Citations

ABSTRACT Aims Opioid use disorder remains a major public health crisis in the United States, driven largely by rising overdose deaths from synthetic opioids, such as fentanyl. Emerging population‐level evidence suggests that GLP‐1 receptor agonists (GLP‐1RAs) may reduce overdose risk. However, their underlying molecular mechanisms are not well understood. We investigated the transcriptional effects of fentanyl and GLP‐1RAs using human induced pluripotent stem cell (iPSC)‐derived forebrain organoids and neurons. Methods Organoids were treated with fentanyl, liraglutide, or exenatide, followed by RNA sequencing. We extended these analyses to iPSC‐derived neurons exposed to additional therapeutic candidates, including the anticonvulsants topiramate and gabapentin, and the metabolic modulator β‐hydroxybutyrate. All compounds were tested at clinically relevant concentrations, and transcriptomic and functional genomic assays were performed. Results Across models and drug classes, we identified modulation of endoplasmic reticulum (ER) stress signaling as a shared molecular mechanism. Fentanyl and GLP‐1RAs consistently downregulated ER stress‐related genes, with TRIB3 as the most strongly suppressed target. We further identified CEBPB as a key upstream regulator and confirmed reduced CEBPB DNA‐binding activity in ER stress‐related genes. Conclusion These findings highlight ER stress modulation as a convergent pathway with potential therapeutic relevance for substance use disorders.

ABSTRACT Melanoma in skin of color (SOC), defined as Fitzpatrick skin tones IV‐VI, presents unique epidemiologic, diagnostic, and therapeutic challenges compared to non‐Hispanic White (NHW). Although SOC patients have a lower incidence of melanoma, they experience higher melanoma‐specific fatality rates, which may be attributable to later‐stage diagnoses, differences in the distribution patterns of melanoma subtypes, and systemic barriers to care. SOC patients, particularly non‐Hispanic Black individuals, have a higher proportion of acral lentiginous and mucosal melanomas, which arise in non‐sun‐exposed areas, carry lower mutational burdens, and respond less favorably to immunotherapy and BRAF/MEK‐targeted therapies. These anatomic and biological differences contribute to delayed recognition and reduced treatment efficacy. Concurrently, the rising incidence of melanoma in situ across racial and ethnic groups without corresponding decreases in invasive disease or similarly increased mortality rates raises concern for overdiagnosis. Artificial intelligence‐based diagnostic tools show promise in NHW populations but are limited by the underrepresentation of SOC in training datasets and diminished positive predictive value in low‐prevalence populations. The estimated number needed to screen to prevent one melanoma death in SOC populations ranges from approximately 46,000 to 201,000, underscoring the challenge of melanoma screening in this group. Suggested solutions and improvements include expanding healthcare access through patient navigators, developing culturally tailored education programs focused on identifying early invasive disease, diversifying AI training datasets to include acral and mucosal melanoma, biobanking rare melanoma subtypes, and decentralizing clinical trials into community settings. A multifaceted approach is essential to addressing overdiagnosis and improving melanoma outcomes in the SOC populations. image

ABSTRACT Background Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, chronic cholestatic liver diseases with heterogeneous progression and limited biomarkers of disease biology. Epigenetic age acceleration has been demonstrated in PSC and PBC, suggesting accelerated biological aging. DNA methylation–derived telomere length (DNAmTL) reflects replicative aging and cellular turnover, but its role in PSC and PBC remains unclear. We aimed to evaluate DNAmTL in PSC and PBC and its association with disease severity. Methods We analysed and compared DNAmTL and age‐adjusted DNAmTL among patients with PSC ( n = 474) versus PSC controls ( n = 484) and patients with PBC ( n = 291) versus PBC controls ( n = 291). Associations with clinical outcomes were assessed using nonparametric tests and multivariable logistic regression models. Correlations with primary sclerosing cholangitis Risk Estimate Tool (PREsTO) score and epigenetic age acceleration (AgeAccelGrim) were evaluated using linear regression. Results Patients with PSC demonstrated significantly shorter age‐adjusted DNAmTL compared with controls (median −0.036 vs. 0.016, p < 0.001). Patients with PBC also exhibited reduced DNAmTL relative to controls (median 6.814 vs. 6.885, p < 0.001). Within PSC, shorter DNAmTL was associated with cirrhosis (OR 0.21, 95% CI 0.06–0.69, p = 0.013) and advanced disease (OR 0.20, 95% CI 0.06–0.67, p = 0.009). Shorter DNAmTL was also observed in hepatic decompensation and hepatobiliary malignancy, including cholangiocarcinoma. DNAmTL inversely correlated with PReSTO score ( p < 0.001). DNAmTL was strongly inversely correlated with AgeAccelGrim in both PSC and PBC ( p < 0.001). Conclusion Cholestatic liver diseases are associated with shortened DNAmTL, which independently correlates with disease severity in PSC. Together with epigenetic age acceleration, these findings support a model of accelerated biological aging in PSC and PBC characterized by converging signatures of accelerated biological aging that may contribute to progressive biliary injury and fibrosis.

Introduction Extracranial internal carotid artery (ICA) aneurysms are rare (<1% of arterial aneurysms) yet clinically significant due to risks of distal embolization, local compressive symptoms, and, less commonly, rupture. High-quality evidence is limited, and no consensus guidelines exist, management is therefore individualized to aneurysm morphology, cervical segment involvement, vessel tortuosity, and operator expertise. Flow diversion with Pipeline Embolization Device (PED) achieves aneurysm exclusion while reconstructing the parent artery and is especially useful in tortuous cervical segments. Clinical Summary A 60-year-old woman with incidentally discovered bilateral cervical ICA aneurysms (left 2.3 cm mid-ICA; right 0.5 cm) and a type III bovine arch underwent PED diversion of the lesion. Via femoral access, a long 6-F Fubuki sheath (Asahi Intecc, Irvine, USA) with Sofia catheter (Micro-Vention, Tustin, USA) support and systemic heparinization (ACT >250 s) enabled deployment of a 5.0 × 25 mm Pipeline Flex (Medtronic Neurovascular, Irvine, USA) across the aneurysm neck. Immediate angiography showed intra-aneurysmal stasis while preserving parent-artery flow . At 12 months, she is asymptomatic with a 70% reduction in the contrast-opacified aneurysm component to 7 mm, and the contralateral small aneurysm remains stable. Conclusion Flow diversion with a PED provided an effective, artery-preserving solution for a mid-cervical ICA aneurysm in tortuous anatomy, achieving immediate flow stasis with parent-artery patency. At 12 months, the patient is asymptomatic with a contrast-opacified component reduced to 7 mm. This case supports using flow diversion for extracranial ICA aneurysms when anatomy is favorable, alongside careful antiplatelet therapy and planned imaging follow-up.

Background: Operative decision-making in gastric gastrointestinal stromal tumor (GIST) surgery is strongly influenced by tumor anatomy. Although surgeons routinely consider anatomic features such as proximity to the gastroesophageal junction, posterior wall location, and endophytic growth during operative planning, their combined association with operative strategy has not been systematically evaluated. Methods: We evaluated whether commonly recognized anatomic features of gastric GISTs were associated with operative strategy in a contemporary minimally invasive surgical cohort. Tumors were characterized according to the presence of three predefined anatomic features: proximal location near the gastroesophageal junction, posterior wall involvement, and endophytic growth pattern. Cases were grouped as lower (0–1 features) or higher (2–3 features) complexity. The primary outcome was operative strategy, categorized as simple (wedge resection or enucleation) or complex (partial gastrectomy or transgastric resection). Associations between anatomic complexity and operative approach were evaluated. Results: A total of 83 patients were included, with 50 (60.2%) classified as lower complexity and 33 (39.8%) as higher complexity. Operative strategy varied significantly by complexity group. Tumors in the higher complexity group were more frequently managed with complex operative techniques, including partial gastrectomy and transgastric resection ( P = .002). This association remained significant after adjustment for tumor size (odds ratio 2.87, 95% CI: 1.12–7.65, P = .031). A graded relationship was observed, with increasing use of complex techniques as the number of anatomical features increased. The robotic platform was used more frequently in higher complexity cases ( P = .03). Perioperative outcomes were comparable between groups. Conclusions: Recognized anatomical features of gastric GISTs were associated with operative strategy and reflected real-world surgical decision-making. Systematically describing these features may facilitate preoperative assessment and improve consistency in reporting operative approaches.

This Perspective discusses whether secondary genomic findings in the clinical context of diagnostic genomic sequencing tests should be sought and reported.

Abstract Skeletal muscle is a major determinant of functional status. The impact of advanced prostate cancer (aPC) systemic therapies on body composition is unknown. We identified aPC patients with serial PET-CTs receiving androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPI), chemotherapy, and/or Lutetium-177. An artificial intelligence algorithm quantified body composition changes from PET-CT images. Linear mixed effects models examined body composition changes over time by treatment type. The algorithm examined 2,342 PET-CTs from 468 patients. On multivariable analysis, ADT was associated with a 9% reduction in muscle density (-1.91 Hounsfield units), ARPIs an additional 6% (-1.4 Hounsfield units), and Lutetium-177 a subsequent 6% (-1.3 Hounsfield units), demonstrating progressive reduction in muscle density across later stages of systemic therapy. This large longitudinal analysis of body composition in aPC patients supports the use of an automated PET-CT algorithm to identify aPC patients on systemic therapy at risk for muscle wasting.

Introduction: Mast cells are central effectors of IgE-mediated allergic responses and reside in barrier tissues, where they encounter diverse environmental compounds. How naturally occurring bioactive compounds influence mast cell function under resting versus allergic conditions remains poorly defined. Methods: We compared the effects of cholera toxin, aconitine, and sennoside A on viability, degranulation, and cytokine production in murine bone marrow-derived mast cells. We then examined the acute physiological effects of oral sennoside A in an ovalbumin-induced mouse model of food allergy. Results: None of the compounds reduced mast cell viability at the concentrations tested. Sennoside A, but not cholera toxin or aconitine, induced modest degranulation in resting mast cells without increasing TNF-α or IL-6 secretion. In contrast, sennoside A markedly suppressed IgE-dependent antigen-induced degranulation, TNF-α and IL-6 secretion, and Il1b expression. Acute oral sennoside A induced dose-dependent diarrhea and hypothermia and increased colonic Tnfa, Il1b, Il33, and Hdc expression. In allergic mice, sennoside A attenuated allergen-induced hypothermia, reduced duodenal Tpsab1 expression, and decreased circulating total IgE, OVA-specific IgE, and OVA-specific IgG1, while increasing Il5 expression. Conclusion: Sennoside A differentially regulates mast cell responses according to activation state and attenuates features of experimental food allergy. These findings identify a previously unrecognized immunomodulatory effect of sennoside A on IgE-driven mast cell activation. However, the mechanisms and the contribution of mast cells to the in vivo phenotype remain to be defined.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, yet therapeutic development is limited by experimental models that incompletely recapitulate human physiology, disease heterogeneity, and treatment responses. Emerging human-relevant models, including patient-derived induced pluripotent stem cells, cardiac organoids, engineered tissues, organ-on-chip systems, genome editing, multi-omics, and computational approaches, are improving the ability to investigate cardiovascular disease mechanisms and therapeutic responses. In this review, we critically compare these technologies with respect to physiological relevance, reproducibility, scalability, throughput, and translational potential. We highlight their applications in disease modeling, drug discovery, toxicity assessment, and precision medicine while examining persistent limitations, including cellular immaturity, incomplete vascularization and systemic integration, model variability, and limited clinical validation. We further discuss how integration of bioengineering, genome editing, multi-omics, and computational methods may improve predictive performance. Standardization, interlaboratory validation, regulatory qualification, and prospective benchmarking against human clinical outcomes will be essential for translating these platforms into reliable tools for cardiovascular research and therapeutic development. Collectively, the convergence of stem cell biology, bioengineering, genome editing, multi-omics, and computational approaches is establishing a new generation of human-centered cardiovascular models with the potential to strengthen mechanistic discovery and accelerate the development of more predictive and personalized therapies.