Citations

Introduction/Objective: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PI3K inhibition may enhance anti-tumor immune activity. Methods: RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS–STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile. Results: The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p<0.006). Triple therapy with the PIM kinase inhibitor PIM447, anti-PD-1, and RT nearly tripled the median survival compared to PIM447 monotherapy (82 days vs 29 days, p=0.002). Mass cytometry analysis revealed that the combination of anti-PD-1 and RT reduced myeloid-derived suppressor cells and tissue-associated macrophages and enhanced CD8+ T-cell infiltration. Discussion: Although prostate cancer is an immunocold entity, RT can trigger immune activation, consistent with engagement of the cGAS–STING signaling pathway (cytosolic dsDNA serving as a surrogate upstream marker). In triple therapy, RT can enhance the efficacy of ICI and PI3K-targeted drug therapy, significantly improving overall survival in a mouse model of CRPC. Conclusions: A combination of RT, ICIs, and PIM kinase inhibition may help overcome immune resistance in prostate cancer. This combination therapy approach supports further preclinical validation and careful clinical evaluation and warrants further clinical investigation to optimize treatment strategies for CRPC.

ABSTRACT HLA‐B*47:14 is characterised by a single nucleotide substitution in codon 97 of exon 3.

Arteriovenous fistulas (AVFs) are the preferred method for establishing long-term vascular access in patients undergoing hemodialysis; however, high-flow AVFs may increase cardiovascular strain after kidney transplantation, often necessitating fistula closure. Currently, no established guideline exists for managing high-flow fistulas in post-transplant patients with stable kidney function, and available studies report heterogeneous results with small sample sizes and different methodologies. We performed a systematic search of PubMed, Cochrane, and Embase up to December 2024 for observational studies and randomized controlled trials comparing AVF ligation versus maintenance in patients with end-stage kidney disease. The meta-analysis was conducted using Cochrane’s RevMan software using mean difference (MD) and 95% confidence interval. Twelve studies including 844 patients were analyzed, of whom 409 (48%) underwent AVF ligation, with follow-up ranging from 3 to 62.5 months. AVF ligation was associated with a significant reduction in left ventricular mass index (MD −10.92 g/m 2 ; 95% confidence interval −17.84 to −3.99; p = 0.007) and cardiac index (MD −0.56 L/min/m 2 ; 95% confidence interval −1.05 to −0.07; p = 0.03), indicating attenuation of the hyperdynamic circulatory state related to a persistent AVF. No significant differences were observed in left ventricular ejection fraction or blood pressure parameters. Serum creatinine levels were modestly reduced following AVF ligation (MD −0.12 mg/dL; 95% confidence interval −0.22 to −0.03; p = 0.02), while estimated glomerular filtration rate remained unchanged. Overall, AVF ligation was associated with favorable cardiac remodeling reflected by reductions in left ventricular mass and cardiac output, with supportive changes in secondary echocardiographic parameters and no apparent deterioration in renal function.

Objective: To evaluate the effectiveness of a standardized hazardous medication surveillance program and identify occupational factors associated with adverse health outcomes among healthcare workers (HCWs). Methods: We analyzed data from 2,625 HCWs enrolled in a multi-site surveillance program (2020–2022). Participants completed a standardized questionnaire and underwent complete blood count testing. Exposure was categorized by weekly time handling hazardous medications. Associations were evaluated using univariate and multivariable analyses. Results: Higher exposure (>8 hours/week) was associated with increased symptom reporting, hazardous medication spills, and adverse reproductive outcomes. Female sex, older age, and spill exposure independently predicted symptom reporting and reproductive outcomes. No significant association was observed between exposure intensity and abnormal blood counts. Conclusion: Questionnaire-based surveillance effectively identified exposure-related health risks, whereas routine complete blood count testing showed limited utility.

Background Carotid artery calcification represents a common feature of atherosclerotic plaques. However, the geometric relationships of calcific clusters have not been systematically investigated. This study aimed to develop a geometry-based atlas, independent of symptom status, characterizing the three-dimensional properties of calcium clusters within carotid plaques and quantifying population-level distributions and data-driven couplings between size, shape, and density. Methods Standardized three-dimensional calcium masks of clinical CT scans were analyzed using connected-component labeling. Extracted features included cluster volume, aspect ratio, eccentricity, compactness, and CT attenuation values (mean μ, standard deviation σ). Associations between cluster features were assessed using Spearman correlations with Benjamini–Hochberg false discovery rate correction. Independent associations were determined using partial Spearman correlation and restricted cubic spline regression. Results Among 107 plaques, 149 distinct clusters were identified, most frequently presenting as a single elongated cluster (aspect ratio = 2.23). Independent associations (all p < 0.001) were identified for: eccentricity with μ (ρ = −0.39), volume with μ (ρ = 0.47), compactness with μ (ρ = 0.39), and volume with eccentricity (ρ = 0.82). Multi-cluster plaques exhibited smaller mean cluster volume (76.1 vs 359.5 mm 3 ; p < 0.001) and lower eccentricity (0.5 vs 1.6; p < 0.001) compared with single-cluster plaques. Conclusion Carotid calcification most frequently manifests as a single elongated cluster, with robust couplings between cluster size, shape, and density. These geometric archetypes provide a quantifiable framework for future biomechanical and biological studies of plaque vulnerability.

Abstract Neurosurgical and neuromodulation therapies such as deep brain stimulation (DBS) require millimeter-level accuracy to effectively target functional brain regions. Yet, many neuroanatomical boundaries remain invisible to current imaging and electrophysiology methods, limiting precision and contributing to suboptimal patient outcomes. Here, we introduce a self-supervised artificial intelligence (AI) framework that learns to delineate functional subregions directly from the spectral content of intraoperative local field potential (LFP) recordings, without the need for predefined biomarkers or anatomical labels. The framework identifies physiologic structure across the full spectrum of the signal and, through explainable AI (XAI), reveals the specific frequency components underlying these distinctions. Validated in the subthalamic nucleus (STN), the model aligned with clinically defined borders and rediscovered known beta oscillations. Applied to the motor thalamus in tremor patients, it consistently identified functional transitions corresponding to the ventral oralis posterior (Vop) and ventral intermediate (Vim) nuclei—regions where conventional methods fail to provide reliable boundaries. To assess clinical relevance, physiologically defined clusters were functionally evaluated using monopolar review data at their first DBS clinic postoperative visit, demonstrating distinct stimulation-response profiles across clusters and linking electrophysiologic segmentation to clinically meaningful programming outcomes. These findings demonstrate that intraoperative LFP recordings can be transformed into both a real-time guidance resource and a data-driven platform for biomarker discovery, establishing a foundation for more precise, individualized neuromodulation therapies and advancing our understanding of functional brain organization.

Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (COX)-2 (gene name, Ptgs2 ). Eosinophil-specific deletion of COX-2 (Ptgs2 fl/fl eoCre +/− ) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE 2 ) signaling. Consistently, Ptgs2 fl/fl eoCre +/− mice exhibited reduced colonic PGE 2 levels, while PGE 2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE 2 as a critical regulator of IL-22 production during colitis, uncovering a eosinophil–ILC3 cross talk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.