Citations

Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in type 1 and type 2 diabetes. Although α-cell dysfunction also contributes to disease pathology, α-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas α-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in β-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes. Article Highlights Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.

Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Background Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. β=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. β=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. β=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

Abstract Objective This study was undertaken to examine acute and chronic electroencephalographic (EEG) and seizure characteristics in new onset refractory status epilepticus (NORSE). Methods Multicenter inpatient and follow‐up clinical and EEG data were analyzed using International League Against Epilepsy definitions and American Clinical Neurophysiology Society (ACNS) EEG terminology. Results Forty‐four patients were included from the Yale NORSE/FIRES Biorepository (median age = 29 years, 33 female, 38 cryptogenic). Nine hundred twenty inpatient EEG days were reviewed (median = 13.5 days/patient). Presenting status epilepticus (SE) types included 24 convulsive SE (CSE), five focal–motor (FMSE), and 15 nonconvulsive (NCSE). Of 39 patients with post discharge follow‐up (median = 14.7 months), 61.5% ( n = 24) had seizures and required more antiseizure medications than seizure‐free patients (median = 4 vs. 1, p < .001). Inpatient EEG captured epileptiform discharges in all and periodic discharges in 38 patients. Seizures were captured in 38 patients: 33 electrographic (11 only electrographic) and 27 electroclinical. Total seizure burden ranged 6.5–29 615.0 min (median = 50.7). Seizures fulfilling ACNS EEG criteria for SE were captured in 20 patients; two had CSE and the remainder NCSE with coma, nine of whom also had FMSE. Inpatient seizure days (median = 50.0 vs. 15.5%, p = .004) and seizure burden (median = 42.9 vs. 0 min, p = .009) were higher in the first half of monitored days. Interictal findings were equally present and did not predict postdischarge seizures, whereas electroclinical seizures (90.9% vs. 45.5%, p = .037), seizure burden (median = 116.8 vs. 32.5 min, p = .045), and proportion of seizure days (36.3% vs. 20.0%, p = .037) did. Among 12 patients with follow‐up EEGs (median = 19.6 months post onset), posterior‐dominant rhythm (PDR) returned in nine; five had periodic discharges, and three had seizure captured. Significance Seizures are most commonly convulsive upon presentation and nonconvulsive or clinically subtle throughout the inpatient course in NORSE. Inpatient seizures, but not interictal abnormalities, occur earlier in the inpatient course and presence of electroclinical seizures, seizure burden, and proportion of seizure days but not interictal findings are associated with postdischarge seizures. Although return of PDR reflects neurological recovery, seizure persistence and EEG abnormalities post‐NORSE are common.

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Cardiogenic shock in adults continues to carry a high mortality despite advances in cardiac care, interventions and critical care. A major advancement in cardiogenic shock care came with the advent of temporary mechanical circulatory support including the intra-aortic balloon pump, ventricular assist devices, and venoarterial extracorporeal membrane oxygenation (VA ECMO). VA ECMO is a type of temporary mechanical circulatory support used in selected patients with cardiogenic shock that have failed to be adequately supported by less invasive approaches including vasoactive medications, volume optimization, and other temporary mechanical circulatory support. VA ECMO is resource intensive support strategy that requires expertise and cooperation from multiple specialties. Complications during VA ECMO support are common and include bleeding, acute kidney injury, stroke, mechanical complications during cannulation, hemolysis, and limb ischemia. VA ECMO circuits drain blood from the venous system, oxygenate and remove carbon dioxide, and return it to the arterial system, providing biventricular support. VA ECMO may be deployed peripherally (through femoral or internal jugular veins and returning blood to axillary or femoral arteries), or centrally from the right atrium to the aorta. Vascular access used for peripheral VA ECMO is large and includes arterial cannulas (usually 15 to 19 French), venous cannulas (usually 21 to 25 French), and a distal perfusion catheter (5 to 8 French). VA ECMO causes significant physiologic changes including reduced pulmonary blood flow, an inflammatory response, increases in left ventricular afterload, dual circulation when initiated through most peripheral sites, and coagulopathy. Management considerations for patients supported by VA ECMO are complex for multiple reasons including the differing approaches to the underlying cause of cardiogenic shock (for example, ischemic vs. non ischemic etiologies), patient comorbidities, whether the goal is recovery, heart transplant, or dischargeable ventricular assist device. Weaning from VA ECMO is a complex process with multiple possible approaches, and decannulation is most commonly accomplished through surgical or percutaneous approaches. There is a paucity of literature on VA ECMO and most guidance is based on retrospective data and expert opinion. What follows is an overview of VA ECMO for cardiogenic shock.

Abstract Background: Canine nodal marginal zone lymphoma (MZL) is the second most common histologic diagnosis of diffuse B-cell lymphomas in dogs, but a molecular profile that can distinguish this condition from the more common canine diffuse large B-cell lymphoma (DLBCL) has been elusive. Here, we use single-cell sequencing to define the transcriptomic signatures of canine MZL before and after oncolytic virotherapy followed by traditional chemotherapy. Objective: The aims of this study were to define the canine MZL transcriptome at single cell resolution and to evaluate its changes in the face of selective pressures introduced by therapy. Methods: Longitudinal biopsies and fine needle aspirates were collected from a dog with MZL enrolled in an immunotherapy trial. Peripheral blood B-cells from healthy dogs served as reference controls. Single-cell sequencing was done using the 10x Genomics Chromium GEM X platform (v3.1), and data was aligned to the canFam4_Y genome. Quality control, clustering, and cell annotation were performed using Seurat in R (v4.4.0). Differential gene expression analysis (DGEA) was performed on 500 randomized MZL B-cells and 500 healthy canine B-cells. InferCNV was deployed on the longitudinal MZL samples for prediction of tumor B-cell CNV profiles. Results: When compared to normal peripheral blood B-cells, the tumor cells were characterized by downregulation of quiescence-associated genes, including KLF2. Copy number analysis uncovered loss on canine chromosome 20 (CFA20) encoding KLF2, gain on CFA13, and gains on CFA32 and CFA36. While an anti-viral T-cell response was identified after VSV treatment, the B-cell subpopulations retained stable transcriptomes, with a disappearance of proliferating B-cells after chemotherapy. Conclusion: This is the first report describing the molecular properties of canine MZL at single cell resolution. Clonal diversity was apparent in the tumor, with copy number loss on CFA20, presumably leading to loss of KLF2. The transcriptional features of the tumor cells remained stable even in the face of a T-cell response to an oncolytic virus. Taken together, the results document silencing of KLF2 as a key phenotypic homology between canine and human MZL, supporting the potential for comparative approaches to enhance our understanding of the significance of KLF2 silencing in this disease. Citation Format: Elise Weir, Grace Walker, Jaime F. Modiano, Aaron L. Sarver, Shruthi Naik, Amy Treeful. Reduced KLF2 expression in canine marginal zone lymphoma mirrors human disease [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A043.