Citations

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

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.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Introduction Trigeminal neuralgia is a debilitating facial pain condition characterized by recurrent, electric shock-like episodes within the trigeminal nerve distribution. While first-line treatment involves pharmacologic therapy, treatment options are limited for patients who are refractory or poor surgical candidates. Case Presentation We present a 75-year-old female with long-standing idiopathic trigeminal neuralgia refractory to combination anticonvulsant therapy and nerve block, with notable medication-related side effects. Management and Outcomes The patient underwent percutaneous cryoneurolysis targeting the maxillary (V2) and mandibular (V3) divisions of the trigeminal nerve under fluoroscopic guidance. She experienced immediate pain reduction and complete symptom resolution at a one-month follow-up with no complications. Conclusion This case highlights percutaneous cryoneurolysis as a minimally invasive treatment option for selected patients with refractory trigeminal neuralgia who are not candidates for open surgical intervention.

Abstract Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and remains difficult to treat due to the absence of targeted therapies. While recent advances in immunotherapy, particularly with immune checkpoint inhibitors (ICIs), have transformed the treatment landscape for many cancers, response rates to ICIs remain low for TNBC, largely due to tumor-intrinsic immune evasion mechanisms. Objective: We identify and characterize a novel immune evasion pathway in TNBC driven by deregulation of cancer cell-intrinsic protease-activated receptor 1 (PAR1), a thrombin receptor frequently upregulated in aggressive tumors. Methods and Results: Through integrative bioinformatic analyses, genetic perturbations, xenograft models (immunodeficient and immunocompetent), flow cytometry-based tumor immune profiling, and RNA-seq, we demonstrate that PAR1 activation enhances immune evasion in TNBC. Mechanistically, we show that the paracaspase MALT1 acts as a critical downstream effector of PAR1 signaling and promotes immune escape by driving PD-L1 expression in TNBC cells. Functional assays reveal that genetic depletion of MALT1 or PD-L1 increases TNBC cell susceptibility to T cell-mediated cytotoxicity in vitro and significantly suppresses tumor growth in vivo. Notably, through knock-in and rescue experiments using a catalytically inactive MALT1 mutant, we reveal that MALT1’s scaffolding - rather than protease - function is essential for PD-L1 regulation. Immune cell depletion assays further identify CD4+ T cells, CD8+ T cells, and natural killer (NK) cells as key mediators of the anti-tumor immune response suppressed by the PAR1-MALT1 axis. These findings are supported by human TNBC specimen analyses, where MALT1 expression inversely correlates with T cell activation and positively associates with PD-L1 in PAR1-high, but not PAR1-low, tumors. Conclusion: Our study reveals immune evasion as a novel mechanism of PAR1-driven breast cancer pathogenesis, mediated by a PAR1/MALT1/PD-L1 signaling cascade. These findings bridge a critical gap by positioning MALT1 at the interface between tumor-intrinsic signaling and the immune microenvironment - two areas of CARMA-BCL10-MALT1 (CBM) complex research that have largely evolved in parallel over the years. Importantly, targeting MALT1 may enhance immunotherapy efficacy in TNBC. Given the availability of MALT1 inhibitors in clinical development, our work supports combining MALT1 inhibition with ICIs or other immune-oncology agents as a promising strategy to overcome immune resistance in TNBC. Citation Format: Dong Hu, Prasanna Ekambaram, Zheqi Li, Linda Klei, Maria L. Beecher, Yi Liu, Zongyou Cai, John Little, Jeffrey A. Meridew, Jia-Ying Lee, E. Aubrey Thompson, Tullia C. Bruno, Lidija Covic, Seung-Oe Lim, Anushka Dongre, Heide L. Ford, Mien-Chie Hung, Adrian V. Lee, Steffi Oesterreich, Linda McAllister-Lucas, Peter C. Lucas. A cancer cell-intrinsic PAR1/MALT1/PD-L1 signaling pathway drives immune evasion in triple-negative breast 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 7392.

Abstract Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine‐rich glioma inactivated 1 (LGI1)‐antibody encephalitis. This study aims to describe the electrophysiologic mechanism underlying these pathognomonic symptoms. LGI1‐antibody encephalitis patients with active symptoms were enrolled from two separate centers in South Korea and the United States. Patients were evaluated with simultaneous magnetoencephalography (306 channels) and electroencephalography. Regional alterations in neuronal excitability represented by interictal epileptiform discharges were present in the faciobrachial area of the motor cortex, insula, and somatosensory cortex, somatotopically aligned with each of the ictal semiologies observed in patients. FBDS and other LGI1‐antibody encephalitis‐specific spells localized to cortical regions neuroanatomically corresponding to ictal semiologies: the faciobrachial homunculus (FBDS), insular cortex (paroxysmal dizziness spells), and somatosensory cortex (thermal sensory attacks). Our findings support the ictal hypothesis underlying these unique phenomena.

Abstract INTRODUCTION Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy. METHODS Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety‐six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and −, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using 11 C‐ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages. RESULTS TSPO was upregulated in human microglia under AD‐like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions. DISCUSSION These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation. Highlights TSPO expression increases in human microglia under AD‐like inflammation. 11 C‐ER176 PET shows stage‐dependent neuroinflammation across the AD spectrum. Neuroinflammation overlaps with tau and is more widespread in amyloid‐positive individuals. Activity peaks in MCI, stabilizes later, and relates to vascular and neurodegenerative changes.