Citations

ABSTRACT Truncating mutations in the tumor suppressor STAG2 , which encodes a component of the cohesin complex, are prevalent across diverse human cancers. Here, we report that acute reconstitution of physiological STAG2 levels in STAG2 -mutant human glioblastoma multiforme cancer cells triggers a rapid reduction in the size of chromatin loops genome-wide. Despite this global change in chromatin loop size, early transcriptional responses to STAG2 restoration are limited to a small number of genes, most of which are induced by STAG2 reconstitution. Notably, the growth-suppressor EFEMP1 (Fibulin-3), a secreted glycoprotein that functions as an extracellular matrix-associated inhibitor of glioblastoma growth and invasion, was the only gene consistently induced across all experimental models. The most robust and conserved STAG2-induced genes all reside within intense chromatin loops whose anchors and overall intensity did not appear to change in response to STAG2 reconstitution. These findings suggest that inactivating mutations of STAG2 promote neoplastic transformation by alleviating a restriction on chromatin loop size, allowing for an expanded range of chromatin interactions that disrupts the maintenance of a tumor-suppressive transcriptome.

e24182 Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a clinically significant complication of anticancer treatments, including anthracyclines and trastuzumab, often necessitating dose reduction or discontinuation of potentially life-saving therapy. While angiotensin receptor-neprilysin inhibitors (ARNI) have demonstrated mortality and hospitalization benefits in heart failure with reduced ejection fraction, their efficacy in preventing chemotherapy-induced cardiotoxicity remains controversial due to conflicting results and a lack of large-scale data. Therefore, we performed a meta-analysis to evaluate the efficacy of ARNI for the prevention of cardiotoxicity in patients receiving chemotherapy. Methods: We searched PubMed, Embase, and Cochrane Central from intercept till 17 December 2025 for studies evaluating the benefit of ARNI in preventing CTRCD among patients undergoing cardiotoxic cancer therapy. The primary outcomes assessed were changes in left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), N-terminal pro-brain natriuretic peptide (NT-proBNP), and troponin T. Statistical analysis was performed using Review Manager, and heterogeneity was assessed using the I2 statistic. The study protocol was registered with PROSPERO (CRD420251266270). Results: A total of 442 patients from four RCTs were included, with follow-up periods ranging from 6 to 18 months. The analysis of changes in LVEF showed a trend toward improvement (mean difference 1.18; 95% CI -0.04 to 2.40; p = 0.06), though this did not reach statistical significance. There were no statistically significant differences observed in changes in GLS (mean difference -0.94; 95% CI -2.43 to 0.55; p = 0.14), NT-proBNP (mean difference -0.94; 95% CI -9.57 to 7.70; p = 0.69), or troponin T (mean difference 0.06; 95% CI -1.13 to 1.26; p = 0.92). Conclusions: In conclusion, prophylactic treatment with ARNI in patients undergoing cardiotoxic cancer therapy did not result in statistically significant changes in LVEF, GLS, or cardiac biomarkers (NT-proBNP and troponin T), although a non-significant trend toward preserved LVEF was observed. The lack of statistical significance may be attributable to limited statistical power due to small sample sizes and heterogeneity across cancer therapies. Given the observed trend in LVEF preservation, further adequately powered, large-scale RCTs focusing on specific chemotherapy regimens are needed.

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Abstract Objectives To examine the extent to which heat-related causes of death are recorded in fatal drug overdoses, how these patterns vary across states and over time, and how overdose characteristics differ between deaths with, versus without, heat involvement recorded. Methods Death certificate data for all drug overdose deaths in US residents from 2001 to 2024 (from the National Center for Health Statistics) were analyzed to identify whether a heat-related cause of death was also listed on the death certificate. Joinpoint regression, descriptive statistics, and nonparametric tests were used to examine temporal trends and compare overdose deaths with versus without recorded heat involvement. Results In 2001, fewer than 10 drug overdose deaths with recorded heat involvement were identified, but this number increased to 558 in 2024. From 2013 to 2024, mortality rates increased significantly, with an estimated annual percent change of 30.1 (95% Confidence Interval, 26.5–47.1). The highest mortality rates and numbers of deaths were observed in residents of Arizona and Nevada. American Indian/Alaska Native, Mexican-heritage, and foreign-born populations accounted for larger shares of overdose deaths with, compared to without, heat involvement recorded. A street or highway was more frequently identified as the place of injury in overdose deaths with (18.9%), versus without (2.2%) heat involvement reported. Psychostimulants such as methamphetamine were involved in 85.9% of overdose deaths with, compared to 28.9% without, recorded heat involvement. Conclusions Although representing only a fraction of all overdose deaths, fatal overdoses involving heat exposure have increased markedly over time and disproportionately impact certain states and demographic groups.

Abstract Parkinson’s disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

ABSTRACT Immediate early genes (IEGs) encode master transcription factors, including EGR1 , FOS , JUN , and MYC genes that drive robust transcription in the G1 phase of cell cycle. Our previous studies indicate that topoisomerase IIβ (TOP2B) critically regulates IEG transcription and that the activities of TOP2B are dynamically controlled through post-translational modifications by BRCA1-BARD1 and ERKs. Here, we show that two E2 enzymes, UBCH5b and UBC13/MMS2, differentiate the effects and functions of TOP2B ubiquitination by BRCA1-BARD1. Comprehensive transcriptomics, proteomics, and biochemical and molecular cellular analyses revealed a close relationship between BARD1 and key mitogen-activated protein kinase pathway genes and identified activated ERK2 as a novel kinase that phosphorylates BARD1 at S391, a previously reported mitotic phosphorylation site, whose genetic mutation has been linked to tumorigenesis. Mechanistically, the catalytic activity of ERK2 stimulates TOP2B ubiquitination mediated by BRCA1-BARD1 in complex with UBCH5b and UBC13/MMS2, which controls the binding and function of TOP2B and BARD1 for transcriptional activation at representative IEGs. Taken together, our data propose that there is a functional regulatory circuit involving TOP2B, BARD1, and ERK2, three key transcriptional activators for IEG transcription, in which the gene association and catalytic activity of TOP2B are regulated through E2-differentiated ubiquitination by BRCA1-BARD1 and the phosphorylation of BARD1 by ERK2 for productive transcription.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001 ) demonstrated improved efficacy for lenalidomide plus rituximab (R 2 ) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R 2 or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R 2 versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R 2 versus R-placebo and manageable safety with R 2 were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R 2 as a standard of care for patients with R/R iNHL.

Abstract Background Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). Results The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Mediastinal radiation potentiates aortic stenosis and complicates its treatment. We compared the short and midterm-outcomes with transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) in patients with prior mediastinal radiation. Electronic databases were searched from inception through December 2024. Dichotomous outcomes were pooled as risk ratios (RRs), and continuous outcomes were pooled as mean differences (MDs) with respective 95% confidence intervals (CIs). Six observational studies were identified, including 2458 TAVR patients and 1873 SAVR patients. In the short-term, TAVR was associated with lower rate of mortality (RR: 0.54; 95% CI: 0.34–0.88), atrial fibrillation (RR: 0.31; 95% CI: 0.15–0.65), acute kidney injury (RR: 0.75; 95% CI: 0.59–0.95), bleeding (RR: 0.37, 95% CI: 0.33–0.42), and shorter length of hospital stay (MD: −4.30; 95% CI: −5.45 to −3.15). One-year mortality was comparable between the 2 groups (RR: 1.04; 95% CI: 0.50–2.13). This meta-analysis of observational studies of patients with prior mediastinal radiation demonstrated that TAVR was associated with better short-term outcomes compared to SAVR. While 1-year mortality appeared similar between the 2 interventions, this finding should be interpreted with caution. However, randomized controlled trials are needed to validate these findings.