Citations

ABSTRACT Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in cancer. We previously demonstrated that re‐expression of the leucine‐rich domain (LRD) of neurofibromin (NF1) suppresses glioblastoma (GBM) invasion and limits microglia/macrophage infiltration into the tumor microenvironment (TME). Given the central role of tumor‐associated microglia/macrophages (TAMs) in GBM progression, we investigated whether NF1‐LRD‐containing EVs (NF1‐LRD‐EVs) could modulate TAM function and remodel the TME. Our results showed that NF1‐LRD‐EVs attenuated microglia and macrophage recruitment in migration assays, consistent with reduced microglia/macrophage recruitment observed in vivo . In parallel, treatment with NF1‐LRD‐EVs enhanced phagocytic activity of both microglia and iPSC‐derived macrophages, accompanied by induction of pro‐inflammatory cytokines TNF‐α, IL‐6, and IL‐1β, and downregulation of immunosuppressive mediators such as Arginase‐1 and IL‐10. Mechanistically, NF1‐LRD‐EVs induced ADAM17‐associated inflammatory signaling, accompanied by NF‐κB activation. Pharmacological inhibition of ADAM17 reduced TNF‐α release and attenuated NF‐κB activation, supporting a role for ADAM17‐dependent signaling in amplifying this inflammatory response. Together, these findings show that NF1‐LRD‐EVs reprogram TAMs toward a pro‐inflammatory phenotype and modulate the GBM immune microenvironment. These results provide a framework for understanding NF1‐LRD‐EV‐mediated immune regulation and support further investigation of EV‐mediated immune modulation of the TME.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Background and Objectives: The Middle East and North Africa (MENA) region has one of the highest age-standardized diabetes prevalence rates globally, yet all-age, diabetes-specific evidence incorporating GBD 2023 estimates through 2023 remains limited. Materials and Methods: Using Global Burden of Disease (GBD) 2023 estimates for 21 MENA countries from 1990 to 2023, this ecological time-trend analysis quantified 33-year trends in incidence, prevalence, mortality, and disability-adjusted life-years (DALYs); compared pre-2019 and post-2019 trajectories using joinpoint regression; characterized age- and sex-specific burden patterns; and quantified contributions of modifiable risk factors. Results: Age-standardized incidence increased 92%, from 251.7 (95% uncertainty interval [UI]: 231.5 to 272.4) to 482.5 (95% UI: 451.5 to 516.4) per 100,000, and prevalence more than doubled, from 5564 (95% UI: 5088 to 6024) to 11,247 (95% UI: 10,382 to 12,132) per 100,000. In 2023, males exhibited higher DALY rates than females in most adult age groups from age 15 years onward, shifting away from the female-predominant pattern seen in 1990; female rates remained higher at several of the oldest age groups. Children aged 0 to 14 years were the only group with declining DALY rates (−52% to −57%). Post-2019 incidence was higher in 15 of 21 countries, and six countries had higher DALY trends with non-overlapping confidence intervals. Because we only have four to five years of data, these short trends are preliminary and require care when evaluating. High body-mass index was the leading modifiable risk factor. Conclusions: These data support country-specific prevention and chronic-care strategies across the MENA region.

Importance Head and neck cancer (HNC) accounts for nearly 1 million new cases and approximately half a million deaths annually worldwide, representing a substantial global health burden. Despite an overall decline in mortality in many regions, patterns vary across anatomical subsites and countries. Objective To evaluate international and national mortality trends in HNC and its major anatomical subsites from 2001 to 2023. Design, Setting, and Participants This observational epidemiologic study analyzed population-based mortality data from the World Health Organization (WHO) Mortality Database for 73 countries between 2001 and 2023. Data collection was conducted in May 2025, and the data were analyzed between May and October 2025. Eligible countries had medium- to high-quality vital registration data. Age-standardized mortality rates (ASRs) were calculated using the new WHO World Standard Population. Country-specific trends from 2010 to 2023 were assessed using joinpoint regression among countries with at least 7 years of available data. Main Outcomes and Measures ASRs and average annual percentage change in HNC mortality overall and by anatomical subsite using population-based analysis. Results From 2001 to 2023, 2 000 066 HNC-related deaths (450 657 females; 1 549 409 males) were recorded. Internationally, ASRs decreased by 38.9%, with greater reductions among male individuals than among female individuals. Substantial divergence was observed across subsites: laryngeal cancer mortality decreased markedly (−50.1%), whereas increasing trends in oropharyngeal cancer mortality were observed in many countries in recent years, particularly in high-income countries such as the UK (average annual percentage change, 4.30%) and the US (average annual percentage change, 3.26%). Conclusions and Relevance Results of this study suggest that, although overall HNC-related ASRs have declined internationally, marked variation across subsites and countries persists. The contrasting trends between laryngeal and oropharyngeal cancers underscore the need for subtype-specific prevention strategies and continued global surveillance.

Background/Objectives: Cardiovascular disease (CVD) burden decreased in the North Africa and Middle East (NAME) region between 1990 and 2019. This study used Global Burden of Disease (GBD) 2023 data to examine whether trends in mortality, disability-adjusted life years (DALYs), incidence, and prevalence continued through 2023 across all 21 NAME countries. Methods: We analysed age-standardised CVD mortality, incidence, prevalence, and DALY rates from 1990 to 2023. Joinpoint regression identified changes in temporal trends and calculated the annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results: Age-standardised CVD mortality decreased from 579.6 per 100,000 in 1990 to 358.2 in 2023 (AAPC: −1.42%; 95% CI: −1.48 to −1.35). However, no significant reduction occurred between 2019 and 2023 (APC: −0.33%; 95% CI: −1.37 to 1.75). DALY, incidence, and prevalence rates followed similar patterns, with no significant decline in the final years of this study. Egypt was the only country with a long-term increase in CVD mortality, which accelerated after 2020 (APC: +5.20%; 95% CI: 1.20 to 12.87). High systolic blood pressure, dietary risks, lead exposure, and air pollution were the leading modifiable risk factors. Conclusions: The earlier decline in CVD burden in the NAME region did not clearly continue after 2019. The region is currently off track to meet Sustainable Development Goal 3.4 by 2030. Future progress may depend on improved blood pressure control, lipid management, dietary habits, and environmental risk reduction.

ABSTRACT Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-κB signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

Abstract Background: Immune checkpoint inhibitors (ICIs) have improved survival in non-small-cell lung cancer (NSCLC), yet only a subset of patients benefits, and biomarkers like PD-L1 remain limited. Here, we introduce a deep learning-based pathomics framework that utilizes routine H&E-stained slides to predict therapeutic response and survival outcomes in ICI-treated metastatic NSCLC. Methods: The study included 797 ICI-treated NSCLC patients from MD Anderson, with external validation in 280 patients from Mayo Clinic, Gustave Roussy, and the Phase III ICI-naïve LUSC Lung-MAP S1400I trial receiving nivolumab with or without ipilimumab. Path-IO (Pathology-Driven Immunotherapy Optimization) comprised of four major steps: (1) pathologist-verified tissue classifier segmented WSIs into eight compartments—Background, Bronchi, Immune, Lung, Necrosis, Stroma, Tumor, and Vessel—and was validated on TCGA and CPTAC dataset; (2) a survival prediction module generating patient-level risk scores in the MD Anderson cohort and validated across external datasets; (3) integration of Path-IO risk scores with radiomics and clinical features to improve prognostic accuracy; and (4) biological interpretability analyses correlating Path-IO risk immune contexture from multiplex immunofluorescence and transcriptomic signatures from NanoString profiling. Results: Path-IO effectively stratified patients into high and low-risk groups with significant survival differences. In the MD Anderson cohort, it achieved HR = 2.11 (p < 0.001) and HR = 2.51 (p < 0.001) for OS in the discovery and validation sets, and HR = 2.34 (p < 0.001) and HR = 1.87 (p < 0.001) for PFS, respectively. In the multicenter Phase III Lung-MAP S1400I trial, Path-IO achieved HR = 1.78 (p = 0.016) for OS and HR = 2.76 (p = 0.006) for PFS. In external validation, it predicted outcomes in the Gustave Roussy (OS = 1.97, p = 0.003; PFS = 1.51, p = 0.046) and Mayo Clinic (OS = 2.46, p = 0.007; PFS = 2.45, p = 0.027) cohorts. Path-IO outperformed PD-L1 and remained an independent predictor in multivariate analysis (p < 0.001). It enabled data-driven frontline selection between anti-PD-1 monotherapy and chemo-immunotherapy, offering guidance toward more personalized treatment decisions. Integration with radiomics and clinical features further improved predictive accuracy (OS 0.63→0.75; PFS C-index 0.58→0.70), while high Path-IO risk scores correlated with immune-cold phenotypes identified by multiplex immunofluorescence and NanoString transcriptomics. Conclusions: Path-IO demonstrates that deep learning models rooted in histopathologic architecture can generate interpretable and biologically informed survival predictions in NSCLC treated with ICIs. By integrating pathology, radiology, and clinical data, Path-IO provides complementary predictive value beyond established biomarkers such as PD-L1. Citation Format: Rukhmini Bandyopadhyay, Linghzi Hong, Mihaela Aldea, Shenduo Li, Lodovica Zullo, Frank R. Rojas, Maliazurina B. Saad, Maricel C. Marin, Muhammad Waqas, Jiexin Zhang, Eman Showkatian, Claudio A. Arrechedera, Xiaoyu Han, Yuliya Kitsel, Sherif Ismail, Muhammad Aminu, Bo Zhu, Carol C. Wu, Brett W. Carter, Joe Y Chang, Zhongxing Liao, Maria R. Ghigna, Davide Soldato, Hai T. Tran, Xiuning Le, Tina Cascone, Bingnan Zhang, Haniel A. Araujo, Mehmet Altan, Simon Heeke, David Jaffray, Don L. Gibbons, Ara Vaporciyan, J Jack Lee, Neda Kalhor, Cara Haymaker, Ignacio Wistuba, John V. Heymach, Yanyan Lou, Natalie Vokes, Luisa M. Solis Soto, Jianjun Zhang, Jia Wu. Path-IO: A deep learning pathomics framework for personalized immunotherapy selection and outcome prediction in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4003.

Background/Objectives: Racial/ethnic and regional disparities in neoplasm-related mortality remain a significant public health challenge. In this study, we aimed to evaluate long-term trends in county-level neoplasm-related mortality rates by race/ethnicity in the United States and examine associations with social determinants of health. Methods: We conducted a cross-sectional ecological study using population-based data from the Global Burden of Disease Study, including individuals residing in 50 states of the United States and the District of Columbia from 2000 to 2019. We analyzed age-standardized neoplasm-related mortality rates by ethnicity/race. Joinpoint regression analysis was used to identify significant changes in mortality trends, summarized as average annual percentage change. County-level correlations between mortality and key social determinants of health were also assessed. Results: Neoplasm-related mortality rates declined across all racial/ethnic groups from 2000 to 2019; however, disparities persisted. The age-standardized neoplasm-related mortality rates per 100,000 population decreased in all racial/ethnic subgroups. The average annual percentage change ranged from −0.94% (Hispanic and non-Hispanic American Indian or Alaska Native) to −1.90% (Black). Sex-specific analyses revealed similar trends. Southeastern states experienced slower declines than Northeastern states did. County-level smoking and poverty rates were positively correlated, whereas the primary care physician-to-population ratio, excessive alcohol consumption rate, mammography screening rate, and median household income were inversely correlated with neoplasm-related mortality rate, varying by race/ethnicity. Conclusions: Targeted, community-specific interventions are required to reduce inequities in cancer outcomes.

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.

Introduction Inhalation of organic dust from concentrated animal production operations induces inflammation in the brain and respiratory tract. We investigated the role of the potassium channel Kv1.3 in models of organic dust (OD)-induced neuroinflammation. Kv1.3 channels play multifaceted roles in microglial immune modulation, cancer, and neurodegenerative diseases, and represent a potential therapeutic target. Methods We used in vivo (C57BL/6 mice), in vitro (microglial cell line, and primary microglia), and ex vivo (brain slice culture) models of OD-induced neuroinflammation. Sterile OD extract (ODE) was prepared, and mice were exposed to either normal saline or ODE intranasally for 5 weeks (5 days/week) to simulate an occupational exposure scenario. Primary microglia were isolated from neonatal mice for total RNA sequencing (RNA-seq). Results The ODE-induced expression of Kv1.3 was quantified using in vitro and ex vivo models with and without PAP-1 treatment. Exposure-induced changes in cytokines and markers of reactive species were measured. Using western blot, we quantified phosphorylated p38 MAPK (p-p38 MAPK) and NOX2. We measured microglial Kv1.3 currents using whole-cell patch-clamp. Exposure to ODE increased the expression of Kv1.3 and p-p38 MAPK in mouse microglia without affecting the Kv1.3 currents at the cell surface. Exposure increased the levels of inflammatory cytokines and NOX2. Kv1.3 inhibition with PAP-1 decreased inflammatory markers (TNF-α in BV2 microglia and IL-6 in Brain slice cultures and BV2 microglia), levels of Kv1.3, p-p38 MAPK, NOX2, and nitrites. Conclusion Our study revealed that pharmacological inhibition of Kv1.3 potassium channels reduces ODE-induced neuroinflammation by decreasing inflammatory and oxidative stress markers.