Distinct and convergent effects of SF3B1 mutations in human breast cancer.
Bergman RE, Keeton CI, Sinha IR, Ling JP, Wang Y, Ha L, Mehta EP, Reed SC, Fox EK, O’Grady TM, Yu Y, Fragkogianni S, Chao C, Davidson BA, Miranda AX, Croessmann S, Zhao S, Liu Q, Shyr Y, Dalton WB, Hurley PJ, Park BH.
Proc Natl Acad Sci U S A. 2025 Oct 14;122(41):e2505374122. doi: 10.1073/pnas.2505374122. Epub 2025 Oct 7.
PMID: 41055979 Free article.
Abstract
Tumor genomic profiling has uncovered many cancer drivers whose implications in terms of tumor biology and therapeutic actionability remain understudied. Hotspot mutations in SF3B1 induce widespread transcriptomic alterations and occur across multiple cancer types. Despite this, the biological and clinical consequences of SF3B1 mutations remain elusive. Characterization of the largest SF3B1 mutant breast cancer clinical cohort to date identifies SF3B1 driver mutations in approximately 2.5% of HR+ HER2- breast cancer, with strong enrichment of K700E substitutions, substantial variation in variant allele fraction (VAF), and significantly improved overall survival due to enrichment in Luminal A disease. In vitro and in vivo studies in representative cell models suggest several of the most prevalent SF3B1 mutations have deleterious effects on cell growth, leading to selective loss of the mutation over time, providing a rationale for the low frequency and low VAF of SF3B1 mutations in breast cancer. Though all introduced hotspot mutations limit growth and are reverted to wildtype (WT) over time, mutations at position R625 have a more pronounced phenotype than K700E, providing an explanation for the clinically observed skew in mutation frequencies. RNA and DNA sequencing analyses were used to identify characteristic pathway-level transcriptomic changes in SF3B1-mutant cells and identify copy number alterations as a mechanism of both improved mutation tolerability and a means to eliminate the mutation over time. These data suggest that while SF3B1 mutations are enriched in some clinical contexts, their role in breast tumorigenesis is highly complex and dependent on secondary events that overcome their deleterious effects on cell growth and survival.
Keywords: SF3B1; breast cancer; oncogene; selection; splicing.
Premorbid Metabolic Syndrome Is Associated with the Hypoinflammatory Phenotype in Acute Respiratory Distress Syndrome and Sepsis.
Bogart AM, Obeidalla SN, van Amstel RBE, Cremer O, Bos LDJ, Bartek B, Sinha P, Calfee CS, Kerchberger VE, Ware LB; MARS Consortium.
Am J Respir Crit Care Med. 2025 Oct 10. doi: 10.1164/rccm.202503-0596RL. Online ahead of print.
PMID: 41072401 No abstract available.
A Deceased Donor Kidney Transplant After 10°C Static Storage.
Petrovic M, Kuo M, Dubray J, Forbes R, Miller A, Reese P, Shaver C, Bacchetta M, Crannell WC.
Clin Transplant. 2025 Oct;39(10):e70331. doi: 10.1111/ctr.70331.
PMID: 41004187 No abstract available.
Glucagon-like peptide-1 receptor signaling deficiency exacerbates hematopoietic stem cell graft rejection in mice.
Rusznak M, Sierra-Hernandez D, Dupuy C, Toki S, Wu AY, Rao U, Abney M, Zhang J, Hu Q, Warren CM, Drucker DJ, Niswender KD, Engelhardt B, Kim TK, Gibson-Corley KN, Cahill KN, Cooke KR, Peebles RS Jr.
J Immunol. 2025 Sep 24:vkaf251. doi: 10.1093/jimmun/vkaf251. Online ahead of print.
PMID: 40990163
Abstract
Graft failure (GF) following hematopoietic stem cell transplantation (HSCT) remains a major complication particularly in the setting of human leukocyte antigen (HLA)-mismatched grafts where residual host lymphocytes can drive immune-mediated rejection. While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.
Keywords: GF; GLP1R; HSCT; rejection.
Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer’s Disease.
Bledsoe X, Wang TC, Wu Y, Archer D, Chen HH, Naj A, Bush WS, Hohman TJ, Dumitrescu L, Below JE, Gamazon ER.
medRxiv [Preprint]. 2025 Sep 19:2025.09.18.25336095. doi: 10.1101/2025.09.18.25336095.
PMID: 41001458 Free PMC article. Preprint.
Abstract
Introduction: Neuroimaging genetics have advanced Alzheimer’s disease (AD) research, yet frameworks mechanistically connecting genes to neurological outcomes via functional genomics are needed to elucidate genetic associations. To address this challenge, we assessed relationships between AD-associated variants and disease via their impact on gene expression and neuroimaging phenotypes.
Methods: We mapped established AD genes to neuroimaging traits using NeuroimaGene atlas and predicted transcript-driven AD neurological features by comparing gene-derived neuroimaging features to clinical neuroimaging data. Genetic correlation and covariance analyses characterized shared genetic architecture between AD endophenotypes and neuroimaging features and identified neuroimaging features associated with dementia family history.
Results: Our analyses implicate PSMC3 expression as a strong contributor to AD pathophysiology and indicate AD endophenotypes, including dementia family history, linked to frontal cortex thickness, volume, and cerebrospinal fluid volume changes.
Discussion: Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.
Keywords: Alzheimer’s Disease; NeuroimaGene; dementia family history; genetic correlation and covariance; neuroimaging-derived phenotypes; transcriptome-wide association studies.
Trsp is required by regulatory T cells to prevent lethal autoimmunity in mice.
Jacobse J, Pilat JM, Harris AB, Kwag A, Aziz Z, Chi C, Schaefer S, Neely MD, Buendia MA, Pahnke A, Williams CS, Deng W, Washington MK, Rathmell JC, Flynn CR, Rings EHHM, Short SP, Prabhu KS, Samsom JN, Goettel JA, Choksi YA.
bioRxiv [Preprint]. 2025 Sep 15:2025.09.09.675163. doi: 10.1101/2025.09.09.675163.
PMID: 41000784 Free PMC article. Preprint.
Sensitivity of quantitative diffusion MRI tractography and microstructure to anisotropic spatial sampling.
McMaster EM, Newlin NR, Cho C, Rudravaram G, Saunders AM, Krishnan AR, Remedios LW, Kim ME, Xu H, Schilling KG, Rheault F, Cutting LE, Landman BA.
Magn Reson Imaging. 2025 Oct 6;124:110539. doi: 10.1016/j.mri.2025.110539. Online ahead of print.
PMID: 41057117 Free article.
Community-Engaged Qualitative Study on Supporting Transgender and Gender-Diverse Standardized Patients in Medical Simulation.
Allon S, Kittleson A, Heifner P, Schlundt D, Bonnet K, Banerjee A, Terndrup C.
J Gen Intern Med. 2025 Sep;40(13):3137-3145. doi: 10.1007/s11606-025-09640-1. Epub 2025 Jun 24.
PMID: 40555902 Free PMC article.
Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women’s Health Initiative Memory Study.
Jakubek YA, Smith AP, Leng XI, Hall ME, Ezzat D, Pershad Y, Collins JM, Uddin MM, Fardo DW, Natarajan P, Bick AG, Kitzman JO, Honigberg MC, Hayden KM, Manson JE, Jaiswal S, Whitsel EA, Reiner AP.
Alzheimers Dement. 2025 Oct;21(10):e70737. doi: 10.1002/alz.70737.
PMID: 41025350 Free PMC article.
Interleukin-17 receptor-A signalling: atheroprotective role in JAK2 clonal haematopoiesis.
Zhao K, Hsu CC, Pershad Y, Vlasschaert C, Corty RW, Wang N, Heimlich JB, Tall AR, Bick AG.
Eur Heart J. 2025 Sep 23:ehaf737. doi: 10.1093/eurheartj/ehaf737. Online ahead of print.
PMID: 40986427 No abstract available.
Reanimation-less Rapid Recovery of a Donor Heart After Circulatory Death With Prolonged 8-Hour Ischemic Time.
Williams AM, Ahmad A, McGann K, Wang CC, Bommareddi S, Lima B, Petrovic M, Quintana E, Absi T, DeVries SA, Lowman J, Bacchetta M, Schlendorf K, Shah AS, Trahanas JM.
J Heart Lung Transplant. 2025 Sep 20:S1053-2498(25)02276-4. doi: 10.1016/j.healun.2025.09.009. Online ahead of print.
PMID: 40983135
Bacteriology of non-oncologic post-operative breast infections: A retrospective cross-sectional study to guide empiric antibiotic coverage.
Abbott EN, James AJ, Kalmar CL, Reddy AP, Chaker SC, Torres-Guzman RA, Cornely RM, Gutama B, Savitz BL, Alter N, Perdikis G, Lineaweaver WC.
J Plast Reconstr Aesthet Surg. 2025 Aug 22;110:27-34. doi: 10.1016/j.bjps.2025.08.021. Online ahead of print.
PMID: 41038037 Free article.
When a mosquito ingests blood, the phagocytic activity of hemocytes increases with warmer environmental temperature and aging.
Barr JS, Saksena SR, Callahan-Muller A, Simpson E, Hillyer JF.
J Invertebr Pathol. 2025 Sep 20;214:108459. doi: 10.1016/j.jip.2025.108459. Online ahead of print.
PMID: 40983202 Free article.
Clinical conditions associated with a high antinuclear antibody titer in individuals without autoimmune disease.
Chung M, Shelley JP, Karakoc G, Still J, Ruan X, Mosley J, Stein CM, Kawai VK.
Arthritis Care Res (Hoboken). 2025 Oct 15. doi: 10.1002/acr.25682. Online ahead of print.
PMID: 41089072