Citations

Background and Aims: Older age increases susceptibility to metabolic dysfunction–associated steatotic liver disease (MASLD), but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. Approach and Results: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use is strongly associated with suppression of senescence-related pathways. Statin use is also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. Conclusions: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.

Abstract Background Electronic health record (EHR)–based prognostic modeling is increasingly used in oncology, yet incorporating pharmacogenomic (PGx) knowledge derived from experimental systems into clinical prediction frameworks remains challenging. This gap is driven by fundamental mismatches between controlled drug–mutation assays and heterogeneous, incomplete real-world clinical data. Methods We propose a representation transfer framework that integrates PGx embeddings learned from large-scale in vitro pharmacogenomic screens into patient-level EHR models. A frozen pharmacogenomic encoder is used to generate interaction-aware embeddings from patient mutation profiles and administered therapies, which are aggregated into a fixed-length PGx Complementarity Representation. These representations are incorporated into multimodal survival prediction models alongside standard clinical features. Performance was evaluated using systematic modality ablation analyses, attribution analyses, and exploratory unsupervised representation analyses. Results Integrating PGx embeddings yielded consistent performance improvements across all evaluated modality combinations. Relative gains were largest in modality-sparse settings, where baseline EHR features encode limited biological context, and were attenuated—but remained significant—in biologically enriched configurations. Attribution analyses indicated that PGx embeddings contributed non-redundant predictive signal beyond standard clinical features. Exploratory unsupervised analyses further demonstrated that the learned representations exhibit interpretable association patterns aligned with known therapeutic exposures and pathway-level associations. Conclusion These findings suggest that externally learned pharmacogenomic representations can be transferred into real-world EHR models as a context-dependent, non-redundant augmentation. By framing PGx knowledge as an interaction-aware representation rather than a mechanistic model, this work provides an informatics framework for integrating experimental pharmacogenomic data into clinical prediction tasks in a reproducible and interpretable manner.

Abstract Background: Although hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are inherited disorders expected to display a 1:1 sex ratio, most studies report a strong female dominance. This study analyzed sex differences in 122 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD using the 2017 criteria. Methods: Self-reported data was obtained from November 1, 2019, to April 25, 2025, ( n =2,451) from an Intake Questionnaire of adult (≤18 years old) patients diagnosed with hEDS or HSD at the EDS Clinic at Mayo Clinic Florida and analyzed by sex. Results: We found that 90.6% ( n =575) of hEDS patients were female and 9.4% ( n =60) were male, with a sex ratio of 9.6:1 female-to-male, while 95.2% ( n =1,728) of HSD patients were female and 4.8% ( n =88) were male, with a sex ratio of 19.6:1 female-to-male. Females were older than males: hEDS 35 vs. 28 years of age ( p <0.001), HSD 34 vs. 31 years of age ( p =0.004). Overall, females self-reported more symptoms/comorbidities than males: hEDS 31/122 (25.4%), HSD 59/122 (48.4%). In contrast, only 5/122 (4.1%) symptoms/comorbidities were self-reported more often in males including attention deficit disorder/attention deficit hyperactivity disorder, delay in developmental milestones, snoring, autism spectrum disorder, and obstructive sleep apnea. Females with HSD had more mast cell-related symptoms (i.e., hives p <0.001) which were reflected in higher mast cell scores than males ( p <0.001). Patients with higher mast cell scores also had higher serum levels of total IgE ( p =0.029). More females with HSD were diagnosed with fibromyalgia ( p <0.001) and reported symptoms associated with autonomic dysfunction than males. Aside from abuse, which was higher in females (hEDS p =0.039, HSD p <0.001), few sex differences were reported for psychological symptoms/comorbidities. In support for the idea that elevated mast cell activity in females may lead to extracellular matrix remodeling that promotes hypermobility, females with hEDS/HSD had greater serum collagen-4α1 ( p <0.0001) and fibronectin ( p =0.015) than males by ELISA. Conclusions: Females with hEDS and HSD report a higher burden of symptoms/comorbidities than males, providing a possible explanation for fewer males being reported in demographic data. Sex differences in symptoms/comorbidities may reflect sex differences in pathogenic drivers of disease.

Abstract Deep learning models enable the prediction of clinical endpoints from whole-slide images (WSIs), but many such models function as “black boxes”, lacking transparency about whether and which histomorphological patterns drive their predictions, hindering interpretability and clinical adoption. Here we propose a human-in-the-loop explanation framework, MorphoXAI, which provides both local and global interpretability for deep learning models by incorporating human-expert interpretations. At the global level, it reveals the histomorphological patterns on which the model consistently relies to distinguish between classes of WSIs, as well as the patterns associated with confusion between classes. At the local level, it indicates which of these patterns are used in the prediction of an individual WSI and which regions within the slide correspond to such patterns. We validated our method on a deep learning model trained for ovarian tumor histologic subtype prediction. The results show that our framework generates explanations that accurately reflect the histomorphology underlying the model’s predictions at both global and local levels. For interpretability and clinical utility in diagnostic contexts, human evaluation results showed that our explanations were easy to interpret, rich in diagnostic features, and directly helpful for diagnostic decision-making, thereby enhancing pathologist-AI collaboration. Our work highlights that unifying global and local explanations and grounding them in expert-interpreted morphology enhances the interpretability and verifiability of deep learning models, thereby facilitating the transparent deployment of such models in clinical practice.

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Objective: To assess the link between retinal vascular health and cognitive performance in a diverse population, using a novel mobile laboratory platform and portable color fundus photography. Background: The retina is an accessible window into brain health. Studies that had highlighted the link between retinal vasculature and cognition included clinical populations or narrowly defined research cohorts, with limited generalizability. To address the need to expand this research to demographic and geographic diverse communities, we launched a mobile laboratory platform across rural and urban Arizona zip codes. Methods: 240 subjects were recruited in our prospective community-based study. We assessed cognition using the MindCrowd web-based testing platform and analyzed verbal paired associates (VPA) task, a validated measure of verbal associative memory sensitive to age-related cognitive decline. Non-mydriatic color fundus photographs were obtained using the portable hand-held Aurora camera (Optomed), two images per eye (disc- and macula-centered). Image processing and vascular feature quantification were automatically conducted using Automorph software. Linear regression models examined the associations between retinal vascular metrics and VPA, adjusting for age, sex, education attainment, and risk factors. Results: Our cohort’s mean age was 45 +/-16.7 years, 32.9% were male and 39.5% had a college degree. In disc-centered fundus images, fractal dimension strongly associated with chronological age (p = 1.04E-10). Greater artery tortuosity in the retinal zones B and C was associated with lower VPA (p = 0.02 and p = 0.004, respectively). In macula-centered images, fractal dimension showed the strongest association with age (p = 4.31E-11), reinforcing its utility as a robust biomarker of vascular aging. Males had wider average artery caliber in zone B (p=0.02). Zone B vein fractal dimension (p=0.002) and vein vessel density (p=0.006) were the strongest predictors of VPA. Conclusions: This study demonstrates the safety, feasibility, and utility of a mobile laboratory to collect high-quality non-mydriatic color photos and cognitive data across a geographically diverse cohort. Arterial tortuosity and venous fractal dimension and density, particularly in retinal zone B, were predictive of cognitive performance, after adjusting for vascular health covariates. Retina may become a scalable and accessible platform for studying brain aging in the general population.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

BACKGROUND: TRPC6 (transient receptor potential canonical 6) channels, encoded by the TRPC6 gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca 2 + homeostasis. Variants in TRPC6 are associated with chemotherapy-related cardiomyopathy. Specifically, the TRPC6 A404V polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored. METHODS: Using patch-clamp recordings, Ca 2 + imaging, computational analysis, and molecular biology techniques, we assessed the effects of doxorubicin and its metabolite, doxorubicinol, on regulating TRPC6 alanine (A) at position 404 replaced by valine (V; A404V) channel expression and function in a heterologous expression system and native cardiac cells. RESULTS: Both additive and recessive models demonstrated a significant association between the TRPC6 A404V variant and doxorubicin-related cardiomyopathy. The TRPC6 A404V channel exhibited higher membrane expression levels compared with the wild type (WT) control. Patch-clamp recordings showed that both TRPC6 WT and A404V channels remained mostly inactive at baseline. Application of 50 μmol/L 1-oleoyl acetyl-sn-glycerol (OAG), a TRPC6 activator, significantly increased the inward- and outward-current densities of WT and A404V channels. Furthermore, a 24-hour treatment with 0.5 μmol/L doxorubicin enhanced TRPC6 mRNA expression and potentiated the OAG effects on both WT and A404V channels, with a more pronounced response in A404V channels. Treatment with 0.5 μmol/L doxorubicinol had no effect on OAG-induced current densities in either WT or A404V channels. Doxorubicin effects on intracellular Ca 2 + levels were confirmed by Ca 2 + imaging in native cardiac cells. Computational modeling revealed that the A404V mutation induces a conformational change in the OAG-binding pocket, enhancing its interaction with OAG in the A404V protein compared with the WT control. CONCLUSIONS: The TRPC6 A404V is a gain-of-function variant that exhibits enhanced activity in the presence of doxorubicin. Therefore, the TRPC6 A404V variant represents a risk factor for anthracycline-induced cardiotoxicity in patients with cancer.

BACKGROUND: The Commission on Cancer (CoC) implemented 6 operative standards to reduce technical variation in cancer surgery. Although designed to guide surgeons in performing key oncologic techniques, these standards also provide a framework for teaching high-quality cancer surgery to trainees. We assessed surgical trainees’ familiarity with the CoC Operative Standards and the underlying principles of cancer surgery to identify knowledge gaps and opportunities for improved education. STUDY DESIGN: The American College of Surgeons Cancer Surgery Standards Program distributed an anonymous survey to general surgery residents and surgical fellows across the US. Questions addressed the CoC Operative Standards and cancer surgery principles, with scores calculated on the basis of correctness. Univariate logistic regression evaluated associations between trainee or program characteristics and knowledge. Trainees were also asked about their role in procedural documentation, given the synoptic operative report requirements of the standards. RESULTS: A total of 244 surveys were completed by 205 residents and 39 fellows. Fellows reported greater familiarity with the CoC Operative Standards (68% vs 24%, p < 0.001). Only 30% of trainees reported receiving a formal curriculum on the standards. Correct response rates were 30% for CoC Operative Standards questions vs 50% for cancer surgery principles, with minimal association between knowledge and trainee or program characteristics. Most residents (71%) reported contributing to operative documentation. CONCLUSIONS: Surgical trainees demonstrated limited knowledge of the CoC Operative Standards, highlighting the need for multifaceted educational strategies at the national and institutional levels. Incorporating education about the CoC Operative Standards into surgical training can help emphasize the importance of performing and documenting critical elements of cancer operations.