A two–year longitudinal investigation of insula subregional cortical thickness and surface area in early psychosis.
Kittleson AR, Woodward ND, McHugo M, Liu J, Vandekar SN, Armstrong K, Rogers B, Heckers S, Sheffield JM.
Schizophr Res. 2025 Aug 21;284:204-213. doi: 10.1016/j.schres.2025.08.007. Online ahead of print.
PMID: 40845555 Free article.
Abstract
Background: Smaller insula volume is consistently observed in psychotic disorders; however, alterations in associated cortical features-thickness and surface area-are less clear. We examined insula thickness and surface area changes in early psychosis to determine whether alterations were a) present in the early stages of psychosis, b) specific to any of the insula’s three cytoarchitectural subregions (agranular, dysgranular, and granular) and c) related to behaviors impacted in psychosis.
Methods: 63 non-affective early psychosis (EP) and 59 healthy comparison (HC) participants completed 2-4 study visits over two years. Cortical thickness and surface area was quantified via T1 MRI and segmented into three anatomic subregions: anterior (agranular), middle (dysgranular), and posterior (granular). Perceptual aberrations, cognition, and psychotic symptoms were measured; group differences and longitudinal changes were tested using linear mixed models.
Results: EP participants had lower cortical thickness in all insula subregions and thickness declined at a normative rate, compared to HC participants. Insula surface area, on the other hand, was intact in EP and also showed a normative pattern of decline over two years. No significant associations were observed between structural metrics and clinical phenotypes.
Conclusions: In early psychosis, insula cortical thickness, but not surface area, is disrupted, and demonstrates normative changes over two years. This pattern is observed for all insula subregions. These data suggest that cortical thickness of the insula is structurally impacted in schizophrenia-spectrum disorders and may be the result of abnormal neurodevelopment occurring prior to illness onset.
Keywords: Cortical thickness; Early psychosis; Insula; Longitudinal; Perceptual aberrations; Schizophrenia; Structural neuroimaging; Surface area.
Clonal hematopoiesis of indeterminate potential influences breast cancer outcomes in a genotype-specific manner.
Reed SC, Potts CR, Luo L, Davidson BA, Bergman RE, Kemp JDJ, Fox EK, Thomas BA, Ha L, Arora V, Cartailler J, Sanders ME, Sanchez V, Gonzalez-Ericsson P, Croessmann S, Hurley PJ, Bick A, Ferrell PB, Park BH.
Clin Cancer Res. 2025 Sep 19. doi: 10.1158/1078-0432.CCR-25-2009. Online ahead of print.
PMID: 40970771
Abstract
Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with adverse outcomes in some solid tumor settings, but its impact on breast cancer remains unclear. We sought to investigate the genotype-specific effects of CHIP on breast cancer outcomes and the tumor microenvironment.
Experimental design: We examined a retrospective cohort of 125 patients with breast cancer, using targeted sequencing to identify CHIP. Metastatic events were recorded, and distant metastasis-free survival probability was analyzed. In parallel, we developed chimeric mouse models of the two most mutated CHIP genes, DNMT3A and TET2. CHIP and control mice were orthotopically injected with syngeneic breast cancer cells. Tumor growth was measured, and immune infiltrate was profiled via mass cytometry.
Results: CHIP was present in 18.4% of patients. High-burden CHIP and non-DNMT3A CHIP were associated with significantly shorter distant metastasis-free survival. In vivo, mice with Tet2-CHIP developed larger primary tumors and were more likely to experience lung metastasis, while Dnmt3a-CHIP did not differ from controls. The general immune subsets observed in both CHIP models were similar, but immunophenotyping revealed clonal expansion and immune cell subset skewing specific to the Tet2-CHIP model.
Conclusions: Our findings demonstrate a genotype-specific impact of CHIP on breast cancer across human and mouse data. Further, the chimeric mouse models we generated offer a clinically relevant tool to study solid tumors in a CHIP background. This work underscores the need for further functional studies and personalized risk assessment to clearly define the impact of various CHIP genotypes on breast cancer.
BCL6 in T cells promotes type 1 diabetes by redirecting fates of insulin-autoreactive B lymphocytes.
Clark LM, McAninch JC, McNitt DH, Padgett ML, Jenkins TW, Bass LE, Nichols CM, Rathmell JC, Bonami RH.
bioRxiv [Preprint]. 2025 Aug 28:2025.08.25.671997. doi: 10.1101/2025.08.25.671997.
PMID: 40909612 Free PMC article. Preprint.
Abstract
Currently approved type 1 diabetes (T1D) immunotherapies broadly target T cells and delay but do not fully prevent diabetes development, highlighting the need for more selective targets. Anti-insulin germinal center B cells are uniquely able to present pathogenic insulin epitopes and drive anti-insulin T cells to adopt a T follicular helper fate. T cell expression of BCL6, a key transcriptional repressor in the germinal center response, is essential for spontaneous diabetes in non-obese diabetic (NOD) mice. However, the impact of T cells on pro-pathogenic anti-insulin B cell activity is still poorly understood. Here, we show that VH125SD.NOD mice with T cell loss of BCL6 still produce peripheral anti-insulin B cells yet are protected against diabetes (relative to Bcl6-sufficient controls). This protection was associated with reduced activation, proliferation, germinal center differentiation, and pancreatic infiltration of insulin-binding B cells. Minimally supervised analysis revealed insulin-binding B cells skew towards atypical memory B cell subsets specifically in pancreas and pancreatic lymph nodes, which was reduced by Bcl6 ΔCD4 loss. Overall, this work suggests BCL6-expressing T cells are pivotal to license pathogenic insulin-binding B cells. Our findings support BCL6 inhibition as a promising T1D immunotherapy, even after insulin autoimmunity is established in the B cell repertoire.
Unmasking Pathogen Traits for Chronic Colonization in Neurogenic Bladder Patients.
Reasoner SA, Frainey BT, Hale OF, Borden A, Graham MK, Turner E, Brenes LR, Soderstrom CBW, Green H, Schmitz JE, Laub MT, Kelly MS, Clayton DB, Hadjifrangiskou M.
bioRxiv [Preprint]. 2025 Aug 14:2025.08.14.669717. doi: 10.1101/2025.08.14.669717.
PMID: 40832318 Free PMC article. Preprint.
Abstract
Individuals with neurogenic bladder are particularly susceptible to both chronic bacterial colonization of the bladder and urinary tract infections (UTIs). Neurogenic bladder can arise from a variety of diseases such as diabetes, spinal cord injuries, and spina bifida. To study the ecological and evolutionary dynamics of the microbiome in neurogenic bladder, we developed a longitudinal cohort of 77 children and young adults with spina bifida from two medical centers. We used enhanced urine culture, 16S rRNA sequencing, and whole genome sequencing to characterize the microbial composition of urine and fecal samples. In addition to prospective sample collection, we retrieved prior bacterial isolates from enrolled patients from Vanderbilt’s clinical microbial biobank, MicroVU. This allowed us to compare bacterial isolates from the same patients over a period of five years. Urine samples were characterized by high abundance of urinary pathogens, such as E. coli and Klebsiella. From longitudinal isolates from individual patients, we identified two common patterns of urinary tract colonization. We observed either the rapid cycling of strains and/or species, often following antibiotic treatment, or we observed the persistence of a single strain across timepoints. Neither persistence of a strain nor colonization with a new strain or species was associated with increased antibiotic resistance. Rather, in paired longitudinally collected strains from the same patients, mutations were identified in genes that code for cell envelope components associated with immune or phage evasion. Experimental testing revealed that O-antigen/LPS biosynthesis mutations confer protection from the immune system while altering susceptibility to phage predation, reflecting a fitness trade-off. We argue that this unparalleled cohort offers the opportunity to identify mechanisms of bacterial adaptation to the urinary tract that can be exploited in future therapeutic approaches.
Keywords: Urobiome; bacterial evolution; spina bifida; urinary microbiome; urinary tract infection.
Alumnus
Dr. Sundermann’s recent publication was highlighted in VUMC News here.
Dating Discrepancies on Research Ultrasonography and Risk of Pregnancy Loss in a Prospective Cohort.
Sundermann AC, Jasper EA, Kumar SE, Hartmann KE, Velez Edwards DR.
Obstet Gynecol. 2025 Oct 1;146(4):515-523. doi: 10.1097/AOG.0000000000006031. Epub 2025 Aug 14.
PMID: 40811814 Free PMC article.
Abstract
Objective: To estimate the risk associated with discrepancies between last menstrual period (LMP)-based and ultrasound-based gestational dating and pregnancy loss in a prospective cohort of individuals of normal fertility who underwent standardized early-pregnancy ultrasonography.
Methods: Participants in a community-based, prospective pregnancy cohort were recruited preconceptionally or in early pregnancy. Participants underwent standardized research ultrasonography targeted for the sixth week of gestation. We calculated the magnitude of lag between ultrasound-based age and LMP-based age at the research ultrasonogram. Cox proportional-hazards models were used to estimate the association between this difference and pregnancy loss. To assess for effect modification, analyses were stratified by week of research ultrasonogram, developmental features observed on the ultrasonogram, and menstrual regularity.
Results: Among 4,935 participants, the median difference between LMP-based and ultrasound-based gestational age on the research ultrasonogram was 1 day (interquartile range -1 to 5 days), and 9.3% of pregnancies ended in loss. Risk of pregnancy loss increased exponentially with each additional day ultrasound-based dating lagged LMP-based dating ( P <.001). This association persisted when stratified by week of ultrasonography and was more pronounced among pregnancies with a measurable crown-rump length. Ultrasound-based gestational age lagging LMP-based gestational age by more than 3 days was associated with a fivefold increased risk of pregnancy loss (adjusted hazard ratio [HR] 5.34, 95% CI, 4.37-6.52), and a lag of more than 5 days was associated with a greater than sixfold increased risk (adjusted HR 6.99, 95% CI, 5.78-8.44). These findings persisted when analyses were restricted to individuals with regular cycles and certain LMP dates.
Conclusion: Increasing lag between ultrasound-based dating and LMP-based dating among asymptomatic patients was strongly associated with pregnancy loss risk. This clinically quantifiable measure can inform concern for pregnancy loss before symptom onset among individuals with a certain LMP.
Intravenous lipid-siRNA conjugate mediates gene silencing at the blood-brain barrier and blood-CSF barrier.
Sorets AG, Schwensen KR, Francini N, Kjar A, Lyons S, Park JC, Palmer D, Abdulrahman AM, Cowell RP, Katdare KA, Hoogenboezem EN, Wang A, Ligocki AP, Embalabala RJ, Dani N, Duvall CL, Lippmann ES.
J Control Release. 2025 Sep 11:114226. doi: 10.1016/j.jconrel.2025.114226. Online ahead of print.
PMID: 40945532
Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer.
Hesterberg AB, Wong HY, Jackson J, Antunovic M, Rios BL, Watkins E, Bergman RE, Davidson BA, Ginther SE, Graves D, Nahmias EF, Googel JA, Martin LB, Sanchez V, Gonzalez-Ericsson PI, Sheng Q, Brown BP, Meiler J, Schaffer KR, Gordetsky JB, Park BH, Hurley PJ.
JCI Insight. 2025 Aug 22;10(16):e187151. doi: 10.1172/jci.insight.187151. eCollection 2025 Aug 22.
PMID: 40857406 Free PMC article.
Nanoparticle Delivery of Alu RNA Adjuvants Enhances Vaccine Immunogenicity.
Kwiatkowski AJ, Schulman JA, Pagendarm HM, Pastora LE, Tossberg JT, Zhang R, Chada NC, Woodruff ME, Sheehy TL, Arora K, Karijolich J, Aune TM, Wilson JT.
ACS Appl Mater Interfaces. 2025 Sep 10;17(36):50560-50572. doi: 10.1021/acsami.5c16047. Epub 2025 Aug 28.
PMID: 40878005
Parasagittal dural space and arachnoid granulations morphology in pre-clinical and early clinical multiple sclerosis.
Toubasi A, Hett K, Xu J, Gheen C, Vinarsky T, Cho C, Eaton JE, Shah S, McKnight C, Dortch RD, Donahue MJ, Bagnato F.
Mult Scler. 2025 Sep 10:13524585251364720. doi: 10.1177/13524585251364720. Online ahead of print.
PMID: 40927825 Free article.
Severe Dietary Zinc Deficiency Does Not Significantly Alter Energy Balance in Adult Mice.
Murdoch CC, Weiss A, Enriquez KT, Traina KA, Drury SL, Winn NC, Lantier LL, Skaar EP.
J Nutr Metab. 2025 Aug 25;2025:6911386. doi: 10.1155/jnme/6911386. eCollection 2025.
PMID: 40901282 Free PMC article.
The C–terminal extension of calprotectin mediates zinc chelation and modulates Staphylococcus aureus biomass accumulation.
Perera YR, Enriquez KT, Rodriguez A, Garcia V, Akizuki T, Naretto A, Togashi M, Guillen R, Skaar EP, Chazin WJ.
Protein Sci. 2025 Oct;34(10):e70294. doi: 10.1002/pro.70294.
PMID: 40944454 Free PMC article.
CT CONTRAST PHASE IDENTIFICATION BY PREDICTING THE TEMPORAL ANGLE USING CIRCULAR REGRESSION.
Su D, Van Schaik KD, Remedios LW, Li T, Maldonado F, Sandler KL, Dawant BM, Landman BA.
Proc IEEE Int Symp Biomed Imaging. 2025 Apr;2025:10.1109/isbi60581.2025.10980877. doi: 10.1109/isbi60581.2025.10980877. Epub 2025 May 12.
PMID: 40822980
Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women.
Ezzat D, Uddin MM, Xue L, Pershad Y, Zhang S, Collins JM, Kitzman JO, Jaiswal S, Desai P, Kooperberg C, Bick AG, Natarajan P, Manson JE, Whitsel EA, Reiner AP, Honigberg MC.
J Am Coll Cardiol. 2025 Aug 27:S0735-1097(25)07388-7. doi: 10.1016/j.jacc.2025.07.058. Online ahead of print.
PMID: 40864016 Free article.
Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
McLoughlin MA, Cheloor Kovilakam S, Dunn WG, Gu M, Tobin J, Pershad Y, Williams N, Leongamornlert D, Dawson K, Bond L, Marando L, Wen S, Wilson R, Valenzano G, Symeonidou V, Rak J, Damaskou A, Gozdecka M, Liu X, Barcena C, Nomdedeu J, Costeas P, Dimitriou ID, Fiorillo E, Orrù V, de Almeida JG, McKerrell T, Cullen M, Mohorianu I, Foukaneli T, Warren AJ, Wong C, Follows G, Godfrey AL, Gudgin E, Cucca F, McKinney E, Baxter EJ, Gerstung M, Mitchell J, Wiseman D, Bick AG, Fabre M, Quiros PM, Nangalia J, Kar S, Vassiliou GS.
Nat Genet. 2025 Sep;57(9):2215-2225. doi: 10.1038/s41588-025-02296-x. Epub 2025 Aug 28.
PMID: 40877435 Free PMC article.
Comparison of Cellular and Acellular Perfusate in the Dynamic Organ Storage System Using a Porcine Donation After Circulatory Death Model.
Shishido Y, Tracy KM, Cortelli M, Simon V, Raietparvar K, Adesanya T, Petrovic M, Simonds E, Kumpfbeck A, Woo Y, Petree B, Adjei E, Peters JK, Crannell WC, Demarest CT, Ukita R, Liang J, Rizzarri MD, Montenovo MI, Magliocca JF, Karp SJ, Rauf MA, Bacchetta M.
ASAIO J. 2025 Aug 25. doi: 10.1097/MAT.0000000000002538. Online ahead of print.
PMID: 40853322 No abstract available.
Donor Heart Preservation at 10°C After Thoracoabdominal Normothermic Regional Perfusion Lowers Rates of Severe Primary Graft Dysfunction and Improves Recipient Transplant Outcomes.
Williams AM, Trahanas JM, Ahmad A, Bommareddi S, Lima B, McGann K, Petrovic M, Wang CC, Quintana E, Siddiqi HK, Amancherla K, Brinkley DM, Lindenfeld J, Menachem J, Ooi H, Pedrotty D, Tsai S, Punnoose L, Rali AS, Sacks S, Wigger M, Zalawadiya S, DeVries SA, Lowman J, Keck CD, Scholl SR, Bacchetta M, Schlendorf K, Shah AS.
Am J Transplant. 2025 Aug 27:S1600-6135(25)02941-7. doi: 10.1016/j.ajt.2025.08.027. Online ahead of print.
PMID: 40882843
Safe Practices: Partial Coverage of Left Ventricular Assist Device Reduces Bleeding Risk during Explant-Heart Transplant without Causing Obstruction.
Wang CC, Trahanas J, Petrovic M, Ahmad A, Garcia JD, Ye E, Williams AM, Bommareddi S, Nguyen DQ, Absi T, Tipograf Y, Siddiqi H, Jelly C, Balakrishna A, Schlendorf KH, Shah AS, Lima B.
J Heart Lung Transplant. 2025 Sep 1:S1053-2498(25)02250-8. doi: 10.1016/j.healun.2025.08.020. Online ahead of print.
PMID: 40902959 Free article.
Use of Antibiotic Prophylaxis for Surgical Site Infection Prevention in Nononcologic Breast Surgery: A Scoping Review.
Abbott EN, Lively BG, James AJ, Torres-Guzman RA, Savitz BL, Reddy AP, Cornely RM, Gutama B, Perdikis G, Lineaweaver WC.
Ann Plast Surg. 2025 Sep 1;95(3S Suppl 1):S6-S10. doi: 10.1097/SAP.0000000000004474.
PMID: 40911828
Plasma Proteomic Signatures for Diverticulitis Risk Stratification.
Ueland TE, Shelley JP, Mosley JD, Robinson JR, Gamazon ER, Maguire LH, Peek R, Hawkins AT.
J Surg Res. 2025 Aug 23:S0022-4804(25)00496-2. doi: 10.1016/j.jss.2025.06.093. Online ahead of print.
PMID: 40850905 Free article.
A Trans-Diagnostic Investigation of Attention and Diverse Phenotypes of “Auditory Hyperreactivity” in Autism, ADHD, and the General Population.
Dwyer P, Williams ZJ, Lawson W, Rivera SM.
J Atten Disord. 2025 Sep 18:10870547251361226. doi: 10.1177/10870547251361226. Online ahead of print.
PMID: 40965092 Free article.
Elevated Suicidal Thoughts and Behaviors and Nonsuicidal Self-Injury in Autistic Youth and Adults: A Multinational Study.
Schwartzman JM, McMorris CA, Brown CM, Trollor JN, Uljarević M, Stokes MA, Williams ZJ, Hedley D.
Autism Adulthood. 2025 Mar 13:10.1089/aut.2024.0225. doi: 10.1089/aut.2024.0225. Online ahead of print.
PMID: 40880732
Characterization of neurite and soma organization in the brain and spinal cord with diffusion MRI.
Schilling KG, Palombo M, Witt AA, O’Grady KP, Pizzolato M, Landman BA, Smith SA.
Imaging Neurosci (Camb). 2025 Aug 19;3:IMAG.a.111. doi: 10.1162/IMAG.a.111. eCollection 2025.
PMID: 40843024 Free PMC article.