
pmid = {40924543},
issn = {1367-4811},
support = {//Research Foundation-Flanders/ ; },
mesh = {*Software ; *Phylogeny ; *SARS-CoV-2/genetics/classification ; Bayes Theorem ; *Ebolavirus/genetics/classification ; Algorithms ; Humans ; *Computational Biology/methods ; COVID-19/virology ; },
abstract = {SUMMARY: In Bayesian phylogenetic and phylodynamic studies, it is common to summarize the posterior distribution of trees with a time-calibrated summary phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel summary tree method-the highest independent posterior subtree reconstruction, or (HIPSTR)-contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both summary trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the summary tree.

RESULTS: HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 datasets show that HIPSTR yields summary trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥0.95) as well as a large number of clades with moderate to high posterior probability (≥50%), whereas HIPSTR-in particular its majority-rule extension MrHIPSTR-achieves near-perfect performance in this respect. HIPSTR and MrHIPSTR also exhibit favourable computational performance over MCC in TreeAnnotator X. Comparison to the recent CCD0-MAP algorithm yielded mixed results and requires a more in-depth investigation in follow-up studies.

TreeAnnotator X is available as part of the BEAST X (v10.5.0) software package, available at https://github.com/beast-dev/beast-mcmc/releases, and on Zenodo (DOI: https://doi.org/10.5281/zenodo.4895234).},
}

*Software
*Phylogeny
*SARS-CoV-2/genetics/classification
Bayes Theorem
*Ebolavirus/genetics/classification
Algorithms
Humans
*Computational Biology/methods
COVID-19/virology

@article {pmid41027157,
year = {2025},
author = {Dominguez Islas, CP and Magaret, CA and Molitor, C and Serebryannyy, L and Narpala, S and Castro, M and Posavad, CM and Roberts, PC and Lyke, KE and Atmar, RL and Janes, H and Deming, ME},
title = {SARS-CoV-2 spike sequence-based distance as a marker of binding antibody response to COVID-19 vaccines.},
journal = {Vaccine},
volume = {65},
number = {},
pages = {127738},
doi = {10.1016/j.vaccine.2025.127738},
pmid = {41027157},
issn = {1873-2518},
abstract = {COVID-19 vaccines based on ancestral SARS-CoV-2 have proven highly effective at reducing the risk of illness, especially severe disease. Both binding and neutralizing antibodies have been demonstrated to be strong predictors of the level of vaccine efficacy (VE). Both VE and vaccine-induced antibody responses have been shown to be lower against emergent SARS-CoV-2 viruses; therefore, predicting COVID-19 VE against emergent viruses is critical for decision-making regarding the composition of new vaccines. The data needed to enable such prediction are unclear. We report on 728 individuals without prior SARS-CoV-2 infection who received primary vaccination with ancestral-virus-based mRNA and vector-based COVID-19 vaccines and who were boosted in a homologous or heterologous fashion with mRNA, vector, or protein-based COVID-19 vaccines including a bivalent B.1.351 mRNA vaccine. Post-prime and post-boost binding antibody responses were used to evaluate the extent and drivers of variability in these responses to 22 SARS-CoV-2 Spike antigens from viruses that emerged between 2020 and 2021. We evaluated how well proteomic distance between the vaccine and assay Spike antigen predicted the vaccine-induced antibody response. Following primary vaccination, antibody responses varied across Spike antigens and were, on average, 36 % lower per 10-amino acid (AA) difference between the vaccine and assay Spike antigen (95 % CI: 30 % to 43 %). The geometric mean antibody response to a given antigen was nearly perfectly predicted by the sequence-based distance of the antigen to the vaccine. Post-boost responses were less variable across antigens and weakly associated with Spike distance (17 % lower per 10-AA difference; 95 % CI: 14 % to 20 %). The high variability in binding antibodies across individuals was only partially explained by participant characteristics. Given that populations now have experienced multiple rounds of prior vaccination and infection, measurement of vaccine-induced antibody responses from representative populations will likely be needed to predict the efficacy of COVID-19 vaccines against future strains.},
}

@article {pmid41025350,
year = {2025},
author = {Jakubek, YA and Smith, AP and Leng, XI and Hall, ME and Ezzat, D and Pershad, Y and Collins, JM and Uddin, MM and Fardo, DW and Natarajan, P and Bick, AG and Kitzman, JO and Honigberg, MC and Hayden, KM and Manson, JE and Jaiswal, S and Whitsel, EA and Reiner, AP},
title = {Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women's Health Initiative Memory Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70737},
pmid = {41025350},
issn = {1552-5279},
support = {//WHI/ ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; },
mesh = {Humans ; Female ; *Cognitive Dysfunction/genetics/epidemiology ; Aged ; *Clonal Hematopoiesis/genetics ; Risk Factors ; Women's Health ; *Dementia/genetics/epidemiology ; Aged, 80 and over ; Middle Aged ; Proportional Hazards Models ; Incidence ; },
abstract = {INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) confers an increased risk of several chronic aging-related diseases. Paradoxically, CHIP was associated with lower risk of dementia in recent studies.

METHODS: We examined associations between baseline CHIP and incident mild cognitive impairment (MCI) and/or probable dementia in the Women's Health Initiative Memory Study. CHIP was detected using blood-based targeted sequencing. Cox proportional hazards models examined time to onset of cognitive impairment, adjusting for traditional risk factors.

RESULTS: Using a conventional variant allele fraction (VAF) threshold of 2%, CHIP was not associated with incident cognitive impairment. The presence of larger CHIP clone (VAF ≥ 8%) was associated with a lower incidence of adjudicated probable dementia (hazard ratio = 0.62 [95% confidence interval = 0.41 to 0.94], p = 0.025), while the association with the composite outcome MCI/probable dementia was weaker and overlapped 1.0.

DISCUSSION: The association of CHIP with lower risk of cognitive impairment in postmenopausal women may be dependent on VAF and impairment severity.

HIGHLIGHTS: The WHIMS comprises ∼5000 postmenopausal women, followed for up to 25 years. CHIP was associated with reduced risk of adjudicated probable dementia in WHIMS. Large CHIP clones (> 8% VAF), but not small clones (<8% VAF), showed an association. CHIP was not associated with MCI in the WHIMS cohort.},
}

Humans
Female
*Cognitive Dysfunction/genetics/epidemiology
Aged
*Clonal Hematopoiesis/genetics
Risk Factors
Women's Health
*Dementia/genetics/epidemiology
Aged, 80 and over
Middle Aged
Proportional Hazards Models
Incidence

@article {pmid41024277,
year = {2025},
author = {Gafken, PR and Paczesny, S},
title = {Blood proteomics for quantitative biomarkers of cellular therapies.},
journal = {Biomarker research},
volume = {13},
number = {1},
pages = {120},
pmid = {41024277},
issn = {2050-7771},
support = {P30CA015704/CA/NCI NIH HHS/United States ; R01CA168814/CA/NCI NIH HHS/United States ; R21AI178981//National Institute of Allergy and Infectious Diseases/ ; R01HL158096/HL/NHLBI NIH HHS/United States ; },
abstract = {Cellular therapies for several blood cancers particularly of lymphoid origin have made remarkable leaps forward. In parallel, blood proteomics, specifically quantitative proteomics, has been a powerful tool for identifying and quantifying protein biomarkers associated with cellular therapies, providing insights into treatment efficacy and toxicity. Both mass spectrometry (MS)-based proteomics and large-scale affinity-based platforms such as Olink and SomaScan have been increasingly implemented in research and clinical laboratories to identify and quantify candidate biomarkers in the blood. Biomarkers are used for risk stratification, early diagnosis, prognosis, and for treatment response prediction and monitoring in context of treatment efficacy and toxicity. These biomarkers might facilitate timely and selective therapeutic intervention and understand pathogenesis mechanisms of responses and adverse events. They are anticipated to undergo faster transition from bench to bedside soon. This review article summarizes recent technical progresses in clinical proteomics. The review also provides current information on validated biomarkers in the field of cellular therapies.},
}

@article {pmid41022768,
year = {2025},
author = {Liu, P and Li, JJ},
title = {mcRigor: a statistical method to enhance the rigor of metacell partitioning in single-cell data analysis.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {8602},
pmid = {41022768},
issn = {2041-1723},
support = {R35GM140888//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1846216//NSF | BIO | Division of Biological Infrastructure (DBI)/ ; 2113754//NSF | Directorate for Mathematical & Physical Sciences | Division of Mathematical Sciences (DMS)/ ; 2022-249355//Silicon Valley Community Foundation (SVCF)/ ; },
mesh = {*Single-Cell Analysis/methods ; Algorithms ; Humans ; RNA-Seq ; Reproducibility of Results ; Gene Expression Profiling/methods ; *Computational Biology/methods ; Software ; },
abstract = {In single-cell data analysis, addressing sparsity often involves aggregating the profiles of homogeneous single cells into metacells. However, existing metacell partitioning methods lack checks on the homogeneity assumption and may aggregate heterogeneous single cells, potentially biasing downstream analysis and leading to spurious discoveries. To fill this gap, we introduce mcRigor, a statistical method to detect dubious metacells, which are composed of heterogeneous single cells, and optimize the hyperparameter(s) of a metacell partitioning method. The core of mcRigor is a feature-correlation-based statistic that measures the heterogeneity of a metacell, with its null distribution derived from a double permutation scheme. As an optimizer for existing metacell partitioning methods, mcRigor has been shown to improve the reliability of discoveries in single-cell RNA-seq and multiome (RNA + ATAC) data analyses, such as uncovering differential gene co-expression modules, enhancer-gene associations, and gene temporal expression. Moreover, mcRigor enables benchmarking and selection of the most suitable metacell partitioning method with optimized hyperparameter(s) tailored to a specific dataset, ensuring reliable downstream analysis. Our results indicate that among existing metacell partitioning methods, MetaCell and SEACells consistently outperform MetaCell2 and SuperCell, albeit with the trade-off of longer runtimes.},
}

*Single-Cell Analysis/methods
Algorithms
Humans
RNA-Seq
Reproducibility of Results
Gene Expression Profiling/methods
*Computational Biology/methods
Software

@article {pmid41021636,
year = {2025},
author = {Giersch, RM and Sevigny, JK and Weinandt, SA and Mayo, C and Garrett, FES and Tindbaek, K and Yonemitsu, MA and Hart, SFM and Metzger, MJ},
title = {Variation in natural infection outcomes and cancer cell release from soft-shell clams (Mya arenaria) with bivalve transmissible neoplasia.},
journal = {PLoS pathogens},
volume = {21},
number = {9},
pages = {e1013537},
doi = {10.1371/journal.ppat.1013537},
pmid = {41021636},
issn = {1553-7374},
support = {R01 CA255712/CA/NCI NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; },
abstract = {Bivalve transmissible neoplasias (BTNs) are leukemia-like cancers found in at least 10 bivalve species, in which the cancer cells themselves transfer from one individual to another, spreading as an unusual form of infectious disease. Before the infectious etiology was known, there were reports of lethality and outbreaks of cancer in the soft-shell clam (Mya arenaria) on the east coast of North America. Using sensitive and specific qPCR assays, we followed the outcomes of BTN in naturally-infected soft-shell clams from Maine, USA. We observed variable outcomes, with about half of clams (9/21) progressing to high levels of cancer and death, about half exhibiting long-term non-progression (11/21), and a single animal showing regression of cancer. We also observe a significant decrease in survival in animals that progress to >10% cancer in their hemolymph, while we see no effect on survival in clams with BTN that are long-term non-progressors. As most bivalves do not physically contact each other, and BTN cells can survive in seawater, it has been proposed that BTN is spread through release of cancer cells into the water. We used qPCR to detect BTN-specific sequences in environmental DNA (eDNA) in the tanks of animals throughout this experiment. We show that BTN-specific eDNA (likely from released cancer cells) can be detected in tank water of most clams with >24% cancer in their hemolymph, but not below this level. This detection of BTN eDNA is variable and occurs in bursts, but in clams with >24% cancer, the detection of BTN eDNA correlates with progression of the cancer in the hemolymph. This study demonstrates the lethality of BTN, but the observation that about half of clams with BTN do not progress to death provides evidence suggesting that there may be a block to the progression of BTN in a large portion of clams in a population with this enzootic disease. This study also further supports the hypothesis that BTN cells transmit through seawater and provides insights into the mechanisms of the transmission dynamics.},
}

@article {pmid41021323,
year = {2025},
author = {Etzioni, R and Owens, L},
title = {Learning from prostate cancer statistics.},
journal = {CA: a cancer journal for clinicians},
volume = {},
number = {},
pages = {},
doi = {10.3322/caac.70037},
pmid = {41021323},
issn = {1542-4863},
}

@article {pmid41019149,
year = {2025},
author = {Mohty, M and Banerjee, R},
title = {Networking for a successful career in clinical hematology: a strategic approach.},
journal = {Clinical hematology international},
volume = {7},
number = {3},
pages = {20-23},
pmid = {41019149},
issn = {2590-0048},
abstract = {Networking is fundamental to career development in clinical hematology, providing avenues for knowledge exchange, collaborations, and professional growth. This manuscript examines specific strategies for networking within this specialized field, detailing effective platforms, strategies, overcoming challenges, and illustrating real-world success stories. References to key studies and expert opinions underscore the importance of building a robust professional network through in-person and online activities. An extensive review of literature highlights how networking contributes to scientific collaboration, mentorship, career opportunities, and the dissemination of cutting-edge hematological research.},
}

@article {pmid41018806,
year = {2025},
author = {Li, S and Gilbert, PB and Duan, R and Luedtke, A},
title = {Data fusion using weakly aligned sources.},
journal = {Journal of the American Statistical Association},
volume = {},
number = {},
pages = {},
pmid = {41018806},
issn = {0162-1459},
support = {DP2 LM013340/LM/NLM NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; },
abstract = {We introduce a new data fusion method that utilizes multiple data sources to estimate a smooth, finite-dimensional parameter. Most existing methods only make use of fully aligned data sources that share common conditional distributions of one or more variables of interest. However, in many settings, the scarcity of fully aligned sources can make existing methods require unduly large sample sizes to be useful. Our approach enables the incorporation of weakly aligned data sources that are not perfectly aligned, provided their degree of misalignment is known up to finite-dimensional parameters. We quantify the additional efficiency gains achieved through the integration of these weakly aligned sources. We characterize the semiparametric efficiency bound and provide a general means to construct estimators achieving these efficiency gains. We illustrate our results by fusing data from two harmonized HIV monoclonal antibody prevention efficacy trials to study how a neutralizing antibody biomarker associates with HIV genotype.},
}

@article {pmid41018563,
year = {2025},
author = {Williamson, BD and King, D and Huang, Y},
title = {Practical Considerations for Variable Screening in the Super Learner.},
journal = {The New England Journal of Statistics in Data Science},
volume = {},
number = {},
pages = {},
pmid = {41018563},
issn = {2693-7166},
support = {S10 OD028685/OD/NIH HHS/United States ; R01 GM106177/GM/NIGMS NIH HHS/United States ; R01 CA277133/CA/NCI NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; },
abstract = {Estimating a prediction function is a fundamental component of many data analyses. The super learner ensemble, a particular implementation of stacking, has desirable theoretical properties and has been used successfully in many applications. Dimension reduction can be accomplished by using variable screening algorithms (screeners), including the lasso, within the ensemble prior to fitting other prediction algorithms. However, the performance of a super learner using the lasso for dimension reduction has not been fully explored in cases where the lasso is known to perform poorly. We provide empirical results that suggest that a diverse set of candidate screeners should be used to protect against poor performance of any one screener, similar to the guidance for choosing a library of prediction algorithms for the super learner. These results are further illustrated through the analysis of HIV-1 antibody data.},
}

@article {pmid41017661,
year = {2025},
author = {Lasowski, P and Tollefson, D and Menacho, L and DePierro, J and Duerr, A},
title = {High prevalence of pain and mental health conditions amongst people well-established in HIV care: results of a cross-sectional survey in Lima, Peru.},
journal = {AIDS care},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/09540121.2025.2562242},
pmid = {41017661},
issn = {1360-0451},
abstract = {People living with HIV (PLWH) are at risk for mental health (MH) disorders and pain, but this burden is largely unknown in low/middle-income countries. From February-October 2023, we conducted a cross-sectional survey at a large HIV clinic in Lima, Peru to quantify the prevalence of MH disorders and pain amongst PLWH established in care and to explore relationships between MH and well-managed HIV. At clinic visits, PLWH were invited to complete validated measures for depression, post-traumatic stress disorder (PTSD), alcohol use disorder (AUD), and pain (PHQ-8, PCL5, AUDIT-C, and BPISF). We abstracted data on treatment and viral suppression from medical charts. We calculated the prevalence of depression (PHQ8 ≥ 10), PTSD (PCL-5 ≥ 30), AUD (AUDIT-C ≥ 4 for men, ≥ 3 for women), and pain severity/interference (none, mild, moderate, or severe). We conducted logistic regression analyses to determine associations between MH/pain and viral suppression. Among 397 participants, 32% (95% CI: 27-37%) reported AUD, 21% (17-26%) reported depression, and 13% (9.5-16%) reported PTSD; 14% (11-18%) and 12% (9.3-16%) reported moderate/severe pain intensity and interference, respectively. There were no associations between MH/pain and viral suppression. High levels of MH disorders and pain among PLWH established in care suggest screening is needed for all PLWH, even those with well-controlled HIV.},
}

@article {pmid41017648,
year = {2025},
author = {Hyde, ET and Bandoli, GE and Zou, J and Crespo, NC and Parada, H and Evenson, KR and Howard, AG and LaMonte, MJ and Stefanick, ML and Tinker, LF and Haring, B and Manson, JE and Lee, IM and LaCroix, AZ},
title = {Prospective associations between accelerometer-measured physical activity, sedentary behavior, and healthy longevity: the Women's Health Accelerometry Collaboration.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf206},
pmid = {41017648},
issn = {1758-535X},
abstract = {BACKGROUND: The influence of physical activity (PA) and sedentary behavior (SB) on survival to late age with intact mobility is unclear. This study investigated associations between accelerometer-measured daily PA, SB, and survival to age 90 birthyear with and without intact mobility in the Women's Health Accelerometry Collaboration (WHAC).

METHODS: Postmenopausal U.S. women aged 78-89 years without mobility disability were followed for an average of 6.1 years. At age 90 birthyear, participants were categorized as: (1) surviving with intact mobility, (2) surviving with mobility disability, or (3) deceased. Participants wore an accelerometer on the hip for up to 7 days at baseline from 2011-2015. Covariate-adjusted multinomial logistic regression models estimated odds ratios (ORs) of PA (light, moderate-to-vigorous [MVPA], total, steps) and SB (sitting time, mean sitting bout duration) with survival outcomes relative to dying.

RESULTS: Among 2,656 women (mean baseline age 83.1 years), 62.8% survived with intact mobility, 22.3% with mobility disability, and 15.0% died. Compared to dying before age 90, the OR (95% confidence intervals [CI]) for every 1-SD increment in accelerometer variables and survival with intact mobility were 1.36 (1.20, 1.54) for light PA, 1.69 (1.47, 1.96) for MVPA, 1.51 (1.33, 1.71) for total PA, 1.75 (1.51, 2.03) for steps, 0.70 (0.61, 0.80) for sitting time, and 0.79 (0.70, 0.89) for sitting bouts. Similar, weaker trends were present for mobility disability.

CONCLUSIONS: These findings corroborate the potential role of increasing physical activity in preserving physical functioning as an important element of healthy longevity.},
}

@article {pmid41017259,
year = {2025},
author = {Sharma, P and George, N and Srivastava, D and Chow, EJ and Alderfer, MA and Leisenring, W and Long, KA and Lown, AE and Oeffinger, KC and Zeltzer, LK and Armstrong, GT and Krull, KR and Brinkman, TM and Buchbinder, D},
title = {Psychosocial Health and Chronic Health Conditions Among Bereaved Siblings: A Report From the Childhood Cancer Survivorship Study (CCSS).},
journal = {Pediatric blood & cancer},
volume = {},
number = {},
pages = {e32076},
doi = {10.1002/pbc.32076},
pmid = {41017259},
issn = {1545-5017},
support = {CA55727/CA/NCI NIH HHS/United States ; //to St. Jude Children's Research Hospital/ ; CA21765//Cancer Center Support/ ; //American Lebanese-Syrian Associated Charities/ ; },
abstract = {OBJECTIVE: To compare psychosocial health and chronic health conditions (CHCs) in bereaved and non-bereaved adult siblings impacted by childhood cancer and to identify predictors of emotional distress and health-related quality of life among bereaved siblings.

METHODS: A total of 4558 adult siblings (733 bereaved; 3825 non-bereaved) of 5-year survivors of childhood cancer completed measures of emotional distress (Brief Symptom Inventory [BSI]-18) and health-related quality of life (Medical Outcomes Survey Short Form [SF]-36) and reported their social attainment milestones (i.e., educational attainment, employment, and marital status). CHCs' burden was classified as none/low versus medium/high/very severe. Cancer-associated complications prior to the patient's death, sibling age at bereavement, and social attainment variables were examined as predictors of emotional distress and health-related quality of life among bereaved siblings using multivariable modified Poisson regression.

RESULTS: Bereaved siblings in this sample reported excellent psychosocial health long term (e.g., depressive symptoms 6.5%, somatization 4.4%, anxiety 3.5%). Bereaved siblings had an elevated risk of depression (relative risk [RR] 1.53; 1.10-2.13, p = 0.01), reduced social quality of life (RR 1.35; 1.00-1.82, p = 0.05), diminished educational attainment, and greater CHC burden than non-bereaved siblings. No differences were observed for other subscales or social attainment outcomes. Among bereaved siblings, risk factors for depression included male sex (RR 0.42; 0.19-0.93, p = 0.05), never being married (RR 3.02; 1.45-6.28, p = 0.05), and greater CHC burden (RR 2.42; 1.18-4.99, p = 0.05). Risk factors for poor social functioning included unemployment (RR 2.24; 1.12-4.45, p = 0.05) and never being married (RR 2.16; 1.22-3.82, p = 0.05).

CONCLUSION: Bereaved siblings report excellent psychosocial health long-term and demonstrate only a marginally elevated risk of experiencing symptoms of depression and poor social quality of life compared to non-bereaved siblings.},
}

@article {pmid41016483,
year = {2025},
author = {K, R and Ac, H and K, B and Je, G and A, A and G, O and D, M and S, K and Z, N and M, F and M, S and F, F and Mh, A and P, S and Y, B and F, L and C, P and K, M and I, M and J, G and A, B and M, S and A, D and K, K and A, L and B, N and Ks, B and K, R and S, C},
title = {Late Effects After Haematopoietic Stem Cell Transplantation in patients with HLH: A Histiocyte Society, PDWP, IEWP and TCWP EBMT Study.},
journal = {The Journal of allergy and clinical immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaci.2025.09.014},
pmid = {41016483},
issn = {1097-6825},
abstract = {BACKGROUND: Hematopoietic stem cell transplantation is the only curative treatment in primary hemophagocytic lymphohistiocytosis. However, hematopoietic stem cell transplantation is associated with a wide range of late effects.

OBJECTIVE: Characterization of the long-term outcome and late effects following hematopoietic stem cell transplantation in primary hemophagocytic lymphohistiocytosis.

METHODS: 274 children with pHLH from the EBMT registry who underwent allogeneic hematopoietic stem cell transplantation between 2004 and 2015 were included. Multivariable logistic regression models were performed to evaluate the adjusted impact of baseline variables on CNS and hormonal late effects, respectively.

RESULTS: A broad spectrum of late effects was identified, with neurological (31%) and hormonal (34.8%) complications being the most prevalent. Chemotherapy (HLH-94/HLH04) before hematopoietic stem cell transplantation was identified as a significant risk factor for endocrinological late effects (p=0.03), highlighting a novel aspect not previously reported. The presence of neurological abnormality at diagnosis was an independent risk factor for neurological late effects (p<0.001) as was incomplete remission status at time of HCT (p=0.04).

CONCLUSION: Hematopoietic stem cell transplantation has significantly improved survival in primary hemophagocytic lymphohistiocytosis patients, however survivors still face significant risks of late effects.},
}

@article {pmid41015745,
year = {2025},
author = {Samady, H and Drangsholt, M and Sebastian, G and Dean, D},
title = {Osteonecrosis of the jaw as a possible adverse effect of tocilizumab.},
journal = {Oral surgery, oral medicine, oral pathology and oral radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.oooo.2025.08.011},
pmid = {41015745},
issn = {2212-4411},
abstract = {We report the case of a 79-year-old female with a complex medical history, presenting with recurrent gingival swelling, progressive gingival hyperplasia, and osteonecrosis of the jaw potentially associated with tocilizumab. Oral complications developed in close proximity to diagnosis of chronic myelomonocytic leukemia, complicating diagnosis and management.},
}

@article {pmid41015336,
year = {2025},
author = {Shoenbill, KA and Ostroff, JS and Taylor, KL and Jafarinia, A and Minion, M and Chichester, LA and Omernik, B and McCall, M and Yeung, S and Wiseman, K and Chen, LS and Salloum, RG and Warren, G},
title = {Recommendations for Standardization of Tobacco Use Treatment Data.},
journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtho.2025.09.1756},
pmid = {41015336},
issn = {1556-1380},
abstract = {INTRODUCTION: Although there is widespread acceptance of the importance of assessing and treating tobacco use in cancer care settings, there is much variation in the documentation and reporting of metrics relevant to tobacco treatment. The Cancer Center Cessation Initiative (C3I), as part of NCI's Cancer Moonshot, convened a Metrics Standardization Workgroup to develop a data dictionary and make recommendations for standardized quality measurement, program evaluation, and tobacco treatment program development.

METHODS: A multidisciplinary workgroup of 12 subject matter experts was convened to deliberate and standardize definitions for tobacco assessment and treatment utilization metrics. Decisions on which data elements to include were informed by clinical guidelines, literature reviews, and workgroup members' expertise. Consensus was reached when all members agreed that the proposed metric was clear, clinically relevant, and could be abstracted and reported.

RESULTS: The group considered metrics in the following categories: (1) patient identification, screening, and referral, (2) tobacco treatment process metrics, and (3) treatment outcomes. We developed a tobacco screening, referral and engagement workflow, and a data library for the following terms: patient population, screening rate, tobacco use prevalence, referral rate, reach, unsuccessful reach attempts, enrollment, treatment engagement, and counseling dose. Outcome metrics (i.e., varied "quit rate" terms) were collated and defined.

DISCUSSION: The proposed standardized data definitions can be used to improve communication and measure effectiveness for tobacco use treatment, research, operational performance, policy, quality improvement, and guideline development.},
}

@article {pmid41014345,
year = {2025},
author = {Zhao, LP and Papadopoulos, GK and McFarland, BJ and Skyler, JS and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, Å},
title = {Correction: Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.},
journal = {Diabetologia},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00125-025-06557-6},
pmid = {41014345},
issn = {1432-0428},
}

@article {pmid41014159,
year = {2025},
author = {Fernandez Turizo, MJ and Velez, MA and Glenn, B and Cummings, AL and Segarra-Vazquez, B and Gorbatov, S and Park, SJ and Shen, C and Lind-Lebuffe, JP and Unger, JM and Garon, EB},
title = {Characteristics of clinical trials associated with appeal and return on investment to participants, A Review and Framework.},
journal = {The oncologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/oncolo/oyaf313},
pmid = {41014159},
issn = {1549-490X},
abstract = {Despite decades of investment in clinical research infrastructure, patient participation in clinical trials remains strikingly low. In the United States, fewer than 1 in 10 adults report ever being invited to participate in a clinical trial, and among those, less than half ultimately enroll. In oncology, across all adult cancer patients, only about 8% enroll in a clinical trial, regardless of eligibility or trial availability. Active engagement of patients in cancer clinical trials substantially enhances scientific knowledge, and patient participation is required to obtain approval for novel therapeutics. Analyses focusing on evaluating if clinical trial participation improves survival for participants have yielded conflicting results. Yet, there is limited data or metrics to assess the specific attributes of oncology trials that hold greater appeal or return on investment to participants, limiting researchers' ability to determine if these factors vary across different populations. Our group demonstrated that patients with limited English proficiency were unlikely to participate in studies not sponsored by industry as compared to industry-sponsored studies. If trial participation for specific populations can differ by sponsor type, it could also differ by the trial's appeal or return on investment. While the underrepresentation of racial and ethnic minority groups in trials is attributed to multiple factors, it is possible that patients from these groups are less likely to be offered participation in studies with higher appeal or return on investment, due to systemic biases, disparities in recruitment practices and/or lack of access. In this manuscript, we propose a systematic framework for evaluating attributes of interventional oncology clinical trials, with an emphasis on the study's purpose, experimental design and investigational agent. This framework aims to pinpoint characteristics that may enhance trials' appeal or return on investment to participants and could lay a foundation for future research. This will allow investigators to assess the return on investment of appeal of studies offered across different patient populations.},
}

@article {pmid40711480,
year = {2025},
author = {Wesolowski, R and Rugo, HS and Specht, JM and Han, HS and Kabos, P and Vaishampayan, U and Wander, SA and Gogineni, K and Spira, A and Schott, AF and Abu-Khalaf, M and Mutka, SC and Suzuki, S and Sullivan, B and Gorbatchevsky, I and Layman, RM},
title = {Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {31},
number = {19},
pages = {4040-4048},
doi = {10.1158/1078-0432.CCR-25-0992},
pmid = {40711480},
issn = {1557-3265},
mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/genetics/metabolism/mortality ; Letrozole/administration & dosage ; Pyridines/administration & dosage/adverse effects ; Piperazines/administration & dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration & dosage ; Receptor, ErbB-2/metabolism/genetics ; Middle Aged ; Receptors, Estrogen/metabolism ; Aged ; Receptors, Progesterone/metabolism ; Adult ; Aged, 80 and over ; Class I Phosphatidylinositol 3-Kinases/genetics ; },
abstract = {PURPOSE: Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor-positive (HR+)/HER2- breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2- advanced breast cancer. Simultaneous blockade of the estrogen receptor, CDK4/6, and PAM pathways may optimize antitumor control in the treatment-naïve advanced breast cancer setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2- advanced breast cancer.

PATIENTS AND METHODS: Treatment-naïve patients from a phase Ib study with HR+/HER2- advanced breast cancer treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival.

RESULTS: Of 41 patients, all had stage IV disease, 93% had measurable disease, 78% had visceral metastases, and 22% had detectable PIK3CA mutations. The objective response rate was 79% in patients with evaluable disease (N = 33). The median duration of response was 48 months for confirmed responders. The median PFS was 48.4 months, and the median overall survival was 77.3 months. The overall response rate and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).

CONCLUSIONS: Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for advanced breast cancer. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2- advanced breast cancer.},
}

Humans
Female
*Breast Neoplasms/drug therapy/pathology/genetics/metabolism/mortality
Letrozole/administration & dosage
Pyridines/administration & dosage/adverse effects
Piperazines/administration & dosage/adverse effects
*Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration & dosage
Receptor, ErbB-2/metabolism/genetics
Middle Aged
Receptors, Estrogen/metabolism
Aged
Receptors, Progesterone/metabolism
Adult
Aged, 80 and over
Class I Phosphatidylinositol 3-Kinases/genetics

@article {pmid41012183,
year = {2025},
author = {Pallerla, S and Kallur Siddaramaiah, L and Mundsperger, P and Katinger, D and Fauland, K and Kreismayr, G and Weik, R and Arslan, O and Shen, M and Ozorowski, G and Lee, WH and Ward, AB and Baboo, S and Diedrich, JK and Yates, JR and Paulson, JC and Blumen, T and Craig, D and Swoyer, R and Yuan, M and Stamatatos, L},
title = {GMP Manufacturing and Characterization of the HIV Booster Immunogen HxB2.WT.Core-C4b for Germline Targeting Vaccine Strategies.},
journal = {Vaccines},
volume = {13},
number = {9},
pages = {},
pmid = {41012183},
issn = {2076-393X},
support = {7E11AI093022-02/NH/NIH HHS/United States ; },
abstract = {BACKGROUND/OBJECTIVES: Despite progress in antiretroviral therapy, HIV remains a major global health challenge with over one million new infections annually. An effective vaccine is urgently needed. Germline-targeting immunogens show promise in initiating broadly neutralizing antibody (bNAb) precursors. This study developed a scalable, cGMP-compliant process to manufacture the HIV vaccine booster immunogen HxB2.WT.Core-C4b, a nanoparticle designed to direct bNAb precursor maturation after priming.

METHODS: A CHO cell platform was established through single-cell cloning from a high-producing stable pool. Upstream and downstream processes were optimized for scalability and yield. Three scales were tested 10 L, 40 L, and 400 L. Key parameters (pH, temperature, feeding, metabolite profiles) were systematically refined. Analytical characterization included glycosylation profiling, electron microscopy, and antigenicity testing. Viral clearance was evaluated per ICH Q5A guidelines.

RESULTS: Optimization ensured consistent yields above 130 mg/L, with titers up to 250 mg/L. The selected clone (4E22) demonstrated strong growth, viability, and reproducibility. Glycan occupancy at 18 N-linked sites, including bNAb epitopes (N276, N332), was stable across scales. Over 70% of self-assembling nanoparticle were fully assembled at the GMP level. Antigenicity and purity met cGMP release criteria. Viral clearance achieved >13-log reduction for enveloped and >7-log for non-enveloped viruses.

CONCLUSIONS: This work establishes a robust, scalable platform for HIV nanoparticle immunogens. Consistent quality and yield across scales support clinical development of HxB2.WT.Core-C4b and provide a model for other glycosylated nanoparticle vaccines. The immunogen is being evaluated in clinical study HVTN 320 (NCT06796686), enabling early testing of next-generation vaccines designed to elicit broadly neutralizing antibodies.},
}

@article {pmid41006096,
year = {2025},
author = {Button, E and Zhang, ARY and Thamm, C and Chan, RJ and Charalambous, A and Ee, C and Merlo, G and McErlean, G and Anderson, BO and Kitson, AL},
title = {The Australian Cancer Plan through a Caring Life Course Lens: Moving from Cancer to Care by Placing the Person at the Center of Care.},
journal = {Seminars in oncology nursing},
volume = {},
number = {},
pages = {152020},
doi = {10.1016/j.soncn.2025.152020},
pmid = {41006096},
issn = {1878-3449},
abstract = {OBJECTIVE: We propose the Caring Life Course Theory (CLCT) as a lens that can inform and enrich national cancer policy and clinical practice. The purpose of this discussion paper is to highlight how a CLCT lens can inform the implementation of a national cancer control plan, using sections of the Australian Cancer Plan as examples-Optimal Care Pathways and the Australian Comprehensive Cancer Network.

METHODS: This discussion paper presents novel suggestions by drawing on CLCT concepts-care biographies, care networks, and self-care. Contrasting "current state" and "future state" vignettes are described to demonstrate how CLCT can help cancer policy move from cancer to care. Based on a robust theoretical lens, recommendations for policy and practice have been made at the micro, meso, and macro levels, with reflection on the nurses' role, and application to other national cancer control plans.

RESULTS: Optimal care pathways should include holistic assessments that incorporate broader histories at key clinical time points. The Australian Comprehensive Care Network should consider the holistic needs of people affected by cancer, and harness innovative approaches for how these needs can be met in a networked approach. In addition to clinical considerations, understanding of an individual's care biography, care network, and self-care can inform the delivery of high-quality cancer care. Implementation of these aspects of care will be led by nurses, supported by a multidisciplinary team.

CONCLUSIONS: A CLCT lens can help support implementation of the aspirational person-centered objectives described in the ACP. The potential exists for application of the CLCT approach to other national cancer control plans, including those in low-resource settings.

Nurses play a vital role in leading the implementation of person-centered dimensions of cancer control plans and core aspects of the CLCT approach.},
}

@article {pmid41005288,
year = {2025},
author = {Symonds, LK and Davidson, NE},
title = {RecOVARY? Using anti-Müllerian hormone to predict ovarian function after anti-HER2 therapy for early breast cancer.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djaf247},
pmid = {41005288},
issn = {1460-2105},
support = {//Breast Cancer Research Foundation/ ; },
}

@article {pmid41004543,
year = {2025},
author = {Müller, NF and Bouckaert, RR and Wu, CH and Bedford, T},
title = {MASCOT-Skyline integrates population and migration dynamics to enhance phylogeographic reconstructions.},
journal = {PLoS computational biology},
volume = {21},
number = {9},
pages = {e1013421},
doi = {10.1371/journal.pcbi.1013421},
pmid = {41004543},
issn = {1553-7358},
abstract = {The spread of infectious diseases is shaped by spatial and temporal aspects, such as host population structure or changes in the transmission rate or number of infected individuals over time. These spatiotemporal dynamics are imprinted in the genomes of pathogens and can be recovered from those genomes using phylodynamics methods. However, phylodynamic methods typically quantify either the temporal or spatial transmission dynamics, which leads to unclear biases, as one can potentially not be inferred without the other. Here, we address this challenge by introducing a structured coalescent skyline approach, MASCOT-Skyline, that allows us to jointly infer spatial and temporal transmission dynamics of infectious diseases using Markov chain Monte Carlo inference. To do so, we model the effective population size dynamics in different locations using a non-parametric function, allowing us to approximate a range of population size dynamics. We show, using a range of different viral outbreak datasets, potential issues with phylogeographic methods. We then use these viral datasets to motivate simulations of outbreaks that illuminate the nature of biases present in the different phylogeographic methods. We show that spatial and temporal dynamics should be modeled jointly, even if one seeks to recover just one of the two. Further, we showcase conditions under which we can expect phylogeographic analyses to be biased, particularly different subsampling approaches, as well as provide recommendations on when we can expect them to perform well. We implemented MASCOT-Skyline as part of the open-source software package MASCOT for the Bayesian phylodynamics platform BEAST2.},
}

@article {pmid41004338,
year = {2025},
author = {Rominger, MC and O'Brien, S and Gupta, S and Moorthi, S and McSharry, M and Kamlapurkar, S and Lowe, AR and Waldum, A and Lo, A and Duke, F and Wu, F and Headley, MB and Cromwell, E and Glabman, R and Koehne, A and Berger, AH},
title = {Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.},
journal = {Cell reports},
volume = {44},
number = {10},
pages = {116185},
doi = {10.1016/j.celrep.2025.116185},
pmid = {41004338},
issn = {2211-1247},
abstract = {Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1[M90I] variant. We show that autochthonous expression of RIT1[M90I] and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1[M90I] and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.},
}

@article {pmid41003951,
year = {2025},
author = {Iyer, HS and Karasaki, S and Yi, L and Hswen, Y and James, P and VoPham, T},
title = {Harnessing Geospatial Artificial Intelligence (GeoAI) for Environmental Epidemiology: A Narrative Review.},
journal = {Current environmental health reports},
volume = {12},
number = {1},
pages = {34},
pmid = {41003951},
issn = {2196-5412},
support = {K01ES035734, P30ES005022/ES/NIEHS NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; UG3OD035533//NIH Office of the Director/ ; P01AG082653/AG/NIA NIH HHS/United States ; R01 HL150119/HL/NHLBI NIH HHS/United States ; K01 DK125612/DK/NIDDK NIH HHS/United States ; },
mesh = {*Artificial Intelligence ; Humans ; *Environmental Exposure ; Geographic Information Systems ; *Environmental Health/methods ; },
abstract = {PURPOSE OF REVIEW: Geospatial analysis is an essential tool for research on the role of environmental exposures and health, and critical for understanding impacts of environmental risk factors on diseases with long latency (e.g. cardiovascular disease, dementia, cancers) as well as upstream behaviors including sleep, physical activity, and cognition. There is emerging interest in leveraging machine learning and artificial intelligence (AI) for environmental epidemiology research. In this review, we provide an accessible overview of recent advances.

RECENT FINDINGS: There have been two major recent shifts in geospatial data types and analytic methods. First, novel methods for statistical prediction, combining geospatial analysis with machine learning and artificial intelligence (GeoAI), allow for scalable geospatial exposure assessment within large population health databases (e.g. cohorts, administrative claims). Second, the widespread adoption of smartphones and wearables with global positioning systems and other sensors has allowed for passive data collection from people, and when combined with geographic information systems, enables exposure assessment at finer spatial scales and temporal resolution than ever before. Illustrative examples include refining models for predicting outdoor air pollution exposure, characterizing populations susceptible to water pollution, and use of deep learning to classify Street View image-derived measures of greenspace. While these tools and approaches may facilitate more rapid, higher quality objective exposure measures, they pose challenges with respect to participant privacy, representativeness of collected data, and curation of high quality validation sets for training of GeoAI algorithms. GeoAI approaches are beginning to be used for environmental exposure assessment and behavioral outcome ascertainment with higher spatial and temporal precision than before. Epidemiologists should continue to apply critical assessment of measurement accuracy and design validity when incorporating these new tools into their work.},
}

*Artificial Intelligence
Humans
*Environmental Exposure
Geographic Information Systems
*Environmental Health/methods

@article {pmid40999576,
year = {2025},
author = {Dela Cruz, FS and Stewart, EA and Surdez, D and Daley, JD and Soragni, A and Tomazou, EM and Alvarez-Perez, J and Feinberg, TY and Amatruda, JF and Ganapathi, SS and Ohm, JE and Heske, CM and Cohen-Gogo, S and Pesic, D and Nash, JO and Shlien, A and Roundhill, EA and Burchill, SA and Crompton, BD and Lawlor, ER and Loeb, DM and Delattre, O and Mora, J and Scotlandi, K and Reed, DR and Grohar, PJ and Grünewald, TGP and Kovar, H and Bailey, KM},
title = {Advancing Preclinical Biology for Ewing Sarcoma: An International Effort.},
journal = {Molecular cancer therapeutics},
volume = {},
number = {},
pages = {OF1-OF23},
doi = {10.1158/1535-7163.MCT-25-0428},
pmid = {40999576},
issn = {1538-8514},
abstract = {Ewing sarcoma is an aggressive bone and soft-tissue cancer affecting adolescents and young adults. In vitro and in vivo models of Ewing sarcoma have been instrumental in advancing our understanding of Ewing sarcoma biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease for which effective treatment options remain limited. Through an international collaborative effort between the Children's Oncology Group Bone Tumor Committee and the Euro Ewing Consortium, we review the current landscape of preclinical modeling used in Ewing sarcoma research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and nonmammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in Ewing sarcoma modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically relevant Ewing sarcoma models to enable translation of preclinical findings into effective therapeutic strategies for patients with Ewing sarcoma.},
}

@article {pmid40666860,
year = {2025},
author = {Harris, ED and McGovern, M and Pernikoff, S and Ikeda, R and Kipnis, L and Hannon, W and Sobolik, EB and Gray, M and Greninger, AL and He, S and Chin, CN and Fu, TM and Pancera, M and Boonyaratanakornkit, J},
title = {DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40666860},
issn = {2692-8205},
support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI171186/AI/NIAID NIH HHS/United States ; },
abstract = {Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.},
}

@article {pmid40661569,
year = {2025},
author = {Risse-Adams, OS and Liquori, JL and Sinnott-Armstrong, N and Musharoff, SA},
title = {Examining the Effect of Social Determinants of Health on Human Trait Heritability.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40661569},
issn = {2692-8205},
support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; U54 CA267738/CA/NCI NIH HHS/United States ; },
abstract = {Social determinants of health (SDOH) data are often excluded from genetic models of human traits. We use individual-level data from the All of Us Research Program to assess whether SDOH survey variables alter heritability estimates. Incorporating SDOH summaries decreases heritability significantly for 4 of 18 anthropometric and metabolic traits in individuals whose self-reported race is "White" (n=67,545). There are no such significant changes in individuals whose self-reported race is "Black or African American" (n=6,538), likely reflecting reduced statistical power. Incorporating genetic principal components consistently lowers heritability estimates in both groups, whether or not SDOH summaries are included. These findings demonstrate that survey-derived SDOH summaries can change heritability estimates and should be considered along with genetic summaries.},
}

@article {pmid39484476,
year = {2025},
author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Gujral, T and Holland, EC},
title = {Integrated transcriptomic landscape of medulloblastoma and ependymoma reveals novel tumor subtype-specific biology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39484476},
issn = {2692-8205},
support = {R35 CA253119/CA/NCI NIH HHS/United States ; },
abstract = {Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. This landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients' bulk RNA-seq data onto the reference framework to predict biology and outcome from nearest neighbor analysis facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application.},
}

@article {pmid39464160,
year = {2025},
author = {Hsieh, YP and O'Keefe, IP and Wang, Z and Sun, W and Yang, H and Vu, LM and Ernst, RK and Dandekar, AA and Malik, HS},
title = {Magnesium depletion unleashes two unusual modes of colistin resistance with different fitness costs.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39464160},
issn = {2692-8205},
support = {R01 AI104895/AI/NIAID NIH HHS/United States ; R35 GM152107/GM/NIGMS NIH HHS/United States ; },
abstract = {Increasing bacterial resistance to colistin, a vital last-resort antibiotic, is an urgent challenge. We previously reported that magnesium sequestration by Candida albicans enables Pseudomonas aeruginosa to become colistin-resistant. Here, we show that Mg[2+] depletion drives P. aeruginosa to evolve greater colistin resistance through genetic changes in lipid A biosynthesis-modification pathways and a putative magnesium transporter. These mutations synergize with the Mg[2+]-sensing PhoPQ two-component signaling system to remodel lipid A structures of the bacterial outer membrane in previously uncharacterized ways. One predominant mutational pathway relies on early mutations in htrB2, a non-essential gene involved in lipid A biosynthesis, which enhances resistance but compromises outer membrane integrity, resulting in fitness costs and increased susceptibility to other antibiotics. A second pathway achieves increased colistin resistance independently of htrB2 mutations without compromising membrane integrity. In both cases, reduced binding of colistin to the bacterial membrane underlies resistance. Our findings reveal that Mg[2+] scarcity unleashes two novel trajectories of colistin resistance evolution in P. aeruginosa. (160).},
}

@article {pmid41000465,
year = {2018},
author = {Mitov, KV and Yanev, NM and Hyrien, O},
title = {MULTITYPE BRANCHING PROCESSES WITH INHOMOGENEOUS POISSON IMMIGRATION.},
journal = {Advances in applied probability},
volume = {50},
number = {A},
pages = {211-228},
pmid = {41000465},
issn = {0001-8678},
support = {R01 AI069351/AI/NIAID NIH HHS/United States ; R01 AI129518/AI/NIAID NIH HHS/United States ; R01 CA134839/CA/NCI NIH HHS/United States ; R01 NS039511/NS/NINDS NIH HHS/United States ; },
abstract = {In this paper we introduce multitype branching processes with inhomogeneous Poisson immigration, and consider in detail the critical Markov case when the local intensity r(t) of the Poisson random measure is a regularly varying function. Various multitype limit distributions (conditional and unconditional) are obtained depending on the rate at which r(t) changes with time. The asymptotic behaviour of the first and second moments, and the probability of nonextinction are investigated.},
}

@article {pmid40998424,
year = {2025},
author = {White, AJ and Hart, JE and Quraishi, SM and Bookwalter, DB and Sweeney, MR and Spalt, EW and Hendryx, MS and Irvin, VL and Lane, DS and Shadyab, AH and Sealy-Jefferson, S and Neuhouser, ML and Whitsel, EA and Kaufman, JD and Laden, F and Sandler, DP},
title = {Air Pollutants and Breast Cancer Risk: A Parallel Analysis of Five Large US Prospective Cohorts.},
journal = {American journal of public health},
volume = {},
number = {},
pages = {e1-e14},
doi = {10.2105/AJPH.2025.308247},
pmid = {40998424},
issn = {1541-0048},
abstract = {Objectives. To determine whether outdoor air pollution exposure is associated with breast cancer incidence. Methods. Residential-level concentrations of nitrogen dioxide (NO2, parts per billion [ppb]), fine particulate matter (PM2.5; ≤ 2.5 μ/m[3]) and ozone (ppb) in the United States were estimated for participants of the Nurses' Health Studies, Women's Health Initiative Clinical Trials and Observational Study Cohort, and Sister Study using high-resolution spatiotemporal models. Cox proportional hazards regression estimated cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), and a random effects model determined summary HRs, overall and by estrogen receptor (ER)/progesterone receptor (PR) subtype and census region. Results. NO2 was positively associated with overall breast cancer incidence (n = 28 811 cases; HR = 1.03; 95% CI = 1.00, 1.05), with little variation by subgroups. PM2.5 was associated with higher incidence of ER-/PR- tumors (n = 2367 cases; HR = 1.14; 95% CI = 1.04, 1.24; P-heterogeneity < .001) and with higher overall incidence in the Midwest (HR = 1.15; 95% CI = 1.01, 1.32; P-heterogeneity = .01). Ozone was not associated with overall incidence, but was associated with ER-/PR- tumors (n = 3406 cases; HR = 1.10; 95% CI = 1.00, 1.21; P-heterogeneity = .03). Conclusions. In this largest US study to date, we confirmed an association between NO2 and breast cancer, and we present novel associations of PM2.5 and ozone with ER-/PR- tumors. (Am J Public Health. Published online ahead of print September 25, 2025:e1-e14. https://doi.org/10.2105/AJPH.2025.308247).},
}

@article {pmid40998267,
year = {2025},
author = {Ardila, V and Onstad, L and Carpenter, P and Pidala, J and Kitko, C and Jurdi, NE and Lee, SJ and Hamilton, BK},
title = {Obesity Associations with Chronic Graft-Versus-Host Disease.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2025.09.030},
pmid = {40998267},
issn = {2666-6367},
abstract = {BACKGROUND: Obesity is increasing in prevalence and has been linked to inflammation, leading to worse outcomes in various disease states. Pre-clinical studies have demonstrated deleterious effects of obesity on graft-versus-host disease (GVHD). Several retrospective clinical studies have investigated the impact of obesity on allogeneic hematopoietic cell transplantation (HCT); however, with varying results and more limited data on the impact on chronic GVHD.

OBJECTIVES: We aimed to investigate the association of obesity on organ involvement, severity, and response to chronic GVHD therapy in a multicenter cohort of patients with chronic GVHD, as well as its impact on overall survival (OS), non-relapse mortality (NRM), failure-free survival (FFS), and quality of life (QOL).

STUDY DESIGN: We conducted a retrospective study of patients enrolled from 2007 to 2019 in two prospective longitudinal observational studies from the Chronic GVHD Consortium. Obesity was defined as a body mass index (BMI) ≥30, as calculated based on height and weight at the time of enrollment. Grade, organ involvement, and response to chronic GVHD therapy were compared between obese (BMI ≥30) and non-obese (BMI <30) patients. Secondary outcomes included OS, NRM, FFS, and QOL measurement with the Lee symptom scale (LSS), Functional Assessment of Cancer Therapy (FACT), and Medical Outcomes Study Short Form 36 (SF-36).

RESULTS: Among 487 patients identified with newly diagnosed chronic GVHD within 3 months of study enrollment, 114 (23.4%) had BMI ≥ 30. The only significant difference between obese and non-obese patients was the presence of diabetes as a comorbidity. There were no significant differences in affected organs, grade, overall response to treatment, or organ-specific response to treatment between obese and non-obese patients. Chronic lung GVHD was more common in obese compared to non-obese patients (24.6% vs 13.9% for mild, 5.3% vs 4.8% for moderate, and 0.9% vs 0.8% for severe lung GVHD, p=0.047) however small case numbers and the lack of between group differences in OS, NRM or FFS limit this interpretation. QOL analyses revealed greater patient-reported symptom burden and worse QOL in obese patients at enrollment and after 6 months.

CONCLUSION: We found obesity is associated with worse QOL but not with chronic GVHD phenotypes, responsiveness to treatment, or survival outcomes in a multicenter cohort of allogeneic HCT recipients. Given the increasing evidence of a multi-factorial role for obesity as a modulator of immune processes, additional studies investigating more accurate measures of obesity and body composition are needed to further understand their role in chronic GVHD.},
}

@article {pmid40998264,
year = {2025},
author = {Kogler, V and Pagano, MB and Fontaine, MJ and Azimi, V and Brancamp, R and Cataife, G and Covington, M and Delaney, M and Eichbaum, Q and Jacquot, C and Kutner, JM and Lu, W and Saifee, NH and Shan, H and Thibodeaux, SR and Wali, JA and Yeh, A and Yokoyama, APH and Yunce, M and Ziman, A and , },
title = {Serologic Characteristics and Clinical Significance of Non-ABO Red Blood Cell Antibodies in Hematopoietic Stem Cell Transplant. The BEST Collaborative Study.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2025.09.040},
pmid = {40998264},
issn = {2666-6367},
abstract = {BACKGROUND: ABO-incompatible hematopoietic stem cell transplant (HSCT) has a number of well-established complications including hemolysis, delayed RBC engraftment, pure red cell aplasia (PRCA), and transfusion dependence. However, the clinical significance of non-ABO RBC antibodies in allogeneic HSCT remains insufficiently explored.

OBJECTIVE: The aim of this study is to characterize the prevalence, incidence, and clinical implications of non-ABO RBC auto- and alloantibodies in the HSCT population.

STUDY DESIGN: This international, multicenter, retrospective study analyzed HSCT 2010-2021 across nine U.S. and one Brazilian academic centers. This study focused on immunohematologic findings in recipients of allogeneic HSCTs, excluding hemoglobinopathies. RBC antibodies were evaluated pre-HSCT and 100 days post-HSCT. Hemolysis was assessed by labs and confirmed by a two-physician review of the medical records. Descriptive statistics and regression analysis were performed. IRB approval and data use agreements were obtained at each center.

RESULT: Study analysis included a total of 8896 transplants. The majority of transplants utilized apheresis collections (78.0%), were matched unrelated (41.6%), involved a non-myeloablative conditioning regimen (51.2%), and were ABO-compatible (56.7%). The prevalence of non-ABO antibodies pre-HSCT, including auto-, alloantibodies, and passive transfer of anti-D, was 4.0% (n=355). The majority of these were alloantibodies (77.5%), followed by warm autoantibodies (7.3%) and both alloantibodies and warm-reactive autoantibodies (6.5%). De-novo antibody formation post-HSCT occurred in 1.5% (n=135). The most frequent pre-HSCT alloantibody specificities were in the Rh blood group system (46%), followed by Kell (17%) and Kidd (13%). The incidence of anti-D in RhD-mismatched transplant was 1% (n=8) for RhD-positive recipients with RhD-negative donors, and 0.2% (n=2) for RhD-negative recipients with RhD-positive donors. Myeloproliferative neoplasms and myelodysplastic syndromes had the highest rate of antibodies pre- and post-HSCT. Hemolysis was observed in 24 cases (antibodies present pre-HSCT) and 15 de-novo cases post-HSCT. Pure red cell aplasia was not observed in any of these cases. The presence of non-ABO RBC antibodies was associated with higher RBC transfusions, but not platelet transfusions; engraftment of neutrophils and platelets were not affected by the presence of RBC antibodies.

CONCLUSION: The current study reports on a low prevalence of RBC antibodies, including allo- and autoantibodies, in HSCT patients during the peri-transplant period, with a rate of 4% for those with pre-existing antibodies prior to transplant and 1% for the de-novo antibody formation post-transplant. They are associated with a low risk of mild to moderate hemolysis, but increased RBC transfusions. Comprehensive immunohematology data should be incorporated into HSCT databases for improved risk assessment, monitoring, and management.},
}

@article {pmid40998194,
year = {2025},
author = {Hammouda, K and Tokuyama, N and Corredor, G and Pathak, T and Dakarapu, R and Genega, E and Mian, OY and Pavicic, PG and Diaz-Montero, CM and Mirtti, T and Farré, X and Gupta, S and Madabhushi, A},
title = {AI-informed computational pathology classifier predicts outcomes across treatment modalities in muscle-invasive urothelial carcinoma.},
journal = {Cancer letters},
volume = {634},
number = {},
pages = {218059},
doi = {10.1016/j.canlet.2025.218059},
pmid = {40998194},
issn = {1872-7980},
abstract = {Urothelial carcinoma (UC) is one of the leading causes of cancer-related mortality, and effective, scalable biomarkers for treatment planning remain limited. We present UC-TIL, an artificial intelligence (AI)-based model that quantifies spatial patterns of tumor-infiltrating lymphocytes (TILs) from routine H&E-stained slides to predict survival and immunotherapy response. We analyzed 558 whole-slide images across three cohorts: TCGA (D0&1, N = 292), Emory (D2, N = 161), and TRRC2819 (D3, N = 105), spanning chemotherapy and immune checkpoint inhibitor (ICI) treatments. UC-TIL classification was associated with OS (HR = 2.11, 95 %CI:1.01-4.41, p = 0.011) and PFS (HR = 3.68, 95 %CI:1.07-12.65, p = 0.0012) in locally advanced disease (D1 and D2), with consistent results in metastatic disease (D3) (HR = 1.73, 95 %CI:1.08-2.77, p = 0.043; PFS HR = 1.73, 95 %CI:1.07-2.81, p = 0.047). In the ICI-treated D3 cohort, UC-TIL achieved AUC = 0.757 and identified non-responders with 91 % specificity. UC-TIL enables reliable risk stratification and treatment response prediction in both locally advanced and metastatic urothelial carcinoma by analyzing spatial TIL patterns from standard pathology slides. These findings position UC-TIL as a readily deployable tool to guide personalized therapy across multiple clinical settings.},
}

@article {pmid40998019,
year = {2025},
author = {Glenny, EM and Lin, T and Bandera, VM and Mirminachi, B and Khumukcham, SS and Gigic, B and Warby, CA and Aksonova, O and Coleman, MF and Carpanese, A and Busch, C and Himbert, C and Ose, J and Nix, DA and Boucher, K and Schirmacher, P and Strehli, I and Hardikar, S and Cohan, JN and Jedrzkiewicz, J and Brobeil, A and Schneider, MA and Kahlert, C and Siegel, EM and Byrd, DA and Toriola, AT and Shibata, D and Li, CI and Figueiredo, JC and Tan, AC and Roper, J and Ulrich, CM and Hursting, SD},
title = {Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: Evidence from mouse models and the ColoCare Study patient cohort.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajcnut.2025.09.031},
pmid = {40998019},
issn = {1938-3207},
abstract = {BACKGROUND: The global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed.

OBJECTIVE: This study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the two species.

METHODS: We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato colon tumor organoids. Epithelial cell adhesion molecule (EpCAM)-positive cells from murine tumors, and 193 human colon tumors and 188 human mesenteric adipose tissue samples from the prospective ColoCare Study cohort underwent transcriptomic analyses.

RESULTS: Diet-induced obesity reduced survival in the mouse model of colon cancer. Integrated transcriptomic analyses of EpCAM-positive murine tumor cells and bulk human tumors revealed obesity-driven enrichment of inflammation and metabolic pathways, including upregulation of genes involved in innate immune sensing (TLR2, MYD88, IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the study patients (63±13 years old, 48% female, BMI: 28.9±6.0 kg/m[2]) indicated that obesity was associated with enriched inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions.

CONCLUSIONS: These results establish obesity-associated adipose tissue dysregulation as a key inter-tissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.},
}

@article {pmid40997296,
year = {2025},
author = {Wang, ES and Montesinos, P and Foran, J and Erba, H and Rodríguez-Arbolí, E and Fedorov, K and Heiblig, M and Heidel, FH and Altman, JK and Baer, MR and Ades, L and Pettit, K and Peterlin, P and Papayannidis, C and Berthon, C and Walter, RB and Shah, MV and Balasubramanian, S and Khawandanah, M and Salamero Garcia, O and Bergeron, J and Madanat, YF and Roboz, GJ and Ulrickson, M and Redner, RL and McCloskey, J and Pigneux, A and de la Fuente Burguera, A and Mitra, A and Soifer, HS and Tabachri, M and Zhang, Z and Riches, M and Corum, D and Leoni, M and Issa, GC and Fathi, AT and , },
title = {Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2501694},
doi = {10.1200/JCO-25-01694},
pmid = {40997296},
issn = {1527-7755},
abstract = {PURPOSE: Ziftomenib-a potent, highly selective, oral menin inhibitor-was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial.

METHODS: In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh).

RESULTS: From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events.

CONCLUSION: Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.},
}

@article {pmid40996773,
year = {2025},
author = {Fasching, PA and Stroyakovskiy, D and Yardley, DA and Huang, CS and Crown, J and Bardia, A and Chia, S and Im, SA and Martin, M and Xu, B and Loi, S and Barrios, C and Untch, M and Moroose, R and Visco, F and Hortobagyi, GN and Slamon, DJ and Fresco, R and Zarate, JP and Li, Z and Waters, S and Hurvitz, SA},
title = {Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial.},
journal = {JAMA oncology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoncol.2025.3700},
pmid = {40996773},
issn = {2374-2445},
abstract = {IMPORTANCE: Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.

OBJECTIVE: To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.

This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.

INTERVENTIONS: Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).

MAIN OUTCOMES AND MEASURES: The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.

RESULTS: Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.

CONCLUSIONS AND RELEVANCE: This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03701334.},
}

@article {pmid40996743,
year = {2025},
author = {Barber, B and Harris, H},
title = {Acid-Resistant Oral Microbiome on Oral Cancer Development-Reply.},
journal = {JAMA otolaryngology-- head & neck surgery},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoto.2025.3047},
pmid = {40996743},
issn = {2168-619X},
}

@article {pmid40996319,
year = {2025},
author = {Janitz, AE and Qiu, W and Schraw, JM and Mostoufi-Moab, S and Mirabello, L and Stewart, DR and Neglia, JP and Turcotte, LM and Bhatia, S and Yasui, Y and Chow, EJ and Armstrong, GT and Lupo, PJ},
title = {Health Outcomes in Childhood Cancer Survivors with Congenital Anomalies in the Childhood Cancer Survivor Study.},
journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1158/1055-9965.EPI-25-0611},
pmid = {40996319},
issn = {1538-7755},
abstract = {BACKGROUND: Congenital anomalies are associated with increased risk of childhood cancer. However, there is a knowledge gap regarding health outcomes for childhood cancer survivors with congenital anomalies.

METHODS: We included childhood cancer survivors from the Childhood Cancer Survivor Study (n=22,247) comparing survivors with and without self-reported anomalies. Using Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) of chronic health conditions (CHC) classified per the Common Terminology Criteria for Adverse Events (CTCAE) from 1 (mild) to 5 (fatal) and subsequent malignant neoplasms (SMN) comparing survivors by anomaly status. We calculated age-sex-calendar year-specific mortality rates and standardized mortality ratios (SMR) for survivors compared to the US population.

RESULTS: Among survivors, 16.9% (n=3,880) reported a congenital anomaly. Survivors with anomalies had a higher rate of any CHC (grades 1-5 HR: 1.24, 95% CI: 1.18-1.31), severe CHCs (grades 3-5 HR: 1.29, 95% CI 1.19-1.40), and multiple CHCs of any grade (≥2 CHCs HR: 1.31, 95% CI 1.24-1.39; ≥3 HR: 1.42, 95% CI 1.33-1.52). Survivors with anomalies had an increased rate of soft-tissue sarcomas (HR: 1.96, 95% CI 1.12-3.44). For deaths related to the original cancer diagnosis, survivors with anomalies (compared to no anomalies) had a lower mortality rate (0.64 vs. 0.90 per 1000 person-years).

CONCLUSIONS: We identified an increased rate of CHCs and SMNs among childhood cancer survivors with anomalies and lower mortality directly related to the cancer diagnosis.

IMPACT: Future work will focus on evaluation of genetic pathways that increase the risk of CHCs and SMNs.},
}

@article {pmid40995047,
year = {2025},
author = {Moore, M and Anderson, L and Bracis, C and Swan, DA and Painter, I and Everson, E and Janes, H and Schiffer, JT and Matrajt, L and Dimitrov, D},
title = {Estimating Population Immunity and Impact of COVID-19 Vaccination in Washington State and Oregon.},
journal = {Open forum infectious diseases},
volume = {12},
number = {9},
pages = {ofaf531},
pmid = {40995047},
issn = {2328-8957},
abstract = {BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine showed high clinical efficacy against the ancestral variant, but immunological waning, emergence of new variants, and the durability of infection-induced immunity complicate the estimation of population-level effectiveness. We used mathematical modeling to calculate the proportion of hospitalizations averted by vaccination in Washington and Oregon.

METHODS: We used an age- and region-structured compartmental model of vaccine-induced and infection-induced immunity from January 2020 until December 2022. We parameterized the strength and durability of immunity via a meta-regression of vaccine efficacy. We calibrated a time-varying contact matrix to weekly hospitalizations reported by the Washington Department of Health and Oregon Health Authority. We validated our model with Centers for Disease Control and Prevention serosurveillance data. To estimate vaccine effectiveness, we created counterfactual scenarios with no vaccination either in the entire population or in select age groups.

RESULTS: We found that total hospitalizations were reduced 74% (95% credible interval [CrI], 69%-78%) and 15% (95% CrI, 9%-19%) by primary vaccination and boosters, respectively. Vaccination effectiveness was highest during the Alpha wave, averting 90% (95% CrI, 88%-93%) of hospitalizations and in people aged 65+, averting 78% (95% CrI, 73%-81%). Relative to only vaccinating individuals aged 50+, vaccination of individuals aged 18-49 averted 52% (95% CrI, 44%-58%) of hospitalizations overall and 42% (95% CrI, 35%-48%) of hospitalizations among individuals 65+.

CONCLUSIONS: The SARS-CoV-2 vaccination program in Washington and Oregon averted the majority of hospitalizations. Vaccinating individuals aged 18-49 significantly reduced hospitalization among individuals aged 65+.},
}

@article {pmid40993182,
year = {2025},
author = {Sarnowski, C and Zhang, Y and Ammous, F and Shade, LMP and DiCorpo, D and Jian, X and Arnett, DK and Austin, TR and Beiser, A and Bis, JC and Blangero, J and Boerwinkle, E and Bressler, J and Curran, JE and DeCarli, CS and Doddapaneni, H and Dupuis, J and Fardo, DW and Florez, JC and Gabriel, S and Gibbs, RA and Glahn, DC and Gupta, N and González, HM and González, KA and Hatzikotoulas, K and Hayden, KM and Heckbert, SR and Hidalgo, B and Huerta-Chagoya, A and Hughes, TM and Kardia, SLR and Kooperberg, CL and Launer, LJ and Longstreth, WT and , and , and Mandla, R and Mathias, RA and Morris, AP and Mosley, TH and Nasrallah, IM and Nyquist, P and Psaty, BM and Qi, Q and Raffield, LM and Rayner, NW and Reiner, AP and Satizabal, CL and Selvin, E and Sevilla-Gonzalez, MDR and Smith, AV and Smith, JA and Smith, K and Snively, BM and Southam, L and Sofer, T and Suzuki, K and Taylor, HJ and Udler, MS and Viaud-Martinez, KA and Wassertheil-Smoller, S and Wood, AC and Yanek, LR and Yin, X and Manning, AK and Rotter, JI and Rich, SS and Meigs, JB and Fornage, M and Seshadri, S and Morrison, AC and , and , },
title = {Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1352},
pmid = {40993182},
issn = {2399-3642},
support = {R00 AG066849/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; *Insulin Resistance/genetics ; Middle Aged ; Female ; Precision Medicine ; Cross-Sectional Studies ; Aged ; Metabolic Syndrome/genetics ; Adult ; },
abstract = {To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10[-5]) and European (PEA = 3.0 × 10[-8]) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.},
}

Humans
Male
*Insulin Resistance/genetics
Middle Aged
Female
Precision Medicine
Cross-Sectional Studies
Aged
Metabolic Syndrome/genetics
Adult

@article {pmid40991892,
year = {2025},
author = {Dorovini-Zis, K and Li, H and Zhe, C and Zhang, B and Small, D and Taylor, TE},
title = {Mapping the expression of endothelial adhesion receptors for Plasmodium falciparum-infected erythrocytes in fatal cerebral malaria in Malawian children.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf104},
pmid = {40991892},
issn = {1554-6578},
support = {5R01AI34969//US National Institutes of Health/ ; },
abstract = {We investigated the expression and distribution of 5 cytoadhesion receptors for the Plasmodium falciparum erythrocyte membrane protein 1 in 12 regions of post-mortem brains of 50 Malawian children, that is, 27 with the clinical and pathological diagnosis of cerebral malaria (CM) and 23 with a non-malarial cause of death. We quantified the expression of each receptor by microvascular endothelium and the colocalization of receptor-expressing microvessels with sequestered infected red blood cells (iRBC) and calculated a receptor-independent sequestration ratio. There were differences in the level of expression and regional distribution of the five receptors: ICAM-1 was the most widely expressed receptor, followed by CD36, VCAM-1, E-selectin, and thrombospondin. Receptor-expressing microvessels were most numerous in the frontal lobe and least numerous in the brainstem and cerebellum. Colocalization of receptor-expressing endothelial cells with iRBC was present in all brain regions; it was highest for ICAM-1 and CD36 and greatest in the frontal lobe. The sequestration ratios were close to 100% for all receptors across all brain regions and were similar in cerebral and extracerebral microvessels. Receptor expression and colocalization ratios were greater in the brain than in the lung, heart, liver, spleen, and subcutaneous tissue. These differences in cerebral endothelial expression of cytoadhesion receptors and their preferential regional distribution may underpin differences in iRBC sequestration and lesion development in CM. Moreover, greater expression of these receptors in the brain vs peripheral organs may explain a comparatively greater degree of iRBC sequestration in the brain.},
}

@article {pmid40991418,
year = {2025},
author = {Matsuk, VY and Khatib, TO and Marcus, LJ and Robinson, IE and Liu, Y and Pasupathy, JK and Shanmugam, M and Mouw, JK and Marcus, AI},
title = {Metabolic programming defines oxygen sensitive subpopulation hierarchies and patterning in collective invasion.},
journal = {Molecular biology of the cell},
volume = {},
number = {},
pages = {mbcE25070314},
doi = {10.1091/mbc.E25-07-0314},
pmid = {40991418},
issn = {1939-4586},
abstract = {Phenotypic heterogeneity - distinct molecular and behavioral variations within a population -significantly influences collective invasion and tumor progression. Here, we employ a molecular approach to explore how the underlying metabolic heterogeneity in non-small cell lung cancer (NSCLC) influences invasion and pack patterning. Assessing three-dimensional (3D) pack patterning revealed invasive heterogeneity across NSCLC cell lines and patient-derived samples. Flow cytometry identified IL13RA2 as a biomarker for invasive potential, enabling isolation of subpopulations with distinct invasive characteristics. By integrating a cell surface biomarker (IL13RA2±) with mitochondrial membrane potential (TMRM), we identified and isolated three distinct subpopulations. Two-dimensional (2D) analyses revealed differences in mitochondrial polarity and transcriptional programs associated with migration and oxygen-sensitivity. In 3D, these subpopulations invaded with distinct patterns, from contiguous circular packs to structured chains. Assessments under varied oxygen tension demonstrated that oxygen availability and subpopulation metabolism together influence collective invasion patterning. When recombined at ratios recapitulating the original population, both stochastic and opportunistic cooperative dynamics emerged, dependent on subpopulation composition and oxygen levels. Our molecular approach, integrating cell surface and metabolic characteristics, enables isolation of unique subpopulations and demonstrates that phenotypic and metabolic heterogeneity, population composition, and oxygen availability collectively pattern invasion packs and drive collective invasion.},
}

@article {pmid40964310,
year = {2025},
author = {Ramsey, EL and Dobersch, S and Freie, B and Hong, NH and Wu, X and Kugel, S and Eisenman, RN and Carroll, PA},
title = {MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40964310},
issn = {2692-8205},
abstract = {MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m[6]A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.},
}

@article {pmid40991382,
year = {2025},
author = {Faulk, KE and Kairalla, JA and Hibbitts, E and Long-Boyle, JR and Devidas, M and August, A and Gore, L and Raetz, EA and Hunger, SP and Loh, ML and Teachey, DT and Brown, PA and Breese, EH and Kotecha, RS and Guest, E},
title = {Age-Based Pegaspargase Dosing is Safe and Achieves Therapeutic Levels in Infants with ALL: Report from COG AALL15P1.},
journal = {Blood advances},
volume = {},
number = {},
pages = {},
doi = {10.1182/bloodadvances.2025017013},
pmid = {40991382},
issn = {2473-9537},
}

@article {pmid40987290,
year = {2025},
author = {Reeves, DB and Rigau, DN and Romero, A and Zhang, H and Simonetti, FR and Varriale, J and Hoh, R and Zhang, L and Smith, KN and Montaner, LJ and Rubin, LH and Gange, SJ and Roan, NR and Tien, PC and Margolick, JB and Peluso, MJ and Deeks, SG and Schiffer, JT and Siliciano, JD and Siliciano, RF and Antar, AAR},
title = {Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.},
journal = {Cell systems},
volume = {},
number = {},
pages = {101402},
doi = {10.1016/j.cels.2025.101402},
pmid = {40987290},
issn = {2405-4720},
abstract = {To determine whether HIV persistence arises from the natural dynamics of memory (m)CD4+ T cells, we compare clonal dynamics of HIV proviruses and mCD4+ T cells from the same people living with HIV (PWH) on antiretroviral therapy and from matched HIV-seronegative people (N = 51). HIV proviruses are more clonal than mCD4+ T cells but similarly clonal to antigen-specific cells. Increasing reservoir clonality over time and differential decay of intact and defective proviruses are not explained by mCD4+ T cell kinetics alone. We develop and validate a stochastic model trained on 10 quantitative data metrics, which shows that negative selection against HIV-infected cells is necessary to explain all metrics. We estimate the strength of negative selection, finding that death of cells harboring intact and defective proviruses is infrequently (∼6% and ∼2% on average) due to HIV-specific factors. Thus, our data indicate that HIV persistence is mostly, but not entirely, driven by natural mCD4+ kinetics.},
}

@article {pmid40986647,
year = {2025},
author = {Ribi, K and Cole, BF and Fleming, GF and Walley, BA and Francis, PA and Abdi, E and Burstein, HJ and Cheng, KL and Chia, SKL and Dakhil, SR and Davidson, NE and Della-Fiorentina, SA and Frith, AE and Levine, E and Lupichuk, S and Pritchard, K and Salim, M and Stearns, V and Stewart, J and Valero, V and van der Westhuizen, A and Pagani, O and Loi, S and Colleoni, M and Gelber, RD and Goldhirsch, A and Coates, AS and Regan, MM and Bernhard, J},
title = {Prognostic value of patient-reported depression in women with hormone-responsive early breast cancer in TEXT and SOFT.},
journal = {Cancer},
volume = {131},
number = {19},
pages = {e70094},
doi = {10.1002/cncr.70094},
pmid = {40986647},
issn = {1097-0142},
support = {//Pfizer/ ; /CA/NCI NIH HHS/United States ; //European Thoracic Oncology Program and International Breast Cancer Study Group Partners Foundation/ ; },
mesh = {Adult ; Female ; Humans ; Middle Aged ; Androstadienes/administration & dosage/therapeutic use ; Antidepressive Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/psychology/mortality/complications ; *Depression/drug therapy ; Disease-Free Survival ; Premenopause ; Prognosis ; Tamoxifen/therapeutic use/administration & dosage ; },
abstract = {BACKGROUND: Depression has been identified as an adverse mental health outcome in women with breast cancer (BC). Depression was investigated as a risk factor for poor survival in premenopausal women with hormone-responsive early BC treated in the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials.

METHODS: The data used were from a subset of patients who participated in TEXT or SOFT and completed the Center of Epidemiologic Studies-Depression scale. Associations between baseline depression-score categories and baseline characteristics were assessed using the Cochran-Mantel-Haenszel test controlling for antidepressant use. Multivariable proportional hazards regression models were used to test the association between baseline depression and disease-free survival (DFS) and overall survival (OS). Regression models were adjusted for factors known to be associated with outcomes, baseline antidepressant use, and early treatment cessation.

RESULTS: Forty percent (2287 of 5738) of the women enrolled in the SOFT and TEXT trials were included in this analysis (SOFT, n = 1259; TEXT, n = 1028). Twenty-seven percent of women reported mild-to-moderate or severe depression at baseline. Race (p = .001), body mass index (p = .02), family history (p = .02), and performance status (p =.007) were significantly associated with the severity of depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .04) for DFS were 1.34 (95% confidence interval [CI], 1.03-1.76) for women with mild-to-moderate depression and 1.34 (95% CI, 0.96-1.87) for those with severe depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .008) for OS were 1.68 for mild-to-moderate depression (95% CI, 1.15-2.44) and 1.67 for those with severe depression (95% CI, 1.05-2.66).

CONCLUSIONS: In premenopausal women with hormone-responsive early BC, depression at baseline is a risk factor for poorer DFS and OFS. Further investigation of the underlying interactive processes is needed.

TRIAL REGISTRATION: Clinicaltrials.gov NCT00066703 (SOFT) and NCT00066690 (TEXT).},
}

Adult
Female
Humans
Middle Aged
Androstadienes/administration & dosage/therapeutic use
Antidepressive Agents/therapeutic use
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
*Breast Neoplasms/drug therapy/psychology/mortality/complications
*Depression/drug therapy
Disease-Free Survival
Premenopause
Prognosis
Tamoxifen/therapeutic use/administration & dosage

@article {pmid40986340,
year = {2025},
author = {Su, Y and Thelen, A and Wirth, LV and Jenkins, CM and Mak, SR and Chen, DG and Gottardo, R and Greenberg, PD},
title = {A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {39},
pages = {e2516951122},
doi = {10.1073/pnas.2516951122},
pmid = {40986340},
issn = {1091-6490},
support = {CA18029/GF/NIH HHS/United States ; CA225517/GF/NIH HHS/United States ; DRQ-13-22//Damon Runyon Cancer Research Foundation (DRCRF)/ ; Hartwell Innovation Award//Hartwell Foundation (HARTWELL)/ ; CA015704/GF/NIH HHS/United States ; },
mesh = {Humans ; *Immunotherapy, Adoptive/methods ; *Lymphocyte Activation/immunology ; *Receptors, Transforming Growth Factor beta/genetics/immunology/metabolism ; *Recombinant Fusion Proteins/genetics/immunology ; Interleukin-2/metabolism ; Signal Transduction ; STAT5 Transcription Factor/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; *Receptors, Interleukin-2/genetics/immunology/metabolism ; Phosphorylation ; Transforming Growth Factor beta ; Immunosuppression Therapy ; T-Lymphocytes/immunology ; },
abstract = {Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8[+] T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.},
}

Humans
*Immunotherapy, Adoptive/methods
*Lymphocyte Activation/immunology
*Receptors, Transforming Growth Factor beta/genetics/immunology/metabolism
*Recombinant Fusion Proteins/genetics/immunology
Interleukin-2/metabolism
Signal Transduction
STAT5 Transcription Factor/metabolism
CD8-Positive T-Lymphocytes/immunology
Tumor Microenvironment/immunology
*Receptors, Interleukin-2/genetics/immunology/metabolism
Phosphorylation
Transforming Growth Factor beta
Immunosuppression Therapy
T-Lymphocytes/immunology

@article {pmid40985344,
year = {2025},
author = {Hausmann, O and Schobert, PP and Ose, J and Himbert, C and Pletneva, M and Jedrzkiewicz, J and Nguyen, A and Lin, T and Warby, CA and Hardikar, S and Peoples, AR and Strehli, I and Huang, LC and Cohan, JN and Pickron, B and Scaife, C and Li, CI and Grady, WM and Shibata, D and Toriola, AT and Schneider, M and Figueiredo, JC and Siegel, EM and Gigic, B and Herzig, S and Ilozumba, MN and Ulrich, CM},
title = {Associations of Biomarkers of Systemic Inflammation, Angiogenesis, and Cell-to-Cell Adhesion With Tumor Budding Among Early-Onset and Later-Onset Colorectal Cancer Patients.},
journal = {Cancer medicine},
volume = {14},
number = {18},
pages = {e71267},
pmid = {40985344},
issn = {2045-7634},
support = {//Stiftung LebensBlicke/ ; P30CA042014/CA/NCI NIH HHS/United States ; K07222060/NH/NIH HHS/United States ; R01CA189184/NH/NIH HHS/United States ; R01CA207371/NH/NIH HHS/United States ; R01CA254108/NH/NIH HHS/United States ; R03CA270473/NH/NIH HHS/United States ; U01CA206110/NH/NIH HHS/United States ; },
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; Angiogenesis ; *Biomarkers, Tumor/blood ; Cell Adhesion ; *Colorectal Neoplasms/pathology/blood ; *Inflammation/blood ; Intercellular Adhesion Molecule-1/blood ; Neoplasm Staging ; *Neovascularization, Pathologic/blood/pathology ; Prognosis ; },
abstract = {BACKGROUND: High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell-to-cell adhesion influence tumor budding.

METHODS: We investigated n = 132 stage I-III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence-based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and non-steroidal anti-inflammatory drug use.

RESULTS: The study population was predominantly non-Hispanic White (95%), with a mean age of 61 years; 56% were male. Most tumors were stage III (47%), located in the colon (64%), and exhibited low-grade tumor budding (58%). Soluble intercellular adhesion molecule 1 was inversely associated with tumor budding overall (M1: β = -0.57, p = 0.03), among females (M1: β = -0.81, p-value = 0.03) and later-onset (≥ 50 years) colorectal cancer (M1: β = -0.71, p-value = 0.008). C-reactive protein was positively associated with tumor budding in males (M1: β = 0.23, p = 0.001), while interleukin-8 (M1: β = 0.96, p-value = 0.01) and soluble vascular adhesion molecule 1 (M2: β = 1.48, p-value = 0.04) were positively associated with tumor budding in early-onset patients. However, these associations did not remain statistically significant after correction for multiple testing.

CONCLUSION: Overall, our findings do not provide evidence of a significant association between biomarkers of systemic inflammation, angiogenesis, and cell-to-cell adhesion with tumor budding count. We observed patterns for some biomarkers, yet none remained statistically significant after correction for multiple testing. These findings provide preliminary insights for future studies.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT02328677.},
}

Aged
Female
Humans
Male
Middle Aged
Age of Onset
Angiogenesis
*Biomarkers, Tumor/blood
Cell Adhesion
*Colorectal Neoplasms/pathology/blood
*Inflammation/blood
Intercellular Adhesion Molecule-1/blood
Neoplasm Staging
*Neovascularization, Pathologic/blood/pathology
Prognosis

@article {pmid40983593,
year = {2025},
author = {Fitchett, G and Campbell, D and Chang, C and Hester, C and King, S and Peery, B and Saks, NT},
title = {Developing and implementing spiritual screening in healthcare: six successful models.},
journal = {Journal of health care chaplaincy},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/08854726.2025.2563472},
pmid = {40983593},
issn = {1528-6916},
abstract = {Healthcare chaplains recognize the importance of informed referrals for spiritual care; they are essential for spiritual care in outpatient settings. Research about the prevalence and harmful effects of religious/spiritual distress underscores the importance of effective methods for identifying patients who would benefit from spiritual care. Spiritual screening is a valuable way to help healthcare colleagues identify patients who would benefit from further assessment and spiritual care. To help spiritual care programs implement spiritual screening, in this article chaplains from six organizations with successful spiritual screening describe the development and implementation of their programs. The settings for these screening programs include hospital inpatients, oncology outpatient centers, palliative care, and population health. The descriptions include the screening questions used, how they are administered, and what it took to get them implemented. Common and unique features of these six approaches to spiritual screening are discussed along with areas for future research.},
}

@article {pmid40982684,
year = {2025},
author = {Alencar, GF and Mohamed, AO and Burnett, MG and Jean, SS and Nelson, AR and Su, Y and Voillet, V and Bates, BM and Rodgers Suarez, M and Ruskin, SL and Trieu, L and Lam, JL and Bekiranov, S and Gottardo, R and Greenberg, PD and Anderson, KG},
title = {Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {39},
pages = {e2419888122},
doi = {10.1073/pnas.2419888122},
pmid = {40982684},
issn = {1091-6490},
support = {CA009657-26A1 CA266737 P30CA044579 CA018029 CA033084//HHS | NIH | National Cancer Institute (NCI)/ ; Ann and Sol Schreiber Mentored Investigator Training Grant//Ovarian Cancer Research Alliance (OCRA)/ ; no number//Parker Institute for Cancer Immunotherapy (PICI)/ ; no number//Lonza Houston (Lonza Houston, Inc.)/ ; no number//Celgene Corporation | Juno Therapeutics/ ; 5T32AI007496-29//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; },
mesh = {Animals ; Female ; *Ovarian Neoplasms/therapy/immunology/pathology/genetics ; Mice ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; *Immunotherapy, Adoptive/methods ; *Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors/immunology/metabolism ; Mesothelin ; Lymphocyte Activation Gene 3 Protein ; *Immune Checkpoint Inhibitors/pharmacology ; *T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Disease Models, Animal ; *Antigens, CD/immunology/metabolism/genetics ; Cell Line, Tumor ; Humans ; },
abstract = {The five-year survival rate for ovarian cancer patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to specifically target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (MSLN) contributes to the malignant and invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in a mouse model of ovarian cancer demonstrated that T cells engineered to express a T cell receptor (TCR) targeting MSLN (TCRMSLN) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function and improve therapeutic efficacy, but administration of monospecific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3, and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCRMSLN with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCRMSLN T cells treated with the triplet antibody combination increased expression of genes involved in interferon responses and metabolic function, and reduced expression of genes associated with exhaustion. These results suggest that strategies to disrupt multiple inhibitory pathways simultaneously may be necessary for improved adoptive T cell therapy efficacy in patients.},
}

Animals
Female
*Ovarian Neoplasms/therapy/immunology/pathology/genetics
Mice
*Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology
*Immunotherapy, Adoptive/methods
*Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors/immunology/metabolism
Mesothelin
Lymphocyte Activation Gene 3 Protein
*Immune Checkpoint Inhibitors/pharmacology
*T-Lymphocytes/immunology
Tumor Microenvironment/immunology
Disease Models, Animal
*Antigens, CD/immunology/metabolism/genetics
Cell Line, Tumor
Humans

@article {pmid40982561,
year = {2025},
author = {Chen, C and Lovendahl, KN and Overbaugh, JM and Lee, KK},
title = {Interprotomer crosstalk in mosaic viral glycoprotein trimers provides insight into polyvalent immunogen co-assembly.},
journal = {PLoS pathogens},
volume = {21},
number = {9},
pages = {e1013143},
doi = {10.1371/journal.ppat.1013143},
pmid = {40982561},
issn = {1553-7374},
abstract = {SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines.},
}

@article {pmid40980587,
year = {2025},
author = {Deo, R and Choudhary, MC and Glover, OT and Ignacio, RB and Boucau, J and Chew, KW and Moser, C and Currier, JS and Eron, JJ and Javan, AC and Giganti, MJ and Aga, E and Gibbs, M and Cohen, T and Streicher, K and Soboleva, K and Fletcher, CV and Daar, ES and Greninger, AL and Coombs, RW and Fischer, W and Hughes, MD and Smith, D and Wohl, DA and Barczak, AK and Li, JZ},
title = {Rapid Elimination of Culturable SARS-CoV-2 With Intramuscular or Intravenous Administration of Antiviral Monoclonal Antibody Therapy.},
journal = {Open forum infectious diseases},
volume = {12},
number = {9},
pages = {ofaf542},
pmid = {40980587},
issn = {2328-8957},
abstract = {We evaluated intramuscular (IM) versus intravenous (IV) administration of tixagevimab/cilgavimab in early COVID-19. Both routes achieved rapid elimination of culturable virus and minimal emergence of resistance. These results support IM delivery as a viable alternative to IV, with important implications for scalable deployment in future viral pandemics.},
}

@article {pmid40979096,
year = {2025},
author = {Muhammad, M and Castro-Reyes, P and Chakoian, M and Duron, Y and Gay, S and Grant, H and Hempstead, B and Hoffman, L and Mapes, D},
title = {Community/patient group champion team retrospective look at engage for equity PLUS: Results from a post-intervention champion team focus group.},
journal = {Journal of clinical and translational science},
volume = {9},
number = {1},
pages = {e179},
pmid = {40979096},
issn = {2059-8661},
abstract = {Community/patient voice has long been stifled in favor of the priorities of powerful health organizations that set the agenda for institutional practices and policies shaping health equity research. Academic Health Centers (AHC) and Clinical Translational Science Centers (CTSC) promote missions that are often unaligned with the realities of community and patient experiences when interacting with researchers and representatives from these institutions. Implementation science has increasingly adopted collaborative and participatory approaches to the design and implementation of health interventions co-created with community/patient group members as equal participants within community-academic partnerships. Community-based participatory research/community-engaged research are widely recognized as approaches to health intervention research that offers the potential for community-patient voice to be heard when the principles of authentic participatory research are adhered to throughout all aspects of the project. For AHC's and CTSC's to be fully engaged, the populations they serve must have access to institutional leadership and influence over decision-making about the organizational resources allocated to community/patient groups beyond efforts to cultivate a positive public image. The E2 community/patient champion team focus groups provide unique perspectives on how equitable institutional transformation can be accomplished in a retrospective assessment of the E2 PLUS Intervention.},
}

@article {pmid40964353,
year = {2025},
author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Radford, C and Worczinski, J and Momot, A and Ahmadov, E and Burger, JA and Havenar-Daughton, C and Deshpande, S and Giovannoni, F and Corti, D and Kreer, C and Ercanoglu, MS and Schommers, P and Georgiev, IS and West, AP and Knüfer, J and Stumpf, R and Kroidl, A and Geldmacher, C and Maganga, L and William, W and Ntinginya, NE and Hoelscher, M and Yang, Z and Wei, Q and Renfrow, M and Green, TJ and Novak, J and van Gils, MJ and Gristick, HB and Gruell, H and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F},
title = {Identification of a broad and potent V3 glycan site bNAb targeting an N332gp120 glycan-independent epitope.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40964353},
issn = {2692-8205},
abstract = {Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here, we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels[1-3] (GeoMean IC50 = 0.012 μg/mL, breadth = 69%, 217 virus strains) by targeting a N332gp120 glycan-independent V3 epitope, a site of Env vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryo-EM structure revealed contacts with the V3 [324]GD/NIR[327] motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs, and bivalent 007 IgG was up to ~300-fold more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure, and vaccine design.},
}

@article {pmid40978447,
year = {2025},
author = {Shukla, S and Stingaciu, LR and Stanley, C and Agarwal, P and Cuneo, M and Stadler, AM and Myles, D},
title = {Dynamical Signatures of Thermotoga maritima Maltose-Binding Proteins Affected by Ligand Binding.},
journal = {ACS omega},
volume = {10},
number = {36},
pages = {41446-41456},
pmid = {40978447},
issn = {2470-1343},
abstract = {Functional segregation among protein isoforms depends on the interplay of their overall structures and the molecular dynamics of these structures. Thermotoga maritima maltose-binding protein (tmMBP) isoforms show size-dependent differential binding of maltose and malto-oligomers while maintaining remarkable fold conservation. This differential behavior needs detailed characterization in native-like aqueous conditions to understand the effects of protein dynamics on ligand binding and recognition. Small-angle neutron scattering (SANS), neutron spin echo (NSE) spectroscopy, and dynamic light scattering (DLS) were used in conjunction with previously published computational molecular dynamics (MD) simulations to understand the dynamic behavior of tmMBPs experimentally. SANS provided information on the overall structure of the molecules, while NSE was used to determine the dynamics in the nanosecond time scale. Both tmMBP2 and tmMBP3 have a bidomain architecture linked with a flexible hinge, with the binding pocket sitting in the cleft between the two domains. tmMBP2 and tmMBP3 showed different solution dynamics, with the translational and rotational components dominating the dynamics of both systems, resulting in a clear differentiation of their diffusion pattern. A faster dynamics component was also observed and was attributed to segmental dynamics. Differences observed between the ligand-free (apo) and ligand-bound (holo) states of the two proteins are attributed to conformational entropy. Our results highlight the intricacies of how structure and dynamics can together shape binding to a repertoire of substrates in structurally similar proteins.},
}

@article {pmid40978103,
year = {2025},
author = {Bukavina, L and Isali, I and Parekh, S and Psutka, S and Uzzo, N and Leonard, S and Calaway, A and Patel, S and Grivas, P and Jia, A and Correa, A and Brown, JR and Kutikov, A and Ponsky, L and Uzzo, R and Sindhani, M and Catto, J and Wu, CW and Abbosh, PH},
title = {Genetic susceptibility and environmental risk factors in bladder cancer: Evidence from the UK biobank.},
journal = {Bladder cancer (Amsterdam, Netherlands)},
volume = {11},
number = {3},
pages = {23523735251370863},
pmid = {40978103},
issn = {2352-3735},
abstract = {PURPOSE: This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility.

EXPERIMENTAL DESIGN: Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset.

RESULTS: Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer.

CONCLUSIONS: Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.},
}

@article {pmid40977057,
year = {2025},
author = {Ebrahimi, E and Naudin, S and Dimou, N and Mayén, AL and Wang, M and Abnet, CC and Åkesson, A and Barnett, MJ and Bellocco, R and Berrington de Gonzalez, A and Bonn, SE and Chen, C and Christiani, DC and Crane, TE and Eliassen, AH and Freudenheim, JL and Gao, YT and Garcia-Closas, M and Gierach, G and Giovannucci, EL and Gram, IT and Håkansson, N and Hirabayashi, M and Hou, T and Huang, BZ and Huerta, JM and Jayasekara, H and Koh, WP and Lacey, JV and Lagerros, YT and Loftfield, E and MacInnis, RJ and Mannisto, S and Martinez, ME and McCullough, ML and Milne, RL and Moore, SC and Mucci, LA and Neuhouser, ML and Platz, EA and Poynter, JN and Prizment, AE and Rees, S and Robien, K and Rohan, TE and Sawada, N and Setiawan, VW and Shams-White, MM and Shu, XO and Sinha, R and Stampfer, MJ and Stolzenberg-Solomon, RZ and Thomson, CA and Um, CY and van den Brandt, PA and Visvanathan, K and Wang, R and Wang, SS and White, E and White, KK and Willet, WC and Wolk, A and Yano, Y and Yaun, SS and Yuan, JM and Zheng, W and Riboli, E and Smith-Warner, SA and Brennan, P and Ferrari, P},
title = {Alcohol consumption and upper aerodigestive tract squamous cell carcinoma: evidence from 28 prospective cohorts.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djaf230},
pmid = {40977057},
issn = {1460-2105},
abstract = {BACKGROUND: This study aimed to investigate the association between alcohol consumption and squamous cell cancers of the upper aerodigestive tract (UADT), using data from 28 cohorts within the Pooling Project of Prospective Studies of Diet and Cancer (DCPP).

METHODS: Individual-level data from 2,365,437 participants were pooled. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models to quantify the association between alcohol consumption (grams/day) and UADT cancers risk, adjusting for potential confounders. Analyses were conducted by sex, smoking status, geographic region, and alcoholic beverages.

RESULTS: Over a median follow-up of 15.5 years, 6,903 UADT cancer cases were identified. Alcohol consumption was positively associated with UADT cancers risk overall. Even at intakes as low as 5-<15 g/day the HR estimate was 1.12 (95% CI 1.03,1.21) compared with the reference group (0.1-<5 g/day). The HR10g/day (95% CI) was 1.16 (1.14,1.18) for women and 1.12 (1.11,1.13) for men (pheterogeneity<0.0001). HR10g/day estimates were 1.14 (1.13,1.15) in current, 1.10 (1.09,1.12) in former, and 1.15 (1.12,1.18) in never-smokers. Consistent UADT HR10g/day estimates were observed across all beverage types. HR10g/day estimates varied across geographic regions, with HR10g/day (95% CI) equal to 1.15 (1.14,1.17) in Europe-Australia, 1.13 (1.11,1.15) in Asia, and 1.11 (1.09,1.12) in North America (pheterogeneity<0.0001).

CONCLUSION: Alcohol consumption was associated with UADT cancer risk, irrespective of smoking status or beverage type. However, due to differential baseline risks, alcohol is expected to impact the UADT cancer burden more in smokers than never-smokers. These findings support public health strategies to reduce alcohol consumption.},
}

@article {pmid40975077,
year = {2025},
author = {Mo, T and Joffe, M and Cubasch, H and Galukande, M and Parham, G and Pinder, L and Zietsman, A and Anderson, BO and Naamala, A and Kaggwa, A and Nakazibwe, T and Nteziryayo, A and Pontac, J and Offiah, SA and Angelica, A and Oyamienlen, CS and Ezeigbo, E and Iwuoha, K and Chen, WC and Walubita, E and Lusaka, M and Nyangasi, M and Mohammed, S and Narh, CT and Boucheron, P and Foerster, M and Schüz, J and Dos-Santos-Silva, I and McCormack, V},
title = {Breast cancer overall survival, annual risks of death, and survival gap apportionment in sub-Saharan Africa (ABC-DO): 7-year follow-up of a prospective cohort study.},
journal = {The Lancet. Global health},
volume = {13},
number = {10},
pages = {e1681-e1690},
pmid = {40975077},
issn = {2214-109X},
mesh = {Humans ; Female ; *Breast Neoplasms/mortality ; Africa South of the Sahara/epidemiology ; Prospective Studies ; Middle Aged ; Adult ; Follow-Up Studies ; Aged ; Young Adult ; },
abstract = {BACKGROUND: There are few estimates of breast cancer survival and its determinants at 5 years and beyond in sub-Saharan Africa. We aimed to estimate survival up to 7 years, estimate annual mortality risk, and apportion survival gaps.

METHODS: The African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort study was done at eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, South Africa, Uganda, and Zambia). We prospectively recruited women (aged ≥18 years) who attended hospital with suspected breast cancer. Vital status was updated telephonically once every 3 months for 7 years. We collected detailed sociodemographic, clinical, and treatment data. The primary outcome was overall survival. We estimated age-standardised net survival, conditional survival, and predicted survival gains if there were favourable shifts in the distribution of prognostic factors aligned with the WHO Global Breast Cancer Initiative (GBCI).

FINDINGS: Between Sept 8, 2014, and Dec 31, 2017, 2313 women were recruited and followed up to Jan 1, 2022, and for a further year in South Africa. We excluded 87 women without breast cancer, 14 women from small racial groups (eight White and six Asian women in South Africa), 57 women with previous treatment or possible recurrences, and two women without follow-up data. The remaining 2153 (93%) women were categorised by country and race, as follows: three groups in Namibia (60 White women, 50 mixed race women, and 367 Black women), two in South Africa (37 mixed race women and 638 Black women), and one group of Black women in each of Uganda (419 women), Zambia (198 women), and Nigeria (384 women). During follow-up to at most 7 years, 1323 (61%) of 2153 women died, 672 (31%) were alive at administrative censoring, and 158 (7%) were lost to follow-up, giving crude survival at 3 years, 5 years, and 7 years of 51%, 40%, and 33%, respectively. Large between-country variations in 5-year age-standardised net survival were observed: 35-42% in Zambia and Nigeria; 52-58% in Black women in Uganda, South Africa, and Namibia; and over 83% in non-Black Namibian women. The annual probability of death (1-year conditional net survival, censored before the COVID-19 pandemic) declined generally from 2-3 years after diagnosis, but remained at 8-21% for Black women in Namibia, Uganda, and Nigeria during the fifth year after diagnosis. Reaching the GBCI 60% stage I or II target and accessing treatment would lead to an approximate reduction in deaths by a third among Black women in Namibia, Nigeria, South Africa, Uganda, and Zambia.

INTERPRETATION: Survival after breast cancer is poor in several sub-Saharan African countries, with a substantial risk of death even among women who have survived beyond 3 years after diagnosis. Understanding and preventing deaths among longer-term breast cancer survivors requires further research.

FUNDING: National Cancer Institute, Susan G Komen, and International Agency for Research on Cancer.

TRANSLATIONS: For the Yoruba, Hausa, Igbo, Luganda and French translations of the abstract see Supplementary Materials section.},
}

Humans
Female
*Breast Neoplasms/mortality
Africa South of the Sahara/epidemiology
Prospective Studies
Middle Aged
Adult
Follow-Up Studies
Aged
Young Adult

@article {pmid40964312,
year = {2025},
author = {Bansal, AM and Horowitz, LF and Yeung, M and Gujral, TS and Folch, A},
title = {BIOPRINTING OF MICRODISSECTED TUMOR "CUBOIDS" IN HYDROGELS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40964312},
issn = {2692-8205},
abstract = {Microscale tumor models made from microdissected tumors that retain much of the original human tumor microenvironment (TME) are emerging as an alternative to preclinical animal models. We have introduced a drug testing approach that utilizes regularly-cut, cuboidal-shaped microdissected tissues, or "cuboids," as a way to maximize creation of microtissues from scarce biopsy materials. However, microtissues (e.g., cuboids, organoids, spheroids, etc.) can be difficult to place in precise locations, especially in applications that require their culture in hydrogels. Here, using cuboids from mouse tumor models, we demonstrate a simple bioprinting strategy for precise placement and immobilization of cuboids in hydrogel. We use a commercial bioprinter to bioprint -containing hydrogel into arrays of small hydrogel dots containing cuboids, or "cuboid dots," either onto a Transwell insert or into traps on a microplate. The hydrogel serves to immobilize the cuboids in place and provides a matrix to support cuboid viability. We demonstrate proof-of-concept applications for cancer drug testing and for protein profiling analysis. This approach will enable interface of cuboids with other devices, such as on top of a sensor or in a microfluidic platform. Furthermore, this automated process of dispensing and localizing cuboids (or other microtissue formats such as spheroids or organoids) could further their application to drug discovery and personalized medicine.},
}

@article {pmid40964006,
year = {2025},
author = {Moosavi, D and Lim, U and Hullar, M and Rettenmeier, C and Kwee, S and Monroe, K and Ernst, T and Randolph, T and Wilkens, L and Marchand, LL and Lampe, J and Park, SY},
title = {Association Between Plant-Based Diet Quality and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in the Multiethnic Cohort Study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {40964006},
issn = {2693-5015},
abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease (NAFLD), is a growing public health concern with limited effective treatments. Diet quality may influence MASLD risk, yet the role of plant-based diet quality across diverse populations remains unclear.

OBJECTIVE: To evaluate the associations of plant-based dietary patterns with liver fat content or MASLD prevalence in multiethnic older adults.

METHODS: We analyzed cross-sectional data on 1,598 participants in the Adiposity Phenotype Study (APS), nested within the Multiethnic Cohort Study. Scores for three established plant-based diet indices were computed from food frequency questionnaire responses: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). Liver fat was measured using MRI, and MASLD was defined, among participants reporting zero to low alcohol intakes. Multivariable linear models of liver fat and logistic models of MASLD were used to estimate their associations with the plant-based diet indices, adjusting for demographic, lifestyle, and anthropometric covariates.

RESULTS: Higher hPDI scores were associated with lower liver fat content (adjusted mean for 4th (5.39) vs. 1st quartile (6.52) and reduced likelihood of MASLD (OR for 4th vs. 1st quartile = 0.58 (95% CI: 0.41-0.81). When stratified across five racial and ethnic groups, stronger inverse associations were observed among Latino and White participants (p-heterogeneity = 0.001) than among African American, Japanese American, or Native Hawaiian participants. No consistent associations were observed for PDI or uPDI. Among hPDI components, higher nut and lower animal fat intakes were associated with lower liver fat and MASLD.

CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with lower liver fat and MASLD prevalence, with some racial and ethnic variation. These findings underscore the importance of plant-food quality and may inform dietary strategies for MASLD prevention in heterogeneous populations.},
}

@article {pmid40975076,
year = {2025},
author = {Stover, J and Sonneveldt, E and Tam, Y and Horton, KC and Phillips, AN and Smith, J and Martin-Hughes, R and Ten Brink, D and Citron, DT and Kim, HY and Akullian, A and Mudimu, E and Pickles, M and Bershteyn, A and Williamson, J and Meyer-Rath, G and Jamieson, L and Sully, EA and White, JN and Heaton, A and Clark, RA and Tong, H and Richards, AS and McQuaid, CF and Houben, RMGJ and White, RG and Dimitrov, D and Kaftan, D},
title = {Effects of reductions in US foreign assistance on HIV, tuberculosis, family planning, and maternal and child health: a modelling study.},
journal = {The Lancet. Global health},
volume = {13},
number = {10},
pages = {e1669-e1680},
pmid = {40975076},
issn = {2214-109X},
mesh = {Humans ; *Tuberculosis/economics/prevention & control/epidemiology ; *HIV Infections/economics/prevention & control/epidemiology ; United States ; *Family Planning Services/economics ; Female ; *Child Health/economics ; Child ; Models, Theoretical ; Pregnancy ; *International Cooperation ; Global Health ; Developing Countries ; *Maternal Health/economics ; },
abstract = {BACKGROUND: The USA has traditionally been the largest donor to health programmes in low-income and middle-income countries (LMICs). In January 2025, almost all such funding was stopped and prospects for its resumption are uncertain. The suddenness of the funding cuts makes it difficult for national health programmes in LMICs to adapt. We aimed to estimate the impact of these cuts on deaths and other outcomes (new infections, number of family planning users, and unplanned pregnancies) for four health areas that have been a focus of a substantial amount of US foreign assistance: HIV, tuberculosis, family planning, and maternal and child health.

METHODS: We applied established mathematical models to the countries receiving US foreign assistance in each domain to estimate health impacts over the period 2025 to 2030. We used six models of HIV, three different approaches to estimate family planning impact, and one model each for tuberculosis and maternal and child health, applying these models to as many as 80 countries. We compared model projections assuming constant funding (status quo) with projections assuming complete elimination of US funding in each country. Some models also considered partial cuts or restoration of funding over time.

FINDINGS: A complete cessation of US funding without replacement by other sources would lead to drastic increases in deaths from 2025 to 2030: 4·1 million (range 1·6-6·6) additional AIDS-related deaths across 55 countries, 606 900 (95% uncertainty interval [UI] 466 000-768 800) additional tuberculosis deaths across 79 countries, 40-55 million additional unplanned pregnancies and 12-16 million unsafe abortions across 51 countries, and 2·5 million (1·3-4·5) additional child deaths from causes other than HIV and tuberculosis across 24 countries. Restoration of funding for HIV treatment but not prevention would avoid most of the increase in deaths but still result in nearly 1 million more new HIV infections from 2025 to 2030.

INTERPRETATION: Substantial progress has been made in improving global health in the past few decades. This progress has strengthened hope in reaching global development goals. However, the recent funding cuts threaten to change these trajectories and could lead to sharp increases in avoidable mortality for the poorest countries. Even a partial restoration of US funding would combat the most severe effects and provide time for countries that have received substantial US foreign assistance to adjust to the new funding landscape.

FUNDING: Economic and Social Research Council; Engineering and Physical Sciences Research Council; European and Developing Countries Clinical Trials Partnership; Gates Foundation; Global Fund to Fight AIDS, Tuberculosis, and Malaria; Open Philanthropy; UK Foreign, Commonwealth & Development Office; UK Medical Research Council; UN Population Fund; UNAIDS; US National Institute of Allergy and Infectious Diseases; University of Edinburgh; US National Institutes of Health; US President's Emergency Plan for AIDS Relief; Wellcome Trust; World Bank; WHO.},
}

Humans
*Tuberculosis/economics/prevention & control/epidemiology
*HIV Infections/economics/prevention & control/epidemiology
United States
*Family Planning Services/economics
Female
*Child Health/economics
Child
Models, Theoretical
Pregnancy
*International Cooperation
Global Health
Developing Countries
*Maternal Health/economics

@article {pmid40975064,
year = {2025},
author = {Nishida-Aoki, N and Zhu, S and Chan, M and Kang, Y and Fujita, M and Jiang, X and McCabe, M and Vaz, JM and Davidson, NE and Ghajar, CM and Hansen, K and Welm, AL and Pillarisetty, VG and Gujral, TS},
title = {Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102357},
doi = {10.1016/j.xcrm.2025.102357},
pmid = {40975064},
issn = {2666-3791},
abstract = {Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.},
}

@article {pmid40974099,
year = {2025},
author = {Dreyzin, A and Ware, M and Stumbras, K and Kairalla, J and Hibbitts, E and Mossman, B and Balsamo, L and Rodwin, R and Ness, KK and Conley, CC and Raetz, E and Devidas, M and Sung, L and Loh, M and Hunger, SP and Schore, RJ and Angiolillo, A and Kadan-Lottick, N},
title = {Caregivers' Perspectives on Changes in Family Life During B-ALL Therapy: A Qualitative Study From the Children's Oncology Group.},
journal = {Pediatric blood & cancer},
volume = {},
number = {},
pages = {e32057},
doi = {10.1002/pbc.32057},
pmid = {40974099},
issn = {1545-5017},
support = {//Children's Oncology Group/ ; U10CA095861/CA/NCI NIH HHS/United States ; U10CA180886-06S1/NH/NIH HHS/United States ; U10CA98543/NH/NIH HHS/United States ; U10CA98413/NH/NIH HHS/United States ; U10CA180886/NH/NIH HHS/United States ; U10CA180899//NCTN Network Group Operations Center/ ; UG1CA189955//NCTN Statistics and Data Center/ ; //NCORP Grant for Cancer Control Studies/ ; T32CA261787//St. Baldrick's Foundation/ ; },
abstract = {BACKGROUND: Treatment of pediatric B-acute lymphoblastic leukemia (B-ALL) impacts both patients and their caregivers. An understanding of family functioning during therapy can inform family-centered care. We aimed to prospectively identify negative and positive changes in family life as perceived by caregivers throughout ALL therapy.

METHODS: Caregivers of children aged ≥4 years with average-risk B-ALL enrolled on the Children's Oncology Group trial AALL0932 who consented to an ancillary study were asked: "How has family life changed since your child's diagnosis of leukemia for the better or for the worse?" Written free responses were collected at approximately 2, 8, 17, 26 (end of therapy for females), and 38 (end of therapy for males) months post-diagnosis. Inductive content analysis was used to create codes, subcategories, and categories. Descriptive statistics were used to characterize the sample and frequencies of reported codes.

RESULTS: Overall, 994 responses were collected from caregivers of 468 children across all timepoints. Twenty-seven individual codes were identified, categorized by negative changes (reported by 89% of caregivers) and positive changes (reported by 58% of caregivers). Subcategories of negative changes, including changes in daily routines, work and finance, patient health and care needs, effects on other family members, and emotional changes, were identified across all timepoints, but were most prevalent early in therapy. Importantly, positive changes were also identified, including family support, community support, and changes in outlook.

CONCLUSION: This study identifies negative and positive family changes perceived by caregivers of children undergoing B-ALL therapy that can inform future interventions to better support families.},
}

@article {pmid40974097,
year = {2025},
author = {Deslandes, B and Wu, X and Lee, MA and Goudswaard, LJ and Jones, GW and Gsur, A and Lindblom, A and Ogino, S and Vymetalkova, V and Wolk, A and Wu, AH and Huyghe, JR and Peters, U and Phipps, AI and Thomas, CE and Pai, RK and Grant, RC and Buchanan, DD and Yarmolinsky, J and Gunter, MJ and Zheng, J and Hazelwood, E and Vincent, EE},
title = {Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development.},
journal = {Journal of leukocyte biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jleuko/qiaf131},
pmid = {40974097},
issn = {1938-3673},
abstract = {Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells - a highly dynamic lymphocyte subtype - undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified six genes - FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258 - with strong evidence for a causal role in CRC development (FDR-P<0.05; colocalisation H4>0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.},
}

@article {pmid40974095,
year = {2025},
author = {Kistler, K and Bedford, T},
title = {Seasonal influenza viruses show distinct adaptive dynamics during growth in chicken eggs.},
journal = {Molecular biology and evolution},
volume = {},
number = {},
pages = {},
doi = {10.1093/molbev/msaf227},
pmid = {40974095},
issn = {1537-1719},
abstract = {Human influenza viruses are grown in chicken eggs for vaccine production. Sequences of these egg-passaged viruses give us the opportunity to examine the evolution that occurs when these human viruses are subjected to the selective pressure of growing in chicken eggs, which (among other things) express different sialic acid receptors. The repetition of this evolutionary experiment in hundreds of strains over the past several decades allows us to identify mutations that adapt the virus to eggs and epistatic constraints that influence them. We analyze influenza A/H3N2, A/H1N1pdm, B/Vic and B/Yam sequences that were passaged in eggs and find that almost all of the adaptive mutations are located around the receptor-binding pocket of hemagglutinin (HA). We observe epistatic interactions both between adaptive mutations and between these mutations and the continually-evolving human influenza HA background sequence. Our results show that this background dependence is greatest for influenza A/H3N2, then A/H1N1pdm, with B/Vic and B/Yam showing little-to-no background dependence. We find that the total number of adaptive mutations and the length of adaptive walk also follow the same pattern between the influenza subtypes, suggesting that background dependence, number of adaptive mutations, and extent of additive versus epistatic interactions may all be related features of the fitness landscape.},
}

@article {pmid40973225,
year = {2025},
author = {Ch'en, PY and Zhang, Y and Hippe, DS and Akaike, T and Miller, NJ and Church, C and Lachance, K and Finberg, A and Gooley, T and Hall, E and Bhatia, S and Nghiem, P},
title = {Real-world outcomes of patients receiving salvage therapies for immune checkpoint inhibitor-resistant Merkel cell carcinoma: a rationale for future clinical trials.},
journal = {Journal for immunotherapy of cancer},
volume = {13},
number = {9},
pages = {},
doi = {10.1136/jitc-2025-012660},
pmid = {40973225},
issn = {2051-1426},
mesh = {Humans ; *Salvage Therapy/methods ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Carcinoma, Merkel Cell/drug therapy/mortality/pathology ; Male ; Female ; Aged ; Middle Aged ; *Drug Resistance, Neoplasm ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/mortality ; Treatment Outcome ; Prospective Studies ; },
abstract = {BACKGROUND: Merkel cell carcinoma is an aggressive skin cancer that progresses to advanced/metastatic disease in~40% of patients. First-line immune checkpoint inhibitors (ICI) that block the programmed cell death protein-1/programmed death-ligand 1 axis provide 3-year progression-free responses in only~40% of patients. The relative efficacy of salvage therapies in this setting is unclear.

METHODS: In a prospectively enrolled single-center cohort, 106 patients had disease progression during or shortly after ICI and received at least one local or systemic salvage therapy. Baseline disease characteristics, treatments, and outcomes data were collected. Patients were stratified by primary resistance (no response to initial ICI) or acquired resistance (loss of ICI response after initial benefit). Primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS). Associations between salvage therapies and outcomes were evaluated using Cox models with time-varying covariates for treatments and adjustments for disease burden and ICI resistance type.

RESULTS: In this cohort, 44 patients (42%) met criteria for primary resistance and 31 (29%) had acquired resistance. Median PFS from salvage initiation was more than double for patients with acquired versus primary resistance (9.5 vs 4.7 months; p=0.006). Median DSS was not reached for acquired resistance and 14.3 months for primary resistance (p=0.006). A minority of patients (n=14) survived ≥3 years after salvage initiation, typically following customized, multimodal salvage strategies. Among salvage regimens (ICI alone, ICI+radiation therapy (RT), chemotherapy, chemotherapy+ICI), only ICI+RT had a statistically significant association with improved DSS relative to ICI alone (after adjustment, including disease burden and ICI resistance type: adjusted HR 0.35, 95% CI 0.14 to 0.91).

CONCLUSIONS: Patients with acquired resistance receiving salvage therapy have improved survival compared with those with primary resistance. While the addition of radiation to ICI was clearly associated with improved DSS, there continues to be a major need for new approaches to address ICI-resistant disease. Nevertheless, a durable benefit in select patients is possible via sequential, individualized, multidisciplinary treatments. We anticipate these data will be relevant for the design of clinical trials for this challenging ICI-resistant setting.},
}

Humans
*Salvage Therapy/methods
*Immune Checkpoint Inhibitors/therapeutic use/pharmacology
*Carcinoma, Merkel Cell/drug therapy/mortality/pathology
Male
Female
Aged
Middle Aged
*Drug Resistance, Neoplasm
Aged, 80 and over
*Skin Neoplasms/drug therapy/mortality
Treatment Outcome
Prospective Studies

@article {pmid40972808,
year = {2025},
author = {Bhat, P and Van Amburg, JC and Potts, CR and Gracie, TJ and Cartailler, JA and Parker, AC and Savona, MR and Lu, R and Lee, SC and Welner, RS and Bick, AG and Jr, PBF},
title = {A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.},
journal = {Experimental hematology},
volume = {},
number = {},
pages = {105252},
doi = {10.1016/j.exphem.2025.105252},
pmid = {40972808},
issn = {1873-2399},
abstract = {Myelodysplastic syndromes (MDS) are a group of malignant clonal disorders that are characterized by functional impairment of hematopoiesis, morphologic dysplasia, and genetic heterogeneity[1]. While less likely to transform to acute leukemia, lower-risk MDS (LR-MDS) include patients with IPSS-M moderate low risk, low risk, and very low risk patients[2] and have a limited median survival of 3 to 10 years[3]. Further, there is growing interest in discovering translational targets of LR-MDS pathophysiology. Clonal populations within the hematopoietic stem and progenitor (HSPC) to myeloid differentiation spectrum are widely considered to be a major contributor to MDS pathophysiology[4]. A granular assessment of cell-type and lineage-specific states that contribute to LR-MDS pathophysiology remains to be elucidated. Here, we leverage single-cell transcriptomics to characterize cell states across the HSPC-myeloid differentiation landscape in LR-MDS. We develop a 30-gene score to classify LR-MDS HSPCs and identify novel molecular features of LR-MDS. The genes in our score suggest dysfunction in vesicular trafficking, which we further resolve across the myeloid differentiation axis. The gene products of vesicular trafficking-related pathways may be suitable translational targets for LR-MDS. TEASER ABSTRACT: We leveraged single-cell transcriptomics to differentiate low-risk MDS and healthy cells from patient bone marrow samples. A combination approach of network analysis and classification was used to identify a 30-gene signature that distinguishes MDS HSPCs from HD HSPCs. Upregulation of pathways related to protein translation, pro-inflammatory cytokine production, and vesicular trafficking were observed. Lastly, we stratify the thirty genes by their expression across the HSPC-myeloid differentiation axis and highlight divergent expression patterns in genes related to vesicular trafficking components.},
}

@article {pmid40972633,
year = {2025},
author = {Agnandji, ST and Bok, J and Alabi, A and Kabwende, AL and Mbouna, A and Bie, J and Moukiti, E and Lalremruata, A and Esen, M and Kreidenweiss, A and Kc, N and Sim, BKL and Richie, TL and Preston Church, LW and McCall, MBB and Hoffman, SL and Kremsner, PG and Mordmüller, B},
title = {Safety, tolerability, and protective efficacy of a radiation-attenuated, whole sporozoite malaria vaccine in children in Gabon: a randomised, double-blind, placebo-controlled, phase 2 trial.},
journal = {The Lancet. Infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1473-3099(25)00434-7},
pmid = {40972633},
issn = {1474-4457},
abstract = {BACKGROUND: Highly effective malaria vaccines are crucial to further reduce the burden of malaria. The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) Vaccine protects adults; however, there are insufficient efficacy data in child populations. We aimed to assess the safety and efficacy of the PfSPZ Vaccine in children aged 1-12 years in Gabon.

METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was conducted at the Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. Healthy children were stratified by age (1-2, 3-6, and 7-12 years) and allocated 2:1 by block randomisation to receive 9·0 × 10[5] PfSPZ Vaccine or placebo (normal saline), administered by direct venous inoculation on days 1, 8, and 29. Artemether-lumefantrine was given before the third vaccination to clear latent parasitaemia. The co-primary endpoints were safety, evaluated in the intention-to-treat population by severe adverse events within 7 days (solicited) and 28 days (unsolicited) of vaccination and by serious adverse events; and vaccine efficacy, measured as time to first P falciparum-positive thick blood smear (TBS), 2-26 weeks after immunisation in those who received three vaccinations (ie, the modified intention-to-treat population). The trial was registered at ClinicalTrials.gov, NCT03521973, and is complete.

FINDINGS: Between June 21, 2018, and April 30, 2019, 345 children were assessed for eligibility, of whom 200 were enrolled to the study: 134 were allocated to receive PfSPZ Vaccine and 66 to receive placebo. 192 participants received three vaccinations and comprised the modified intention-to-treat population. Systemic adverse events were reported by 33 (25%) of 134 participants in the vaccine group (47 events) and 15 (23%) of 66 participants in the placebo group (25 events); subjective fever was the most reported event in both groups. Three grade 3 systemic adverse events were reported (two cases of elevated body temperature and one case of subjective fever), all in the placebo group. 32 serious adverse events were reported across 22 study participants, 13 (10%) of 134 in the vaccine group and nine (14%) of 66 in the placebo group, all of which were considered unrelated to the intervention. There were no treatment-related deaths. 25 (19%) of 129 vaccine recipients and 14 (23%) of 63 placebo recipients became TBS-positive for P falciparum at 2-26 weeks after vaccination. The age-stratum-adjusted vaccine efficacy (1 - hazard ratio) was 9% (95% CI -75 to 53; p=0·78).

INTERPRETATION: PfSPZ Vaccine is well tolerated and safe, but it did not prevent P falciparum infection in children in Gabon. Whether presumptive treatment during immunisation or more potent PfSPZ vaccines can establish vaccine efficacy is currently under investigation.

FUNDING: German Center for Infection Research, European and Developing Countries Clinical Trials Partnership, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.},
}

@article {pmid40972587,
year = {2025},
author = {Wellington, R and Cheng, X and Dutta, S and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S},
title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102641},
doi = {10.1016/j.stemcr.2025.102641},
pmid = {40972587},
issn = {2213-6711},
abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE) via endothelial-to-hematopoietic transition (EHT). While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, bona fide HSC generation from iPSCs remains challenging. We map single-cell dynamics of EHT from iPSCs and integrate it with human embryo datasets to identify ligand-receptor interactions that drive transcriptional divergence between iPSC-derived and embryonic cell states. The expression of endothelial genes predicted to be regulated by FGF signaling was incompletely repressed during iPSC-derived EHT. FGF activity declined at the onset of EHT to enable normal hematopoiesis in the zebrafish, and chemical inhibition of FGF signaling during EHT enhanced HSC and progenitor generation in the zebrafish and from iPSCs. In summary, we generate a single-cell map of iPSC-derived EHT, identify ligand-receptor interactions that can improve iPSC differentiation, and uncover elevated FGF signaling as a barrier to hematopoiesis.},
}

@article {pmid40972578,
year = {2025},
author = {Wang, N and Ockerman, FP and Zhou, LY and Grove, ML and Alkis, T and Barnard, J and Bowler, RP and Clish, CB and Chung, S and Drzymalla, E and Evans, AM and Franceschini, N and Gerszten, RE and Gillman, MG and Hutton, SR and Kelly, RS and Kooperberg, C and Larson, MG and Lasky-Su, J and Meyers, DA and Woodruff, PG and Reiner, AP and Rich, SS and Rotter, JI and Silverman, EK and Vasan, RS and Weiss, ST and Wong, KE and Wood, AC and Wu, L and , and Yarden, R and Blackwell, TW and Smith, AV and Chen, H and Raffield, LM and Yu, B},
title = {Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2025.08.022},
pmid = {40972578},
issn = {1537-6605},
abstract = {Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.},
}

@article {pmid40972035,
year = {2025},
author = {Watling, CZ and Petrick, JL and Graubard, BI and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, JM and Hofmann, JN and Huang, WY and Kang, JH and Koshiol, J and Loftfield, E and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Palmer, JR and Purdue, MP and Rosenberg, L and Sesso, HD and Shrubsole, M and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Watts, EL and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Campbell, PT and Barupal, D and Mcglynn, KA},
title = {Pre-diagnostic circulating bile acid concentrations and liver cancer risk: a nested case-control analysis of 12 cohorts.},
journal = {JNCI cancer spectrum},
volume = {},
number = {},
pages = {},
doi = {10.1093/jncics/pkaf086},
pmid = {40972035},
issn = {2515-5091},
abstract = {BACKGROUND: Bile acids are produced in the liver and are important for lipid digestion. Higher circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk.

METHODS: We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen pre-diagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk.

RESULTS: Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] of glycocholic acid, 95% CI: 1.32, 1.24-1.40; glycochenodeoxycholic acid: 1.33, 1.24-1.43; taurocholic acid: 1.28, 1.22-1.35; and taurchenodeoxycholic acid: 1.32, 1.24-1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16-1.39). When analyses were separated into the two main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all p-values < 0.001) that showed positive significant associations with HCC but not ICC.

CONCLUSIONS: These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.},
}

@article {pmid40971983,
year = {2025},
author = {Carone, M and Wolock, CJ and Olivas-Martinez, A and Rotnitzky, A and Gilbert, PB},
title = {Immune Correlates and Vaccine Immunobridging: Statistical Innovations, Challenges, and Opportunities.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiaf451},
pmid = {40971983},
issn = {1537-6613},
support = {/NH/NIH HHS/United States ; },
abstract = {In immunobridging, an investigational vaccine is approved based on a randomized trial of this vaccine versus an approved vaccine with an immunogenicity primary endpoint. Justification for immunobridging requires demonstration that meeting trial success criteria implies the investigational vaccine provides worthwhile protection against a relevant endpoint for a context of use. We consider recent statistical approaches whose integration supports immunobridging: (1) variable importance prediction analysis characterizing immune markers as correlates of risk; (2) controlled risk causal analysis evaluating markers as correlates of protection; and (3) transportability analysis combining data from efficacy and immunobridging trials for estimating investigational versus approved relative-vaccine efficacy.},
}

@article {pmid40964329,
year = {2025},
author = {Semenova, G and Frank, S and Dumpit, R and Han, W and Coleman, I and Gulati, R and Morrissey, C and Haffner, MC and Nelson, PS and Lee, JK},
title = {Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40964329},
issn = {2692-8205},
abstract = {Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied in the treatment of hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC and the mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using a new integrated approach for custom ADC design and multiplexing. To nominate rational combinations of ADC targets and ADC payloads, we (1) examined protein co-expression of three clinically relevant surface antigens-B7 homolog 3 (B7-H3), prostate specific membrane antigen (PSMA), and six-transmembrane epithelial antigen of prostate-1 (STEAP1)-in a series of human mCRPC samples and (2) screened established ADC payloads and their combinations in mCRPC cell lines with different phenotypes. We identified synergistic interactions between DNA-damaging payloads and Bcl-xL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway. The functional relevance of isolated p53 loss and impaired PC responses to three genotoxic ADCs (B7-H3-seco-DUBA, PSMA-SG3249, and STEAP1-DXd) and their combinations with A-1331852 was established using genetic knockout models. Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC.},
}

@article {pmid40951278,
year = {2025},
author = {Peoples, AR and Obón-Santacana, M and Kim, AE and Kawaguchi, ES and Fu, Y and Qu, C and Moratalla-Navarro, F and Morrison, J and Lin, Y and Arndt, V and Berndt, SI and Bien, SA and Bishop, DT and Bouras, E and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Conti, DV and Corley, DA and Devall, MA and Dimou, N and Drew, DA and Gruber, SB and Gunter, MJ and Harlid, S and Harrison, TA and Hoffmeister, M and Hsu, L and Huyghe, JR and Keku, TO and Kundaje, A and Lewinger, JP and Li, L and Lynch, BM and Marchand, LL and Martín, V and Murphy, N and Newton, CC and Ogino, S and Hardikar, S and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Pinchev, M and Platz, EA and Potter, JD and Rennert, G and Ruiz-Narvaez, EA and Sakoda, LC and Schoen, RE and Shcherbina, A and Stern, MC and Su, YR and Thomas, CE and Tian, Y and Tsilidis, KK and Um, CY and van Duijnhoven, FJB and van Guelpen, B and Visvanathan, K and Wang, J and White, E and Wolk, A and Woods, MO and Wu, AH and Ulrich, CM and Peters, U and Gauderman, WJ and Moreno, V},
title = {Genetic risk factors modulate the association between physical activity and colorectal cancer.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {40951278},
issn = {2693-5015},
support = {75N92021D00005/WH/WHI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; R01 CA244588/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U01 CA084968/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; },
abstract = {BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis.

METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity.

RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10[- 8]). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10[- 8]). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82).

CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.},
}

@article {pmid40661642,
year = {2025},
author = {Gao, J and Brusselmans, M and Carvalho, LM and Suchard, MA and Baele, G and Matsen, FA},
title = {Biological causes and impacts of rugged tree landscapes in phylodynamic inference.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40661642},
issn = {2692-8205},
support = {R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; },
abstract = {Phylodynamic analysis has been instrumental in elucidating the epidemiological and evolutionary dynamics of pathogens. The Bayesian approach to phylodynamics integrates out phylogenetic uncertainty, which is typically substantial in phylodynamic datasets due to low genetic diversity. Bayesian phylodynamic analysis does not, however, scale with modern datasets, partly due to difficulties in traversing tree space. Here, we set out to characterize tree space of phylodynamic inference and assess its impacts on analysis difficulty and key biological estimates. By running extensive Bayesian analyses of 15 classic large phylodynamic datasets and carefully analyzing the posterior samples, we find that the posterior landscape in tree space ("tree landscape") is diffuse yet rugged, leading to widespread tree sampling problems that usually stem from the sequences in a small part of the tree. We develop clade-specific diagnostics to show that a few sequences-including putative recombinants and recurrent mutants-frequently drive tree space ruggedness and sampling problems, although existing data-quality tests show limited power to detect such sequences. The sampling problems can significantly impact phylodynamic inferences or even distort major biological conclusions; the impact is usually stronger on "local" estimates (e.g., introduction history) that are associated with particular clades than on "global" parameters (e.g., demographic trajectory) that are governed by the general tree shape. We evaluate existing and newly-developed MCMC diagnostics, and offer strategies for optimizing MCMC settings and mitigating impacts of the sampling problems. Our findings highlight the need for and directions to develop efficient traversal over the rugged tree landscape, ultimately advancing scalable and reliable phylodynamics.},
}

@article {pmid40502094,
year = {2025},
author = {Hurlburt, NK and Lubow, J and Goo, L and Pancera, M},
title = {Structural basis for antibody cross-neutralization of Dengue and Zika viruses.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40502094},
issn = {2692-8205},
support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; },
abstract = {Safe and effective vaccines against co-circulating mosquito-borne orthoflaviviruses such as Zika virus (ZikV) and the four serotypes of Dengue virus (DenV1-4) must elicit broadly neutralizing antibodies (bnAbs) to prevent the risk of enhancement of infection by non-neutralizing antibodies. We recently discovered new orthoflavivirus-directed bnAbs, including F25.S02, which neutralizes DenV1-4 and ZikV with comparable or superior potency to the previously characterized E dimer epitope (EDE) bnAbs. Mutagenesis studies of viral envelope proteins showed that the epitope specificity of F25.S02 is distinct from EDE1 bnAbs. Here, we used cryoEM and X-ray crystallography to understand the basis of cross-neutralization of F25.S02 at the molecular level. We obtained a ~4.2 Å cryoEM structure of F25.S02 Fab bound to a stabilized DenV3 soluble E protein dimer and a 2.3 Å crystal structure of F25.S02 Fab bound to ZikV soluble E protein dimer. Like previously described EDE1 bnAbs, the structural epitope of F25.S02 is at the E dimer interface, encompassing predominantly conserved regions in domain II, including the fusion loop. However, unlike EDE1 bnAbs, F25.S02 binding is almost entirely dependent on the heavy chain and is shifted slightly away from the dimer symmetry axis. Our findings emphasize the importance of this cross-neutralizing site of vulnerability for DenV and ZikV that can facilitate rational design of vaccines and therapeutics.},
}

@article {pmid40971753,
year = {2025},
author = {Loeb, S and Keith, SW and Gross, L and Hartman, RL and Beer, TM and Brierley, KL and Cheng, HH and Couvillon, A and Dicker, AP and Friedman, S and Gomella, LG and Karsh, L and Kelly, WK and Lallas, CD and Leader, AE and Mann, MJ and Mark, JR and Mille, P and Paller, CJ and Rana, HQ and Sokolova, AO and Trabulsi, EJ and Whang, YE and Giri, VN},
title = {Patient-Reported Outcomes From Males Regarding Germline Testing for Prostate Cancer: Results From the PROGRESS Registry.},
journal = {JCO precision oncology},
volume = {9},
number = {},
pages = {e2500571},
doi = {10.1200/PO-25-00571},
pmid = {40971753},
issn = {2473-4284},
mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis ; Middle Aged ; Registries ; *Genetic Testing ; *Patient Reported Outcome Measures ; Aged ; Germ-Line Mutation ; Adult ; },
abstract = {PURPOSE: Prostate cancer (PCA) germline testing (GT) informs precision therapy, cancer screening, and hereditary cancer risk for patients and families. To support patient-centered PCA GT, studying patient-reported outcomes (PROs) is essential.

METHODS: PROGRESS was a national patient-driven registry (January 2021-April 2022) for English-speaking males older than 18 years with previous/current PCA GT and Internet access. Surveys collected demographics, PCA history, family cancer history, mode of genetics care delivery, satisfaction with genetic counseling, decisional conflict, cancer genetics knowledge, and attitudes toward GT. Multiple linear regression modeling was used to estimate and draw inferences (α = .05) on strength of relationships between participant characteristics and PROs.

RESULTS: Analyses focused on 414 participants: White (88%), Black (3%), Asian (6%), and mixed/other (3%). Most participants were non-Hispanic (95.2%) and 46.9% had PCA. Genetic results were positive (pathogenic/likely pathogenic variants; mutations) in 27.9%. The three most common modes of genetics care were meeting with genetics professional (in-person or remotely; 30.9%), discussing with doctor (21.1%), and using website (20.8%). In covariate-adjusted models, satisfaction scores were highest with pretest counseling by phone (β = 1.31; 95% CI, 0.26 to 2.36) or discussion with doctor (β = 1.25; 95% CI, 0.38 to 2.12). Lower decisional conflict scores were reported for pretest counseling by phone (β = -3.76; 95% CI, -7.28 to -0.24). Males with mutations reported higher GT benefit scores (β = .30; 95% CI, 0.02 to 0.59) and importance of GT (β = .34; 95% CI, 0.08 to 0.61). Asian Americans reported lower GT satisfaction (β = -2.91; 95% CI, -4.34 to -1.48) and higher decisional conflict (β = 8.93; 95% CI, 4.36 to 13.51).

CONCLUSION: PROGRESS Registry informs the first comprehensive report of PROs among males undergoing PCA GT, providing insights into opportunities to improve patient experience and leverage the benefit of GT.},
}

Humans
Male
*Prostatic Neoplasms/genetics/diagnosis
Middle Aged
Registries
*Genetic Testing
*Patient Reported Outcome Measures
Aged
Germ-Line Mutation
Adult

@article {pmid40971752,
year = {2025},
author = {Raychaudhuri, R and Garraway, IP and Maxwell, KN and Rettig, M and Desai, H and Schoen, MW and Schweizer, MT and Beltran, H and Nelson, PS and Montgomery, B},
title = {Prognostic Significance of RB1 Alterations on Outcomes in Metastatic Prostate Cancer.},
journal = {JCO precision oncology},
volume = {9},
number = {},
pages = {e2500341},
doi = {10.1200/PO-25-00341},
pmid = {40971752},
issn = {2473-4284},
mesh = {Humans ; Male ; Aged ; *Retinoblastoma Binding Proteins/genetics ; Prognosis ; Retrospective Studies ; Middle Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/mortality/pathology ; *Ubiquitin-Protein Ligases/genetics ; Neoplasm Metastasis ; *Prostatic Neoplasms/genetics/mortality/pathology ; },
abstract = {PURPOSE: Emerging evidence suggests that RB1 inactivation may be a strong predictor of poor survival for men with prostate cancer (PC); however, large-scale validation is lacking.

METHODS: We analyzed whether RB1 alterations are associated with inferior survival in advanced PC and evaluated the impact of co-occurring genomic alterations on outcomes using retrospective data from the Veteran's Health Administration and Veterans Affairs Multi-Omics Analysis Platform for Prostate Cancer from 2016 to 2023.

RESULTS: The primary outcome was overall survival (OS) from onset of metastatic castration-resistant prostate cancer (mCRPC), as well as OS from initiation of life-prolonging therapy other than androgen deprivation therapy, and time to development of mCRPC. Eighty-seven (3.5%) of the 2,512 included patients had an RB1 alteration detected. The median age at diagnosis in the RB1-altered group was 71 (IQR, 65-76) years, and 68 (IQR, 62-73) years in the RB1 wild-type group. The median overall survival from diagnosis of mCRPC was 1.31 years (95% CI, 0.89 to 1.84) in those with an RB1 alteration compared with 2.99 years (95% CI, 2.79 to 3.23). RB1 alteration alone conferred similar poor prognosis when compared with patients who had combined PTEN and TP53 alterations. A dose effect was seen with increasing numbers of tumor suppressor genes (TSGs-RB1, TP53, and PTEN) conferring poorer outcomes. The median survival of patients from diagnosis of mCRPC with zero, one, two, and three TSGs was 3.74, 2.61, 1.61, and 0.87 years, respectively. BRCA2 alterations were not associated with significantly worse outcomes unless accompanied by RB1 alteration.

CONCLUSION: In this large, real-world cohort of men with mCRPC, RB1 alterations emerged as a strong indicator of poor prognosis and can be used to stratify studies alone or in conjunction with other TSG alterations.},
}

Humans
Male
Aged
*Retinoblastoma Binding Proteins/genetics
Prognosis
Retrospective Studies
Middle Aged
*Prostatic Neoplasms, Castration-Resistant/genetics/mortality/pathology
*Ubiquitin-Protein Ligases/genetics
Neoplasm Metastasis
*Prostatic Neoplasms/genetics/mortality/pathology